Evidence for a Turner Syndrome Locus or Loci at Xp11.2-p22.1
Identifieur interne : 004F93 ( Istex/Corpus ); précédent : 004F92; suivant : 004F94Evidence for a Turner Syndrome Locus or Loci at Xp11.2-p22.1
Auteurs : Andrew R. Zinn ; Vijay S. Tonk ; Zhong Chen ; Wendy L. Flejter ; H. Allen Gardner ; Rudy Guerra ; Harvey Kushner ; Stuart Schwartz ; Virginia P. Sybert ; Daniel L. Van Dyke ; Judith L. RossSource :
- The American Journal of Human Genetics [ 0002-9297 ] ; 1998.
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- KwdEn :
Abstract
SummaryTurner syndrome is the complex human phenotype associated with complete or partial monosomy X. Principle features of Turner syndrome include short stature, ovarian failure, and a variety of other anatomic and physiological abnormalities, such as webbed neck, lymphedema, cardiovascular and renal anomalies, hypertension, and autoimmune thyroid disease. We studied 28 apparently nonmosaic subjects with partial deletions of Xp, in order to map loci responsible for various components of the Turner syndrome phenotype. Subjects were carefully evaluated for the presence or absence of Turner syndrome features, and their deletions were mapped by FISH with a panel of Xp markers. Using a statistical method to examine genotype/phenotype correlations, we mapped one or more Turner syndrome traits to a critical region in Xp11.2-p22.1. These traits included short stature, ovarian failure, high-arched palate, and autoimmune thyroid disease. The results are useful for genetic counseling of individuals with partial monosomy X. Study of additional subjects should refine the localization of Turner syndrome loci and provide a rational basis for exploration of candidate genes.
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DOI: 10.1086/302152
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Evidence for a Turner Syndrome Locus or Loci at Xp11.2-p22.1</title><author><name sortKey="Zinn, Andrew R" sort="Zinn, Andrew R" uniqKey="Zinn A" first="Andrew R." last="Zinn">Andrew R. Zinn</name><affiliation><mods:affiliation>E-mail: Andrew.Zinn@email.swmed.edu</mods:affiliation></affiliation><affiliation><mods:affiliation>Eugene McDermott Center for Human Growth and Development and Department of Internal Medicine, The University of Texas Southwestern Medical School</mods:affiliation></affiliation></author><author><name sortKey="Tonk, Vijay S" sort="Tonk, Vijay S" uniqKey="Tonk V" first="Vijay S." last="Tonk">Vijay S. Tonk</name><affiliation><mods:affiliation>Departments of Pediatrics and Pathology, Texas Tech University Health Sciences Center, Lubbock</mods:affiliation></affiliation></author><author><name sortKey="Chen, Zhong" sort="Chen, Zhong" uniqKey="Chen Z" first="Zhong" last="Chen">Zhong Chen</name><affiliation><mods:affiliation>Genzyme Genetics, Santa Fe</mods:affiliation></affiliation></author><author><name sortKey="Flejter, Wendy L" sort="Flejter, Wendy L" uniqKey="Flejter W" first="Wendy L." last="Flejter">Wendy L. Flejter</name><affiliation><mods:affiliation>Department of Pediatrics, University of Utah, Salt Lake City</mods:affiliation></affiliation></author><author><name sortKey="Gardner, H Allen" sort="Gardner, H Allen" uniqKey="Gardner H" first="H. Allen" last="Gardner">H. Allen Gardner</name><affiliation><mods:affiliation>Oshawa General Hospital, Oshawa, Ontario, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto</mods:affiliation></affiliation></author><author><name sortKey="Guerra, Rudy" sort="Guerra, Rudy" uniqKey="Guerra R" first="Rudy" last="Guerra">Rudy Guerra</name><affiliation><mods:affiliation>Department of Statistical Science, Southern Methodist University, Dallas</mods:affiliation></affiliation></author><author><name sortKey="Kushner, Harvey" sort="Kushner, Harvey" uniqKey="Kushner H" first="Harvey" last="Kushner">Harvey Kushner</name><affiliation><mods:affiliation>Biomedical Computing Thomas Jefferson University, Philadelphia</mods:affiliation></affiliation></author><author><name sortKey="Schwartz, Stuart" sort="Schwartz, Stuart" uniqKey="Schwartz S" first="Stuart" last="Schwartz">Stuart Schwartz</name><affiliation><mods:affiliation>Department of Genetics and Center for Human Genetics, Case Western Reserve University and University Hospitals of Case Western Reserve University, Cleveland</mods:affiliation></affiliation></author><author><name sortKey="Sybert, Virginia P" sort="Sybert, Virginia P" uniqKey="Sybert V" first="Virginia P." last="Sybert">Virginia P. Sybert</name><affiliation><mods:affiliation>Departments of Genetics and Dermatology, University of Washington, Seattle</mods:affiliation></affiliation></author><author><name sortKey="Van Dyke, Daniel L" sort="Van Dyke, Daniel L" uniqKey="Van Dyke D" first="Daniel L." last="Van Dyke">Daniel L. Van Dyke</name><affiliation><mods:affiliation>Department of Medical Genetics, Henry Ford Hospital, Detroit</mods:affiliation></affiliation></author><author><name sortKey="Ross, Judith L" sort="Ross, Judith L" uniqKey="Ross J" first="Judith L." last="Ross">Judith L. Ross</name><affiliation><mods:affiliation>Department of Pediatrics, Thomas Jefferson University, Philadelphia</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:A9C4E5A4FBB921A5AFB0F9BBF7DD7D252CC9A373</idno><date when="1998" year="1998">1998</date><idno type="doi">10.1086/302152</idno><idno type="url">https://api.istex.fr/document/A9C4E5A4FBB921A5AFB0F9BBF7DD7D252CC9A373/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">004F93</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">004F93</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Evidence for a Turner Syndrome Locus or Loci at Xp11.2-p22.1</title><author><name sortKey="Zinn, Andrew R" sort="Zinn, Andrew R" uniqKey="Zinn A" first="Andrew R." last="Zinn">Andrew R. Zinn</name><affiliation><mods:affiliation>E-mail: Andrew.Zinn@email.swmed.edu</mods:affiliation></affiliation><affiliation><mods:affiliation>Eugene McDermott Center for Human Growth and Development and Department of Internal Medicine, The University of Texas Southwestern Medical School</mods:affiliation></affiliation></author><author><name sortKey="Tonk, Vijay S" sort="Tonk, Vijay S" uniqKey="Tonk V" first="Vijay S." last="Tonk">Vijay S. Tonk</name><affiliation><mods:affiliation>Departments of Pediatrics and Pathology, Texas Tech University Health Sciences Center, Lubbock</mods:affiliation></affiliation></author><author><name sortKey="Chen, Zhong" sort="Chen, Zhong" uniqKey="Chen Z" first="Zhong" last="Chen">Zhong Chen</name><affiliation><mods:affiliation>Genzyme Genetics, Santa Fe</mods:affiliation></affiliation></author><author><name sortKey="Flejter, Wendy L" sort="Flejter, Wendy L" uniqKey="Flejter W" first="Wendy L." last="Flejter">Wendy L. Flejter</name><affiliation><mods:affiliation>Department of Pediatrics, University of Utah, Salt Lake City</mods:affiliation></affiliation></author><author><name sortKey="Gardner, H Allen" sort="Gardner, H Allen" uniqKey="Gardner H" first="H. Allen" last="Gardner">H. Allen Gardner</name><affiliation><mods:affiliation>Oshawa General Hospital, Oshawa, Ontario, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto</mods:affiliation></affiliation></author><author><name sortKey="Guerra, Rudy" sort="Guerra, Rudy" uniqKey="Guerra R" first="Rudy" last="Guerra">Rudy Guerra</name><affiliation><mods:affiliation>Department of Statistical Science, Southern Methodist University, Dallas</mods:affiliation></affiliation></author><author><name sortKey="Kushner, Harvey" sort="Kushner, Harvey" uniqKey="Kushner H" first="Harvey" last="Kushner">Harvey Kushner</name><affiliation><mods:affiliation>Biomedical Computing Thomas Jefferson University, Philadelphia</mods:affiliation></affiliation></author><author><name sortKey="Schwartz, Stuart" sort="Schwartz, Stuart" uniqKey="Schwartz S" first="Stuart" last="Schwartz">Stuart Schwartz</name><affiliation><mods:affiliation>Department of Genetics and Center for Human Genetics, Case Western Reserve University and University Hospitals of Case Western Reserve University, Cleveland</mods:affiliation></affiliation></author><author><name sortKey="Sybert, Virginia P" sort="Sybert, Virginia P" uniqKey="Sybert V" first="Virginia P." last="Sybert">Virginia P. Sybert</name><affiliation><mods:affiliation>Departments of Genetics and Dermatology, University of Washington, Seattle</mods:affiliation></affiliation></author><author><name sortKey="Van Dyke, Daniel L" sort="Van Dyke, Daniel L" uniqKey="Van Dyke D" first="Daniel L." last="Van Dyke">Daniel L. Van Dyke</name><affiliation><mods:affiliation>Department of Medical Genetics, Henry Ford Hospital, Detroit</mods:affiliation></affiliation></author><author><name sortKey="Ross, Judith L" sort="Ross, Judith L" uniqKey="Ross J" first="Judith L." last="Ross">Judith L. Ross</name><affiliation><mods:affiliation>Department of Pediatrics, Thomas Jefferson University, Philadelphia</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">The American Journal of Human Genetics</title><title level="j" type="abbrev">AJHG</title><idno type="ISSN">0002-9297</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1998">1998</date><biblScope unit="volume">63</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="1757">1757</biblScope><biblScope unit="page" to="1766">1766</biblScope></imprint><idno type="ISSN">0002-9297</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0002-9297</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aneuploidy</term><term>Gonadal dysgenesis</term><term>Haploinsufficiency</term><term>Sex-chromosome abnormalities</term><term>Turner syndrome</term><term>X chromosome</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">SummaryTurner syndrome is the complex human phenotype associated with complete or partial monosomy X. Principle features of Turner syndrome include short stature, ovarian failure, and a variety of other anatomic and physiological abnormalities, such as webbed neck, lymphedema, cardiovascular and renal anomalies, hypertension, and autoimmune thyroid disease. We studied 28 apparently nonmosaic subjects with partial deletions of Xp, in order to map loci responsible for various components of the Turner syndrome phenotype. Subjects were carefully evaluated for the presence or absence of Turner syndrome features, and their deletions were mapped by FISH with a panel of Xp markers. Using a statistical method to examine genotype/phenotype correlations, we mapped one or more Turner syndrome traits to a critical region in Xp11.2-p22.1. These traits included short stature, ovarian failure, high-arched palate, and autoimmune thyroid disease. The results are useful for genetic counseling of individuals with partial monosomy X. Study of additional subjects should refine the localization of Turner syndrome loci and provide a rational basis for exploration of candidate genes.</div></front></TEI><istex><corpusName>elsevier</corpusName><keywords><teeft><json:string>deletion</json:string><json:string>chromosome</json:string><json:string>phenotype</json:string><json:string>genet</json:string><json:string>turner syndrome</json:string><json:string>ovarian</json:string><json:string>ovarian failure</json:string><json:string>syndrome</json:string><json:string>short stature</json:string><json:string>phenotypic</json:string><json:string>abnormality</json:string><json:string>autoimmune</json:string><json:string>genetics</json:string><json:string>ogata</json:string><json:string>lymphedema</json:string><json:string>autoimmune thyroid disease</json:string><json:string>pdha1</json:string><json:string>metaphase</json:string><json:string>monosomy</json:string><json:string>zinn</json:string><json:string>breakpoints</json:string><json:string>locus</json:string><json:string>webbed neck</json:string><json:string>karyotype</json:string><json:string>webbed</json:string><json:string>mosaicism</json:string><json:string>pseudoautosomal</json:string><json:string>partial monosomy</json:string><json:string>target height</json:string><json:string>statistical analyses</json:string><json:string>marker</json:string><json:string>turner</json:string><json:string>trait</json:string><json:string>pseudoautosomal region</json:string><json:string>critical region</json:string><json:string>aortic coarctation</json:string><json:string>turner syndrome phenotype</json:string><json:string>phenotype mapping</json:string><json:string>statistical analysis</json:string><json:string>palate</json:string><json:string>inactivation</json:string><json:string>turner syndrome patients</json:string><json:string>ovarian function</json:string><json:string>turner syndrome features</json:string><json:string>human genetics</json:string><json:string>medical school</json:string><json:string>gonadal dysgenesis</json:string><json:string>position marker</json:string><json:string>delta proportion</json:string><json:string>cubitus valgus</json:string><json:string>hypoplastic nails</json:string><json:string>glucose tolerance</json:string><json:string>growth retardation</json:string><json:string>growth failure</json:string><json:string>turner syndrome locus</json:string><json:string>turner syndrome stigmata</json:string><json:string>chromosome encodes</json:string><json:string>renal anomalies</json:string><json:string>national center</json:string><json:string>castrate levels</json:string><json:string>salt lake city</json:string><json:string>medical records</json:string><json:string>abnormal nails</json:string><json:string>present department</json:string><json:string>complex traits</json:string><json:string>value times</json:string><json:string>thomas jefferson university</json:string><json:string>genet ogata</json:string><json:string>chromosome mapping</json:string><json:string>thyroid antibodies</json:string><json:string>horseshoe kidney</json:string><json:string>phenotypic traits</json:string><json:string>higharched palate</json:string><json:string>abnormal palate</json:string><json:string>additional subjects</json:string><json:string>same interval</json:string><json:string>possible locus</json:string><json:string>other studies</json:string><json:string>mutational analysis</json:string><json:string>turner syndrome traits</json:string><json:string>reserve university</json:string><json:string>palate abnormalities</json:string><json:string>phenotypic variability</json:string><json:string>phenotypic differences</json:string><json:string>chromosome inactivation</json:string><json:string>proc natl acad</json:string><json:string>marcel dekker</json:string><json:string>cystic hygroma</json:string><json:string>turner syndrome genes</json:string></teeft></keywords><author><json:item><name>Andrew R. Zinn</name><affiliations><json:string>E-mail: Andrew.Zinn@email.swmed.edu</json:string><json:string>Eugene McDermott Center for Human Growth and Development and Department of Internal Medicine, The University of Texas Southwestern Medical School</json:string></affiliations></json:item><json:item><name>Vijay S. Tonk</name><affiliations><json:string>Departments of Pediatrics and Pathology, Texas Tech University Health Sciences Center, Lubbock</json:string></affiliations></json:item><json:item><name>Zhong Chen</name><affiliations><json:string>Genzyme Genetics, Santa Fe</json:string></affiliations></json:item><json:item><name>Wendy L. Flejter</name><affiliations><json:string>Department of Pediatrics, University of Utah, Salt Lake City</json:string></affiliations></json:item><json:item><name>H. Allen Gardner</name><affiliations><json:string>Oshawa General Hospital, Oshawa, Ontario, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto</json:string></affiliations></json:item><json:item><name>Rudy Guerra</name><affiliations><json:string>Department of Statistical Science, Southern Methodist University, Dallas</json:string></affiliations></json:item><json:item><name>Harvey Kushner</name><affiliations><json:string>Biomedical Computing Thomas Jefferson University, Philadelphia</json:string></affiliations></json:item><json:item><name>Stuart Schwartz</name><affiliations><json:string>Department of Genetics and Center for Human Genetics, Case Western Reserve University and University Hospitals of Case Western Reserve University, Cleveland</json:string></affiliations></json:item><json:item><name>Virginia P. Sybert</name><affiliations><json:string>Departments of Genetics and Dermatology, University of Washington, Seattle</json:string></affiliations></json:item><json:item><name>Daniel L. Van Dyke</name><affiliations><json:string>Department of Medical Genetics, Henry Ford Hospital, Detroit</json:string></affiliations></json:item><json:item><name>Judith L. Ross</name><affiliations><json:string>Department of Pediatrics, Thomas Jefferson University, Philadelphia</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Original Articles</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Aneuploidy</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Gonadal dysgenesis</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Haploinsufficiency</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Sex-chromosome abnormalities</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Turner syndrome</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>X chromosome</value></json:item></subject><articleId><json:string>61621</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>Full-length article</json:string></originalGenre><abstract>SummaryTurner syndrome is the complex human phenotype associated with complete or partial monosomy X. Principle features of Turner syndrome include short stature, ovarian failure, and a variety of other anatomic and physiological abnormalities, such as webbed neck, lymphedema, cardiovascular and renal anomalies, hypertension, and autoimmune thyroid disease. We studied 28 apparently nonmosaic subjects with partial deletions of Xp, in order to map loci responsible for various components of the Turner syndrome phenotype. Subjects were carefully evaluated for the presence or absence of Turner syndrome features, and their deletions were mapped by FISH with a panel of Xp markers. Using a statistical method to examine genotype/phenotype correlations, we mapped one or more Turner syndrome traits to a critical region in Xp11.2-p22.1. These traits included short stature, ovarian failure, high-arched palate, and autoimmune thyroid disease. The results are useful for genetic counseling of individuals with partial monosomy X. Study of additional subjects should refine the localization of Turner syndrome loci and provide a rational basis for exploration of candidate genes.</abstract><qualityIndicators><score>7.516</score><pdfVersion>1.4</pdfVersion><pdfPageSize>612 x 792 pts (letter)</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>7</keywordCount><abstractCharCount>1177</abstractCharCount><pdfWordCount>5542</pdfWordCount><pdfCharCount>38234</pdfCharCount><pdfPageCount>10</pdfPageCount><abstractWordCount>168</abstractWordCount></qualityIndicators><title>Evidence for a Turner Syndrome Locus or Loci at Xp11.2-p22.1</title><pii><json:string>S0002-9297(07)61621-8</json:string></pii><genre><json:string>research-article</json:string></genre><serie><title>Current protocols in human genetics</title><language><json:string>unknown</json:string></language><volume>Vol 2</volume><pages><first>A.3.H.1</first><last>A.3.H.5</last></pages><editor><json:item><name>N Dracopoli</name></json:item><json:item><name>J Haines</name></json:item><json:item><name>B Korf</name></json:item><json:item><name>D Moir</name></json:item><json:item><name>C Morton</name></json:item><json:item><name>C Seidman</name></json:item><json:item><name>J Seidman</name></json:item></editor></serie><host><title>The American Journal of Human Genetics</title><language><json:string>unknown</json:string></language><publicationDate>1998</publicationDate><issn><json:string>0002-9297</json:string></issn><pii><json:string>S0002-9297(07)X6052-X</json:string></pii><volume>63</volume><issue>6</issue><pages><first>1757</first><last>1766</last></pages><genre><json:string>journal</json:string></genre></host><categories><wos><json:string>science</json:string><json:string>genetics & heredity</json:string></wos><scienceMetrix><json:string>health sciences</json:string><json:string>biomedical research</json:string><json:string>genetics & heredity</json:string></scienceMetrix></categories><publicationDate>1998</publicationDate><copyrightDate>1998</copyrightDate><doi><json:string>10.1086/302152</json:string></doi><id>A9C4E5A4FBB921A5AFB0F9BBF7DD7D252CC9A373</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/A9C4E5A4FBB921A5AFB0F9BBF7DD7D252CC9A373/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/A9C4E5A4FBB921A5AFB0F9BBF7DD7D252CC9A373/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/A9C4E5A4FBB921A5AFB0F9BBF7DD7D252CC9A373/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Evidence for a Turner Syndrome Locus or Loci at Xp11.2-p22.1</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>ELSEVIER</publisher><availability><p>©1998 The American Society of Human Genetics</p></availability><date>1998</date></publicationStmt><notesStmt><note type="content">Figure 1: Graphic representation of deletions. Bars represent material present in deleted X chromosomes. Positions of molecular-cytogenetic markers are indicated.</note><note type="content">Figure 2: Strength of associations between deleted markers and five phenotypic traits: adjusted height, ovarian failure (ovary), high-arched palate (palate), thyroid autoantibodies (thyroid), and increased carrying angle of the elbow (carrying angle). A score of “0” indicates that there is no association. Scores >∼3 are statistically significant (see Subjects and Methods).</note><note type="content">Table 1: Reported Karyotypes and Chronological Ages of Subjects at the Time of Evaluation</note><note type="content">Table 2: Molecular-Cytogenetic Markers</note><note type="content">Table 3: Phenotypic Data</note><note type="content">Table 4: Mean ± SD Z-Score for Mid–Parental Height or Target Height</note><note type="content">Table 5: Ovarian-Failure Trait</note><note type="content">Table 6: High Arched–Palate Trait</note><note type="content">Table 7: Autoimmune Thyroid–Disease Trait</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Evidence for a Turner Syndrome Locus or Loci at Xp11.2-p22.1</title><author xml:id="author-0000"><persName><forename type="first">Andrew R.</forename><surname>Zinn</surname></persName><email>Andrew.Zinn@email.swmed.edu</email><affiliation>Address for correspondence and reprints: Dr. Andrew R. Zinn, University of Texas Southwestern Medical School, 6000 Harry Hines Boulevard, Dallas, TX 75235-8591.</affiliation><affiliation>Eugene McDermott Center for Human Growth and Development and Department of Internal Medicine, The University of Texas Southwestern Medical School</affiliation></author><author xml:id="author-0001"><persName><forename type="first">Vijay S.</forename><surname>Tonk</surname></persName><affiliation>Departments of Pediatrics and Pathology, Texas Tech University Health Sciences Center, Lubbock</affiliation></author><author xml:id="author-0002"><persName><forename type="first">Zhong</forename><surname>Chen</surname></persName><note type="biography">Present affiliation: Department of Pediatrics, University of Utah, Salt Lake City.</note><affiliation>Present affiliation: Department of Pediatrics, University of Utah, Salt Lake City.</affiliation><affiliation>Genzyme Genetics, Santa Fe</affiliation></author><author xml:id="author-0003"><persName><forename type="first">Wendy L.</forename><surname>Flejter</surname></persName><note type="biography">Present affiliation: Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem.</note><affiliation>Present affiliation: Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem.</affiliation><affiliation>Department of Pediatrics, University of Utah, Salt Lake City</affiliation></author><author xml:id="author-0004"><persName><forename type="first">H. Allen</forename><surname>Gardner</surname></persName><affiliation>Oshawa General Hospital, Oshawa, Ontario, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto</affiliation></author><author xml:id="author-0005"><persName><forename type="first">Rudy</forename><surname>Guerra</surname></persName><affiliation>Department of Statistical Science, Southern Methodist University, Dallas</affiliation></author><author xml:id="author-0006"><persName><forename type="first">Harvey</forename><surname>Kushner</surname></persName><affiliation>Biomedical Computing Thomas Jefferson University, Philadelphia</affiliation></author><author xml:id="author-0007"><persName><forename type="first">Stuart</forename><surname>Schwartz</surname></persName><affiliation>Department of Genetics and Center for Human Genetics, Case Western Reserve University and University Hospitals of Case Western Reserve University, Cleveland</affiliation></author><author xml:id="author-0008"><persName><forename type="first">Virginia P.</forename><surname>Sybert</surname></persName><affiliation>Departments of Genetics and Dermatology, University of Washington, Seattle</affiliation></author><author xml:id="author-0009"><persName><forename type="first">Daniel L.</forename><surname>Van Dyke</surname></persName><affiliation>Department of Medical Genetics, Henry Ford Hospital, Detroit</affiliation></author><author xml:id="author-0010"><persName><forename type="first">Judith L.</forename><surname>Ross</surname></persName><affiliation>Department of Pediatrics, Thomas Jefferson University, Philadelphia</affiliation></author><idno type="istex">A9C4E5A4FBB921A5AFB0F9BBF7DD7D252CC9A373</idno><idno type="DOI">10.1086/302152</idno><idno type="PII">S0002-9297(07)61621-8</idno><idno type="ArticleID">61621</idno></analytic><monogr><title level="j">The American Journal of Human Genetics</title><title level="j" type="abbrev">AJHG</title><idno type="pISSN">0002-9297</idno><idno type="PII">S0002-9297(07)X6052-X</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1998"></date><biblScope unit="volume">63</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="1757">1757</biblScope><biblScope unit="page" to="1766">1766</biblScope></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1998</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>SummaryTurner syndrome is the complex human phenotype associated with complete or partial monosomy X. Principle features of Turner syndrome include short stature, ovarian failure, and a variety of other anatomic and physiological abnormalities, such as webbed neck, lymphedema, cardiovascular and renal anomalies, hypertension, and autoimmune thyroid disease. We studied 28 apparently nonmosaic subjects with partial deletions of Xp, in order to map loci responsible for various components of the Turner syndrome phenotype. Subjects were carefully evaluated for the presence or absence of Turner syndrome features, and their deletions were mapped by FISH with a panel of Xp markers. Using a statistical method to examine genotype/phenotype correlations, we mapped one or more Turner syndrome traits to a critical region in Xp11.2-p22.1. These traits included short stature, ovarian failure, high-arched palate, and autoimmune thyroid disease. The results are useful for genetic counseling of individuals with partial monosomy X. Study of additional subjects should refine the localization of Turner syndrome loci and provide a rational basis for exploration of candidate genes.</p></abstract><textClass><keywords scheme="keyword"><list><head>article-category</head><item><term>Original Articles</term></item></list></keywords></textClass><textClass xml:lang="en"><keywords scheme="keyword"><list><item><term>Aneuploidy</term></item><item><term>Gonadal dysgenesis</term></item><item><term>Haploinsufficiency</term></item><item><term>Sex-chromosome abnormalities</term></item><item><term>Turner syndrome</term></item><item><term>X chromosome</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="1998">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/A9C4E5A4FBB921A5AFB0F9BBF7DD7D252CC9A373/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier doc found" wicri:toSee="Elsevier, no converted or simple article"><istex:xmlDeclaration>version="1.0" encoding="UTF-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//ES//DTD journal article DTD version 5.0.1//EN//XML" URI="art501.dtd" name="istex:docType"><istex:entity SYSTEM="gr1" NDATA="IMAGE" name="gr1"></istex:entity><istex:entity SYSTEM="gr2" NDATA="IMAGE" name="gr2"></istex:entity></istex:docType><istex:document><article docsubtype="fla" version="5.0" xml:lang="en"><item-info><jid>AJHG</jid><aid>61621</aid><ce:pii>S0002-9297(07)61621-8</ce:pii><ce:doi>10.1086/302152</ce:doi><ce:copyright type="society" year="1998">The American Society of Human Genetics</ce:copyright><ce:doctopics><ce:doctopic><ce:text>Original Articles</ce:text></ce:doctopic></ce:doctopics></item-info><ce:floats><ce:figure id="fig1"><ce:label>Figure 1</ce:label><ce:caption><ce:simple-para view="all" id="simple-para.0010">Graphic representation of deletions. Bars represent material present in deleted X chromosomes. Positions of molecular-cytogenetic markers are indicated.</ce:simple-para></ce:caption><ce:link locator="gr1"></ce:link></ce:figure><ce:figure id="fig2"><ce:label>Figure 2</ce:label><ce:caption><ce:simple-para view="all" id="simple-para.0015">Strength of associations between deleted markers and five phenotypic traits: adjusted height, ovarian failure (ovary), high-arched palate (palate), thyroid autoantibodies (thyroid), and increased carrying angle of the elbow (carrying angle). A score of “0” indicates that there is no association. Scores >∼3 are statistically significant (see <ce:cross-ref refid="sc2">Subjects and Methods</ce:cross-ref>).</ce:simple-para></ce:caption><ce:link locator="gr2"></ce:link></ce:figure><ce:table id="tbl1" frame="topbot" rowsep="0" colsep="0"><ce:label>Table 1</ce:label><ce:caption><ce:simple-para view="all" id="simple-para.0020">Reported Karyotypes and Chronological Ages of Subjects at the Time of Evaluation</ce:simple-para></ce:caption><tgroup cols="3" altimg="si1.gif"><colspec colnum="1" colname="col1"></colspec><colspec colnum="2" colname="col2"></colspec><colspec colnum="3" colname="col3"></colspec><thead><row><entry valign="bottom">Subject</entry><entry align="center" valign="bottom">Karyotype</entry><entry align="center" valign="bottom">Age (years)</entry></row></thead><tbody><row><entry>SW16</entry><entry>46,X,der(X)t(X;1)(p11;q44)mat</entry><entry align="char" char=".">17.4</entry></row><row><entry>SW46</entry><entry>46,X,del(X)(p21)</entry><entry align="char" char=".">33.7</entry></row><row><entry>SW71</entry><entry>46,X,del(X)(p11.2)</entry><entry align="char" char=".">20.2</entry></row><row><entry>SW74</entry><entry>46,X,del(X)(p11.21)</entry><entry align="char" char=".">13.2</entry></row><row><entry>SW75</entry><entry>46,X,del(X)(p11.3)</entry><entry align="char" char=".">12.6</entry></row><row><entry>SW80</entry><entry>46,X,del(X)(p11.4)</entry><entry align="char" char=".">13.0</entry></row><row><entry>SW85</entry><entry>46,X,del(X)(p11.2)</entry><entry align="char" char=".">45.2</entry></row><row><entry>SW86</entry><entry>46,X,der(X)t(X;X)(p11;q24)</entry><entry align="char" char=".">10.7</entry></row><row><entry>SW92</entry><entry>46,X,del(X)(p11.23)</entry><entry align="char" char=".">4.5</entry></row><row><entry>SW93</entry><entry>46,X,del(X)(p11.23)</entry><entry align="char" char=".">10.1</entry></row><row><entry>SW96</entry><entry>46,X,del(X)(p21.2)</entry><entry align="char" char=".">12.9</entry></row><row><entry>SW97</entry><entry>46,X,del(X)(p21.2)</entry><entry align="char" char=".">12.9</entry></row><row><entry>SW103</entry><entry>46,X,del(X)(p11.2)</entry><entry align="char" char=".">1.3</entry></row><row><entry>SW105</entry><entry>46,X,der(X)t(X;1)(p11;q44)mat</entry><entry align="char" char=".">25.4</entry></row><row><entry>SW106</entry><entry>46,X,del(X)(p22.3)</entry><entry align="char" char=".">7.0</entry></row><row><entry>SW109</entry><entry>46,X,del(X)(p11.1)</entry><entry align="char" char=".">45.9</entry></row><row><entry>SW111</entry><entry>46,X,del(X)(p11.21)</entry><entry align="char" char=".">15.2</entry></row><row><entry>SW112</entry><entry>46,X,del(X)(p11.2)</entry><entry align="char" char=".">10.7</entry></row><row><entry>SW122</entry><entry>46,X,del(X)(p21.2)</entry><entry align="char" char=".">16.2</entry></row><row><entry>SW144</entry><entry>46,X,del(X)(p22.12p22.33)</entry><entry align="char" char=".">35.8</entry></row><row><entry>SW145</entry><entry>46,X,del(X)(p22.12p22.33)mat</entry><entry align="char" char=".">14.2</entry></row><row><entry>SW146</entry><entry>46,X,del(X)(p22.12p22.33)mat</entry><entry align="char" char=".">12</entry></row><row><entry>SW151</entry><entry>46,X,del(X)(p11.2)</entry><entry align="char" char=".">7</entry></row><row><entry>SW157</entry><entry>46,X,del(X)(p22.31p22.33)</entry><entry align="char" char=".">41.5</entry></row><row><entry>SW161</entry><entry>46,X,del(X)(p11.23)</entry><entry align="char" char=".">8.6</entry></row><row><entry>SW174</entry><entry>46,X,der(X)t(X;A)(p22.3;p11.2)mat<ce:cross-ref refid="tb1fna"><ce:sup loc="post">a</ce:sup></ce:cross-ref></entry><entry align="char" char=".">21.9</entry></row><row><entry>SW175</entry><entry>46,X,der(X)t(X;A)(p22.3;p11.2)<ce:cross-ref refid="tb1fna"><ce:sup loc="post">a</ce:sup></ce:cross-ref></entry><entry align="char" char=".">39.7</entry></row><row><entry>SW190</entry><entry>46,(X),del(X)(p22.1)</entry><entry align="char" char=".">40</entry></row></tbody></tgroup><ce:table-footnote id="tb1fna"><ce:label>a</ce:label><ce:note-para>A = acrocentric chromosome positive for NOR staining and beta satellite but not alpha satellite sequences by FISH.</ce:note-para></ce:table-footnote></ce:table><ce:table id="tbl2" frame="topbot" rowsep="0" colsep="0"><ce:label>Table 2</ce:label><ce:caption><ce:simple-para view="all" id="simple-para.0025">Molecular-Cytogenetic Markers</ce:simple-para></ce:caption><tgroup cols="5" altimg="si2.gif"><colspec colnum="1" colname="col1"></colspec><colspec colnum="2" colname="col2"></colspec><colspec colnum="3" colname="col3"></colspec><colspec colnum="4" colname="col4"></colspec><colspec colnum="5" colname="col5"></colspec><thead><row><entry valign="bottom">Locus<ce:cross-ref refid="tb2fna"><ce:sup loc="post">a</ce:sup></ce:cross-ref></entry><entry align="center" valign="bottom">Position<ce:cross-ref refid="tb2fnb"><ce:sup loc="post">b</ce:sup></ce:cross-ref> (Mb)</entry><entry align="center" valign="bottom">Band</entry><entry align="center" valign="bottom">Probe</entry><entry align="center" valign="bottom">Source</entry></row></thead><tbody><row><entry><ce:underline>DXYS14</ce:underline></entry><entry align="center">0</entry><entry>Xp22.33</entry><entry>c11D2</entry><entry>G. Rappold</entry></row><row><entry><ce:underline>DXS7470</ce:underline></entry><entry align="center">9</entry><entry>Xp22.32</entry><entry>b9P2</entry><entry>Research Genetics</entry></row><row><entry><ce:underline>PDHA1</ce:underline></entry><entry align="center">20</entry><entry>Xp22.13</entry><entry>cPDH3</entry><entry>H. Dahl</entry></row><row><entry>DXS274</entry><entry align="center">23</entry><entry>Xp22.13</entry><entry>ICRFc104A0359</entry><entry>RLDB (Zehetner and Lehrach <ce:cross-ref refid="bib16">1994</ce:cross-ref>)</entry></row><row><entry><ce:underline>GK</ce:underline></entry><entry align="center">33</entry><entry>Xp21.3</entry><entry>ICRFc104E07137</entry><entry>RLDB</entry></row><row><entry><ce:underline>DXS1110</ce:underline></entry><entry align="center">40</entry><entry>Xp11.4-p21.1</entry><entry>b227D11</entry><entry>Research Genetics</entry></row><row><entry>SYN1</entry><entry align="center">47</entry><entry>Xp11.3</entry><entry>cSY11</entry><entry>T. Südhof</entry></row><row><entry><ce:underline>SYP</ce:underline></entry><entry align="center">50</entry><entry>Xp11.23</entry><entry>c38-10</entry><entry>T. Südhof</entry></row><row><entry>DXS423E</entry><entry align="center">54</entry><entry>Xp11.22</entry><entry>ICRFc100H0164</entry><entry>RLDB</entry></row><row><entry>ZXDB</entry><entry align="center">58</entry><entry>Xp11.21</entry><entry>ICRFc104A07135</entry><entry>RLDB</entry></row><row><entry><ce:underline>DXZ1</ce:underline></entry><entry align="center">60</entry><entry>Xcen</entry><entry>pBAMX7</entry><entry>H. Willard</entry></row></tbody></tgroup><ce:table-footnote id="tb2fna"><ce:label>a</ce:label><ce:note-para>Data from markers that are underlined were used for statistical analyses.</ce:note-para></ce:table-footnote><ce:table-footnote id="tb2fnb"><ce:label>b</ce:label><ce:note-para>From the Sixth International Workshop on X Chromosome Mapping (Nelson et al. <ce:cross-ref refid="bib9">1995</ce:cross-ref>).</ce:note-para></ce:table-footnote></ce:table><ce:table id="tbl3" frame="topbot" rowsep="0" colsep="0"><ce:label>Table 3</ce:label><ce:caption><ce:simple-para view="all" id="simple-para.0030">Phenotypic Data</ce:simple-para></ce:caption><tgroup cols="6" altimg="si3.gif"><colspec colnum="1" colname="col1"></colspec><colspec colnum="2" colname="col2"></colspec><colspec colnum="3" colname="col3"></colspec><colspec colnum="4" colname="col4"></colspec><colspec colnum="5" colname="col5"></colspec><colspec colnum="6" colname="col6"></colspec><thead><row><entry valign="bottom">Subject</entry><entry align="center" valign="bottom">SD from Mid–Parental Height<ce:cross-ref refid="tb3fna"><ce:sup loc="post">a</ce:sup></ce:cross-ref></entry><entry align="center" valign="bottom">Palate<ce:cross-ref refid="tb3fnb"><ce:sup loc="post">b</ce:sup></ce:cross-ref></entry><entry align="center" valign="bottom">Carrying Angle<ce:cross-ref refid="tb3fnb"><ce:sup loc="post">b</ce:sup></ce:cross-ref></entry><entry align="center" valign="bottom">Thyroid Antibodies</entry><entry align="center" valign="bottom">Ovarian Failure?<ce:cross-ref refid="tb3fna"><ce:sup loc="post">a</ce:sup></ce:cross-ref></entry></row></thead><tbody><row><entry>SW75</entry><entry align="char" char=".">−2.2</entry><entry>High arched</entry><entry>Markedly increased</entry><entry align="center">Absent</entry><entry align="center">No</entry></row><row><entry>SW74</entry><entry align="char" char=".">−3.3</entry><entry>High arched</entry><entry>Mildly increased</entry><entry align="center">Present</entry><entry align="center">No</entry></row><row><entry>SW93</entry><entry align="char" char=".">−3.5</entry><entry>High arched</entry><entry>Mildly increased</entry><entry align="center">Present</entry><entry align="center">Yes</entry></row><row><entry>SW97</entry><entry align="char" char=".">−.4</entry><entry>High arched</entry><entry>Mildly increased</entry><entry align="center">Absent</entry><entry align="center">No</entry></row><row><entry>SW86</entry><entry align="char" char=".">−1.2</entry><entry>High arched</entry><entry>Mildly increased</entry><entry align="center">Absent</entry><entry align="center">Yes</entry></row><row><entry>SW106</entry><entry align="char" char=".">−1.6</entry><entry>Normal</entry><entry>Markedly increased</entry><entry align="center">Absent</entry><entry align="center">ND</entry></row><row><entry>SW96</entry><entry align="char" char=".">−1.2</entry><entry>Normal</entry><entry>Mildly increased</entry><entry align="center">Absent</entry><entry align="center">Yes</entry></row><row><entry>SW109</entry><entry align="char" char=".">−4.7</entry><entry>High arched</entry><entry>Mildly increased</entry><entry align="center">Absent</entry><entry align="center">Yes</entry></row><row><entry>SW175</entry><entry align="char" char=".">−1.82</entry><entry>Normal</entry><entry>Mildly increased</entry><entry align="center">Absent</entry><entry align="center">No</entry></row><row><entry>SW174</entry><entry align="char" char=".">−.8</entry><entry>Normal</entry><entry>Normal</entry><entry align="center">Absent</entry><entry align="center">No</entry></row><row><entry>SW161</entry><entry align="char" char=".">−3.3</entry><entry>High arched</entry><entry>Mildly increased</entry><entry align="center">Present</entry><entry align="center">ND</entry></row><row><entry>SW111</entry><entry align="char" char=".">−3.3</entry><entry>High arched</entry><entry>Mildly increased</entry><entry align="center">Present</entry><entry align="center">Yes</entry></row><row><entry>SW112</entry><entry align="char" char=".">−3.9</entry><entry>Ogival</entry><entry>Mildly increased</entry><entry align="center">Present</entry><entry align="center">Yes</entry></row><row><entry>SW46</entry><entry align="char" char=".">−.3</entry><entry>(Normal)</entry><entry>(Normal)</entry><entry align="center">Absent</entry><entry align="center">No</entry></row><row><entry>SW85</entry><entry align="char" char=".">−3.4</entry><entry>Ogival</entry><entry>Mildly increased</entry><entry align="center">Absent</entry><entry align="center">Yes</entry></row><row><entry>SW122</entry><entry align="char" char=".">−2.7</entry><entry>Normal</entry><entry>Mildly increased</entry><entry align="center">Absent</entry><entry align="center">Yes</entry></row><row><entry>SW151</entry><entry align="char" char=".">−2.5</entry><entry>High arched</entry><entry>Normal</entry><entry align="center">Present</entry><entry align="center">ND</entry></row><row><entry>SW103</entry><entry align="char" char=".">−2.7</entry><entry>Ogival</entry><entry>Mildly increased</entry><entry align="center">Absent</entry><entry align="center">Yes</entry></row><row><entry>SW146</entry><entry align="char" char=".">−.4</entry><entry>(Normal)</entry><entry>(Normal)</entry><entry align="center">Absent</entry><entry align="center">No</entry></row><row><entry>SW144</entry><entry align="char" char=".">−.6</entry><entry>(Normal)</entry><entry>(Normal)</entry><entry align="center">Absent</entry><entry align="center">No</entry></row><row><entry>SW145</entry><entry align="char" char=".">−1.4</entry><entry>(Normal)</entry><entry>(Normal)</entry><entry align="center">Absent</entry><entry align="center">No</entry></row><row><entry>SW71</entry><entry align="char" char=".">−2</entry><entry>Normal</entry><entry>Markedly increased</entry><entry align="center">Absent</entry><entry align="center">Yes</entry></row><row><entry>SW157</entry><entry align="char" char=".">−.9</entry><entry>Normal</entry><entry>Mildly increased</entry><entry align="center">Absent</entry><entry align="center">No</entry></row><row><entry>SW190</entry><entry align="char" char=".">.8</entry><entry>Normal</entry><entry>Mildly increased</entry><entry align="center">Absent</entry><entry align="center">No</entry></row><row><entry>SW105</entry><entry align="char" char=".">−3.3</entry><entry>Normal</entry><entry>Normal</entry><entry align="center">Present</entry><entry align="center">Yes</entry></row><row><entry>SW16</entry><entry align="char" char=".">−3.5</entry><entry>High arched</entry><entry>Normal</entry><entry align="center">Absent</entry><entry align="center">Yes</entry></row><row><entry>SW92</entry><entry align="char" char=".">−2.4</entry><entry>Ogival</entry><entry>Mildly increased</entry><entry align="center">Present</entry><entry align="center">Yes</entry></row><row><entry>SW80</entry><entry align="char" char=".">ND</entry><entry>High arched</entry><entry>Markedly increased</entry><entry align="center">Present</entry><entry align="center">Yes</entry></row></tbody></tgroup><ce:table-footnote id="tb3fna"><ce:label>a</ce:label><ce:note-para>ND = not determined (see text).</ce:note-para></ce:table-footnote><ce:table-footnote id="tb3fnb"><ce:label>b</ce:label><ce:note-para>Phenotypes in parentheses were by report only and were not used in statistical analyses.</ce:note-para></ce:table-footnote></ce:table><ce:table id="tbl4" frame="topbot" rowsep="0" colsep="0"><ce:label>Table 4</ce:label><ce:caption><ce:simple-para view="all" id="simple-para.0035">Mean <ce:bold>±</ce:bold> SD <ce:italic>Z</ce:italic>-Score for Mid–Parental Height or Target Height</ce:simple-para></ce:caption><tgroup cols="7" altimg="si4.gif"><colspec colnum="1" colname="col1"></colspec><colspec colnum="2" colname="col2"></colspec><colspec colnum="3" colname="col3"></colspec><colspec colnum="4" colname="col4"></colspec><colspec colnum="5" colname="col5"></colspec><colspec colnum="6" colname="col6"></colspec><colspec colnum="7" colname="col7"></colspec><thead><row><entry></entry><entry></entry><entry namest="col3" nameend="col4" align="center" valign="bottom"><ce:small-caps>Mean ± SD <ce:italic>Z</ce:italic>-Score for Parent-Adjusted Height</ce:small-caps>(<ce:italic>n</ce:italic>), <ce:small-caps>for</ce:small-caps></entry><entry></entry><entry></entry><entry></entry></row><row><entry valign="bottom"><ce:small-caps>Marker</ce:small-caps></entry><entry align="center" valign="bottom"><ce:small-caps>Position</ce:small-caps></entry><entry align="center" valign="bottom">Deleted Marker</entry><entry align="center" valign="bottom">Marker Not Deleted</entry><entry align="center" valign="bottom"><ce:small-caps>Difference in Means</ce:small-caps></entry><entry align="center" valign="bottom"><ce:italic>t</ce:italic></entry><entry align="center" valign="bottom">df</entry></row></thead><tbody><row><entry>DXYS14</entry><entry align="center" valign="bottom">0</entry><entry align="char" char=".">−2.20 ± 1.25 (26)</entry><entry align="char" char=".">+.80 ± .00 (1)</entry><entry align="char" char=".">3.00</entry><entry align="center">…</entry><entry></entry></row><row><entry>DXS7470</entry><entry align="center" valign="bottom">9</entry><entry align="char" char=".">−2.21 ± 1.38 (24)</entry><entry align="char" char=".">−1.17 ± .55 (3)</entry><entry align="char" char=".">1.04</entry><entry align="char" char=".">1.27</entry><entry align="center" valign="bottom">25</entry></row><row><entry>PDHA1</entry><entry align="center" valign="bottom">20</entry><entry align="char" char=".">−2.23 ± 1.41 (23)</entry><entry align="char" char=".">−1.28 ± .50 (4)</entry><entry align="char" char=".">.96</entry><entry align="char" char=".">1.33</entry><entry align="center" valign="bottom">25</entry></row><row><entry>GK</entry><entry align="center" valign="bottom">33</entry><entry align="char" char=".">−3.01 ± .86 (15)</entry><entry align="char" char=".">−.94 ± .89 (12)</entry><entry align="char" char=".">2.07</entry><entry align="char" char=".">6.13</entry><entry align="center" valign="bottom">25</entry></row><row><entry>DXS1110</entry><entry align="center" valign="bottom">40</entry><entry align="char" char=".">−3.01 ± .86 (15)</entry><entry align="char" char=".">−.94 ± .89 (12)</entry><entry align="char" char=".">2.07</entry><entry align="char" char=".">6.13</entry><entry align="center" valign="bottom">25</entry></row><row><entry>SYP</entry><entry align="center" valign="bottom">50</entry><entry align="char" char=".">−3.51 ± .58 (8)</entry><entry align="char" char=".">−1.49 ± 1.11 (19)</entry><entry align="char" char=".">2.02</entry><entry align="char" char=".">4.82</entry><entry align="center" valign="bottom">25</entry></row></tbody></tgroup></ce:table><ce:table id="tbl5" frame="topbot" rowsep="0" colsep="0"><ce:label>Table 5</ce:label><ce:caption><ce:simple-para view="all" id="simple-para.0040">Ovarian-Failure Trait</ce:simple-para></ce:caption><tgroup cols="6" altimg="si5.gif"><colspec colnum="1" colname="col1"></colspec><colspec colnum="2" colname="col2"></colspec><colspec colnum="3" colname="col3"></colspec><colspec colnum="4" colname="col4"></colspec><colspec colnum="5" colname="col5"></colspec><colspec colnum="6" colname="col6"></colspec><thead><row><entry></entry><entry></entry><entry namest="col3" nameend="col4" align="center" valign="bottom"><ce:small-caps>No. with Trait/No. without Trait, for</ce:small-caps></entry><entry></entry><entry></entry></row><row><entry valign="bottom"><ce:small-caps>Marker</ce:small-caps></entry><entry align="center" valign="bottom"><ce:small-caps>Position</ce:small-caps></entry><entry align="center" valign="bottom">Deleted Marker</entry><entry align="center" valign="bottom">Marker Not Deleted</entry><entry align="center" valign="bottom"><ce:small-caps>Delta Proportion</ce:small-caps></entry><entry align="center" valign="bottom"><ce:italic>Z</ce:italic></entry></row></thead><tbody><row><entry>DXYS14</entry><entry align="center">0</entry><entry align="center">14/10</entry><entry align="center">0/1</entry><entry align="char" char="." valign="bottom">.583</entry><entry align="char" char="." valign="bottom">.123</entry></row><row><entry>DXS7470</entry><entry align="center">9</entry><entry align="center">14/8</entry><entry align="center">0/3</entry><entry align="char" char="." valign="bottom">.636</entry><entry align="char" char="." valign="bottom">1.463</entry></row><row><entry>PDHA1</entry><entry align="center">20</entry><entry align="center">14/8</entry><entry align="center">0/3</entry><entry align="char" char="." valign="bottom">.636</entry><entry align="char" char="." valign="bottom">1.463</entry></row><row><entry>GK</entry><entry align="center">33</entry><entry align="center">12/2</entry><entry align="center">2/9</entry><entry align="char" char="." valign="bottom">.675</entry><entry align="char" char="." valign="bottom">2.971</entry></row><row><entry>DXS1110</entry><entry align="center">40</entry><entry align="center">12/2</entry><entry align="center">2/9</entry><entry align="char" char="." valign="bottom">.675</entry><entry align="char" char="." valign="bottom">2.971</entry></row><row><entry>SYP</entry><entry align="center">50</entry><entry align="center">8/1</entry><entry align="center">6/10</entry><entry align="char" char="." valign="bottom">.514</entry><entry align="char" char="." valign="bottom">2.065</entry></row></tbody></tgroup></ce:table><ce:table id="tbl6" frame="topbot" rowsep="0" colsep="0"><ce:label>Table 6</ce:label><ce:caption><ce:simple-para view="all" id="simple-para.0045">High Arched–Palate Trait</ce:simple-para></ce:caption><tgroup cols="6" altimg="si6.gif"><colspec colnum="1" colname="col1"></colspec><colspec colnum="2" colname="col2"></colspec><colspec colnum="3" colname="col3"></colspec><colspec colnum="4" colname="col4"></colspec><colspec colnum="5" colname="col5"></colspec><colspec colnum="6" colname="col6"></colspec><thead><row><entry></entry><entry></entry><entry namest="col3" nameend="col4" align="center" valign="bottom"><ce:small-caps>No. with Trait/No. without Trait, for</ce:small-caps></entry><entry></entry><entry></entry></row><row><entry valign="bottom"><ce:small-caps>Marker</ce:small-caps></entry><entry align="center" valign="bottom"><ce:small-caps>Position</ce:small-caps></entry><entry align="center" valign="bottom">Deleted Marker</entry><entry align="center" valign="bottom">Marker Not Deleted</entry><entry align="center" valign="bottom"><ce:small-caps>Delta Proportion</ce:small-caps></entry><entry align="center" valign="bottom"><ce:italic>Z</ce:italic></entry></row></thead><tbody><row><entry>DXYS14</entry><entry align="center">0</entry><entry align="center">15/8</entry><entry align="center">0/1</entry><entry align="char" char=".">.652</entry><entry align="char" char=".">.264</entry></row><row><entry>DXS7470</entry><entry align="center">9</entry><entry align="center">15/6</entry><entry align="center">0/3</entry><entry align="char" char=".">.714</entry><entry align="char" char=".">1.753</entry></row><row><entry>PDHA1</entry><entry align="center">20</entry><entry align="center">15/5</entry><entry align="center">0/4</entry><entry align="char" char=".">.750</entry><entry align="char" char=".">2.263</entry></row><row><entry>GK</entry><entry align="center">33</entry><entry align="center">14/2</entry><entry align="center">1/7</entry><entry align="char" char=".">.750</entry><entry align="char" char=".">3.130</entry></row><row><entry>DXS1110</entry><entry align="center">40</entry><entry align="center">14/2</entry><entry align="center">1/7</entry><entry align="char" char=".">.750</entry><entry align="char" char=".">3.130</entry></row><row><entry>SYP</entry><entry align="center">50</entry><entry align="center">8/1</entry><entry align="center">7/8</entry><entry align="char" char=".">.422</entry><entry align="char" char=".">1.633</entry></row></tbody></tgroup></ce:table><ce:table id="tbl7" frame="topbot" rowsep="0" colsep="0"><ce:label>Table 7</ce:label><ce:caption><ce:simple-para view="all" id="simple-para.0050">Autoimmune Thyroid–Disease Trait</ce:simple-para></ce:caption><tgroup cols="6" altimg="si7.gif"><colspec colnum="1" colname="col1"></colspec><colspec colnum="2" colname="col2"></colspec><colspec colnum="3" colname="col3"></colspec><colspec colnum="4" colname="col4"></colspec><colspec colnum="5" colname="col5"></colspec><colspec colnum="6" colname="col6"></colspec><thead><row><entry></entry><entry></entry><entry namest="col3" nameend="col4" align="center" valign="bottom"><ce:small-caps>No. with Trait/No. without Trait, for</ce:small-caps></entry><entry></entry><entry></entry></row><row><entry valign="bottom"><ce:small-caps>Marker</ce:small-caps></entry><entry align="center" valign="bottom"><ce:small-caps>Position</ce:small-caps></entry><entry align="center" valign="bottom">Deleted Marker</entry><entry align="center" valign="bottom">Marker Not Deleted</entry><entry align="center" valign="bottom"><ce:small-caps>Delta Proportion</ce:small-caps></entry><entry align="center" valign="bottom"><ce:italic>Z</ce:italic></entry></row></thead><tbody><row><entry>DXYS14</entry><entry align="center">0</entry><entry align="center">9/18</entry><entry align="center">0/1</entry><entry align="char" char=".">.333</entry><entry align="char" char=".">.389</entry></row><row><entry>DXS7470</entry><entry align="center">9</entry><entry align="center">9/16</entry><entry align="center">0/3</entry><entry align="char" char=".">.360</entry><entry align="char" char=".">.607</entry></row><row><entry>PDHA1</entry><entry align="center">20</entry><entry align="center">9/15</entry><entry align="center">0/4</entry><entry align="char" char=".">.375</entry><entry align="char" char=".">.909</entry></row><row><entry>GK</entry><entry align="center">33</entry><entry align="center">9/7</entry><entry align="center">0/12</entry><entry align="char" char=".">.563</entry><entry align="char" char=".">2.745</entry></row><row><entry>DXS1110</entry><entry align="center">40</entry><entry align="center">9/7</entry><entry align="center">0/12</entry><entry align="char" char=".">.563</entry><entry align="char" char=".">2.745</entry></row><row><entry>SYP</entry><entry align="center">50</entry><entry align="center">5/4</entry><entry align="center">4/15</entry><entry align="char" char=".">.345</entry><entry align="char" char=".">1.393</entry></row></tbody></tgroup></ce:table></ce:floats><head><ce:title>Evidence for a Turner Syndrome Locus or Loci at Xp11.2-p22.1</ce:title><ce:author-group><ce:author><ce:given-name>Andrew R.</ce:given-name><ce:surname>Zinn</ce:surname><ce:cross-ref refid="aff1"><ce:sup loc="post">1</ce:sup></ce:cross-ref><ce:cross-ref refid="cor1"><ce:sup loc="post">*</ce:sup></ce:cross-ref><ce:e-address type="email">Andrew.Zinn@email.swmed.edu</ce:e-address></ce:author><ce:author><ce:given-name>Vijay S.</ce:given-name><ce:surname>Tonk</ce:surname><ce:cross-ref refid="aff3"><ce:sup loc="post">3</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Zhong</ce:given-name><ce:surname>Chen</ce:surname><ce:cross-ref refid="aff4"><ce:sup loc="post">4</ce:sup></ce:cross-ref><ce:cross-ref refid="fn1">*</ce:cross-ref></ce:author><ce:author><ce:given-name>Wendy L.</ce:given-name><ce:surname>Flejter</ce:surname><ce:cross-ref refid="aff5"><ce:sup loc="post">5</ce:sup></ce:cross-ref><ce:cross-ref refid="fn2"><ce:sup loc="post">†</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>H. Allen</ce:given-name><ce:surname>Gardner</ce:surname><ce:cross-ref refid="aff6"><ce:sup loc="post">6</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Rudy</ce:given-name><ce:surname>Guerra</ce:surname><ce:cross-ref refid="aff2"><ce:sup loc="post">2</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Harvey</ce:given-name><ce:surname>Kushner</ce:surname><ce:cross-ref refid="aff7"><ce:sup loc="post">7</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Stuart</ce:given-name><ce:surname>Schwartz</ce:surname><ce:cross-ref refid="aff9"><ce:sup loc="post">9</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Virginia P.</ce:given-name><ce:surname>Sybert</ce:surname><ce:cross-ref refid="aff10"><ce:sup loc="post">10</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Daniel L.</ce:given-name><ce:surname>Van Dyke</ce:surname><ce:cross-ref refid="aff11"><ce:sup loc="post">11</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Judith L.</ce:given-name><ce:surname>Ross</ce:surname><ce:cross-ref refid="aff8"><ce:sup loc="post">8</ce:sup></ce:cross-ref></ce:author><ce:affiliation id="aff1"><ce:label>1</ce:label><ce:textfn>Eugene McDermott Center for Human Growth and Development and Department of Internal Medicine, The University of Texas Southwestern Medical School</ce:textfn></ce:affiliation><ce:affiliation id="aff2"><ce:label>2</ce:label><ce:textfn>Department of Statistical Science, Southern Methodist University, Dallas</ce:textfn></ce:affiliation><ce:affiliation id="aff3"><ce:label>3</ce:label><ce:textfn>Departments of Pediatrics and Pathology, Texas Tech University Health Sciences Center, Lubbock</ce:textfn></ce:affiliation><ce:affiliation id="aff4"><ce:label>4</ce:label><ce:textfn>Genzyme Genetics, Santa Fe</ce:textfn></ce:affiliation><ce:affiliation id="aff5"><ce:label>5</ce:label><ce:textfn>Department of Pediatrics, University of Utah, Salt Lake City</ce:textfn></ce:affiliation><ce:affiliation id="aff6"><ce:label>6</ce:label><ce:textfn>Oshawa General Hospital, Oshawa, Ontario, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto</ce:textfn></ce:affiliation><ce:affiliation id="aff7"><ce:label>7</ce:label><ce:textfn>Biomedical Computing Thomas Jefferson University, Philadelphia</ce:textfn></ce:affiliation><ce:affiliation id="aff8"><ce:label>8</ce:label><ce:textfn>Department of Pediatrics, Thomas Jefferson University, Philadelphia</ce:textfn></ce:affiliation><ce:affiliation id="aff9"><ce:label>9</ce:label><ce:textfn>Department of Genetics and Center for Human Genetics, Case Western Reserve University and University Hospitals of Case Western Reserve University, Cleveland</ce:textfn></ce:affiliation><ce:affiliation id="aff10"><ce:label>10</ce:label><ce:textfn>Departments of Genetics and Dermatology, University of Washington, Seattle</ce:textfn></ce:affiliation><ce:affiliation id="aff11"><ce:label>11</ce:label><ce:textfn>Department of Medical Genetics, Henry Ford Hospital, Detroit</ce:textfn></ce:affiliation><ce:correspondence id="cor1"><ce:label>*</ce:label><ce:text>Address for correspondence and reprints: Dr. Andrew R. Zinn, University of Texas Southwestern Medical School, 6000 Harry Hines Boulevard, Dallas, TX 75235-8591.</ce:text></ce:correspondence><ce:footnote id="fn1"><ce:label>*</ce:label><ce:note-para>Present affiliation: Department of Pediatrics, University of Utah, Salt Lake City.</ce:note-para></ce:footnote><ce:footnote id="fn2"><ce:label>†</ce:label><ce:note-para>Present affiliation: Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem.</ce:note-para></ce:footnote></ce:author-group><ce:date-received day="30" month="6" year="1998"></ce:date-received><ce:date-accepted day="29" month="9" year="1998"></ce:date-accepted><ce:abstract class="author"><ce:abstract-sec><ce:section-title>Summary</ce:section-title><ce:simple-para view="all" id="simple-para.0055">Turner syndrome is the complex human phenotype associated with complete or partial monosomy X. Principle features of Turner syndrome include short stature, ovarian failure, and a variety of other anatomic and physiological abnormalities, such as webbed neck, lymphedema, cardiovascular and renal anomalies, hypertension, and autoimmune thyroid disease. We studied 28 apparently nonmosaic subjects with partial deletions of Xp, in order to map loci responsible for various components of the Turner syndrome phenotype. Subjects were carefully evaluated for the presence or absence of Turner syndrome features, and their deletions were mapped by FISH with a panel of Xp markers. Using a statistical method to examine genotype/phenotype correlations, we mapped one or more Turner syndrome traits to a critical region in Xp11.2-p22.1. These traits included short stature, ovarian failure, high-arched palate, and autoimmune thyroid disease. The results are useful for genetic counseling of individuals with partial monosomy X. Study of additional subjects should refine the localization of Turner syndrome loci and provide a rational basis for exploration of candidate genes.</ce:simple-para></ce:abstract-sec></ce:abstract><ce:keywords class="keyword"><ce:keyword><ce:text>Aneuploidy</ce:text></ce:keyword><ce:keyword><ce:text>Gonadal dysgenesis</ce:text></ce:keyword><ce:keyword><ce:text>Haploinsufficiency</ce:text></ce:keyword><ce:keyword><ce:text>Sex-chromosome abnormalities</ce:text></ce:keyword><ce:keyword><ce:text>Turner syndrome</ce:text></ce:keyword><ce:keyword><ce:text>X chromosome</ce:text></ce:keyword></ce:keywords></head><body view="all"><ce:sections><ce:section id="sc1" view="all"><ce:section-title>Introduction</ce:section-title><ce:para view="all" id="para.0010">Turner syndrome is the phenotype associated with complete or partial monosomy X in human females. The phenotype consists of short stature, ovarian failure, and other variable features, such as webbed neck, aortic coarctation, high-arched palate, low-set ears, increased carrying angle of the elbow (cubitus valgus), hypoplastic nails, multiple pigmented nevi (moles), impaired glucose tolerance, hypertension, autoimmune thyroid disease, and other minor stigmata. The neurocognitive profile is characterized by selective nonverbal deficits usually without global impairment.</ce:para><ce:para view="all" id="para.0015">The pathogenesis of the Turner syndrome phenotype is complex. Most authors believe that growth retardation, ovarian failure, and other physical abnormalities are separate and distinct genetic effects. Growth failure may result from deficiency of X-linked gene(s), perhaps together with nonspecific effects of aneuploidy. Similarly, ovarian failure may be due to inadequate dosage of X-linked genes (Krauss et al. <ce:cross-ref refid="bib111">1987</ce:cross-ref>) and/or incomplete meiotic-chromosome pairing (Burgoyne and Baker <ce:cross-ref refid="bib104">1985</ce:cross-ref>). Webbed neck, aortic coarctation, and hypoplastic nails may all be secondary to in utero lymphedema (Lippe <ce:cross-ref refid="bib114">1991</ce:cross-ref>). Alternatively, neural crest–cell defects may be the etiology of cardiovascular anomalies, as well as of multiple pigmented nevi (Miyabara et al. <ce:cross-ref refid="bib119">1989</ce:cross-ref>, <ce:cross-ref refid="bib118">1997</ce:cross-ref>). The pathogenesis of impaired glucose tolerance, hypertension, autoimmune thyroid disease, and cognitive deficits is obscure.</ce:para><ce:para view="all" id="para.0020">The task of identification of specific genes responsible for Turner syndrome may, at first glance, seem herculean, since the X chromosome encodes probably thousands of genes. However, there are some mitigating factors. Most X-linked genes are subject to X inactivation during early embryogenesis and are thus functionally haploid in both 45,X and 46,XX fetuses during critical developmental stages (Lyon <ce:cross-ref refid="bib7">1961</ce:cross-ref>). These genes are thus unlikely to be involved in the Turner syndrome phenotype, with the possible exception of ovarian failure, since the inactive X is reactivated during oogenesis. Furthermore, it appears that the Y chromosome supplies the second dose of critical Turner syndrome genes in normal males. Therefore, Turner syndrome genes are predicted to be X-Y homologous and to escape X inactivation (Zinn et al. <ce:cross-ref refid="bib17">1993</ce:cross-ref>). There are presently only 18 such candidate genes, and this number is unlikely to increase substantially (Lahn and Page <ce:cross-ref refid="bib112">1997</ce:cross-ref>). The challenge is to determine which of these genes, acting alone or in concert, cause the Turner syndrome phenotype.</ce:para><ce:para view="all" id="para.0025">One way of addressing this problem is to compare the phenotypes of individuals missing various portions of one sex chromosome. Previous cytogenetic and molecular studies suggest that most Turner syndrome physical features map to the short arms of the X and Y chromosomes (Ferguson-Smith <ce:cross-ref refid="bib2">1965</ce:cross-ref>; Kalousek et al. <ce:cross-ref refid="bib6">1979</ce:cross-ref>; Fryns et al. <ce:cross-ref refid="bib3">1981</ce:cross-ref>; Goldman et al. <ce:cross-ref refid="bib4">1982</ce:cross-ref>; Simpson <ce:cross-ref refid="bib14">1988</ce:cross-ref>; Jacobs et al. <ce:cross-ref refid="bib5">1990</ce:cross-ref>; Temtamy et al. <ce:cross-ref refid="bib15">1992</ce:cross-ref>; Ogata and Matsuo <ce:cross-ref refid="bib10">1995</ce:cross-ref>). The 2.6-Mb Xp-Yp pseudoautosomal region would seem likely to play a role in Turner syndrome: X- and Y copies of the region are identical, and all genes within the region appear to escape X inactivation (Rappold <ce:cross-ref refid="bib12">1993</ce:cross-ref>). However, short stature is the only clinical finding consistently associated with deletions of just this region (Ballabio et al. <ce:cross-ref refid="bib102">1989</ce:cross-ref>; Ogata et al. <ce:cross-ref refid="bib120">1992<ce:italic>a</ce:italic></ce:cross-ref>, <ce:cross-ref refid="bib121">1992<ce:italic>b</ce:italic></ce:cross-ref>; Ogata and Matsuo <ce:cross-ref refid="bib10">1995</ce:cross-ref>).</ce:para><ce:para view="all" id="para.0030">Identification of genes or critical regions responsible for individual Turner syndrome features other than short stature (e.g., renal malformations, palate abnormalities, short fourth metacarpal, strabismus, lymphedema, etc.) has been problematic. Most studies have used only cytogenetic, not molecular, techniques to define X-chromosome abnormalities (Ferguson-Smith <ce:cross-ref refid="bib2">1965</ce:cross-ref>; Kalousek et al. <ce:cross-ref refid="bib6">1979</ce:cross-ref>; Fryns et al. <ce:cross-ref refid="bib3">1981</ce:cross-ref>; Goldman et al. <ce:cross-ref refid="bib4">1982</ce:cross-ref>; Simpson <ce:cross-ref refid="bib14">1988</ce:cross-ref>; Jacobs et al. <ce:cross-ref refid="bib5">1990</ce:cross-ref>; Temtamy et al. <ce:cross-ref refid="bib15">1992</ce:cross-ref>; Ogata and Matsuo <ce:cross-ref refid="bib10">1995</ce:cross-ref>). The precision and accuracy of cytogenetics may not be adequate for genotype correlations. Mosaicism, frequently present in Turner syndrome patients, may confound karyotype/phenotype associations. Literature reviews with large sample sizes are subject to interobserver variation in phenotypic evaluation. Last, the variability of Turner syndrome features, even among 45,X patients, necessitates statistical methodology for genotype/phenotype correlations.</ce:para><ce:para view="all" id="para.0035">Our goal in the current study was to improve the phenotype mapping of Turner syndrome. To this end, we assembled a cohort of 28 subjects with partial monosomy for Xp and carefully analyzed their phenotypes and chromosome abnormalities. We also applied a quantitative statistical method for testing the relationships between phenotypes and X-chromosome deletions. Our results provide evidence for the presence of one or more loci in Xp11.2-p22.1 that are involved in growth, ovarian function, and some but not all Turner syndrome physical abnormalities. These results provide a framework for identification of candidate Turner syndrome genes.</ce:para></ce:section><ce:section id="sc2" view="all"><ce:section-title>Subjects and Methods</ce:section-title><ce:section id="sc2.1" view="all"><ce:section-title>Subjects</ce:section-title><ce:para view="all" id="para.0040">This study was approved by the human-studies committees at Thomas Jefferson University and University of Texas Southwestern Medical School. Informed consent and assent was obtained either from the participants or, in the case of minors, from a parent or legal guardian. Prospective subjects were identified on the basis of abnormal karyotypes that included partial Xp monosomy due to either a deletion or an unbalanced translocation. We excluded patients with any of the following: (1) known sex-chromosome mosaicism; (2) X isochromosomes, because of the high likelihood of mosaicism and the possible confounding effects of Xq and proximal Xp duplication (Wolff et al. <ce:cross-ref refid="bib127">1996</ce:cross-ref>); (3) ring X chromosomes, since such patients are also likely to have mosaicism because of mitotic instability of rings; and/or (4) autosomal aneuploidy other than unbalanced X;autosome translocations.</ce:para></ce:section><ce:section id="sc2.2" view="all"><ce:section-title>Cytogenetic and Molecular Analyses</ce:section-title><ce:para view="all" id="para.0045">Repeat karyotypes were obtained for subjects not evaluated cytogenetically during the preceding 2 years. At least 20 cells were examined for mosaicism, for each subject. A blood sample was drawn at the time of clinical evaluation, for molecular-cytogenetic studies. Lymphoblastoid cell lines were derived by standard methods (Gilbert <ce:cross-ref refid="bib108">1995</ce:cross-ref>). DNA prepared from 1 ml of whole blood by means of a commercial kit (Promega) was tested for skewed X inactivation, by the androgen receptor–methylation assay (Allen et al. <ce:cross-ref refid="bib101">1992</ce:cross-ref>).</ce:para><ce:para view="all" id="para.0050">We examined metaphase spreads from cultured peripheral blood leukocytes (PBLs), for the presence of either 45,X mosaicism or cryptic X translocations, using FISH with an X-centromere probe (DXZ1) and a whole X-chromosome paint. At least 50 metaphases were examined for each subject. We then mapped deletions by FISH, using single-copy Xp probes and metaphases prepared from PBLs and/or lymphoblastoid cell lines. Every probe detected two loci in >85% of metaphases from control 46,XX cells. Each hybridization included the DXZ1 centromere probe as a control for random X-chromosome loss during preparation of metaphase spreads. A marker was scored as not deleted if two loci were detected in most metaphases. A marker was scored as deleted if two loci were never detected in five or more metaphases. Hybridizations were repeated if necessary, so that at least five metaphases were examined. In no case was the presence or absence of a marker on the deleted X chromosome ambiguous. Markers were tested sequentially until the closest loci flanking each breakpoint were determined.</ce:para></ce:section><ce:section id="sc2.3" view="all"><ce:section-title>Phenotype Evaluation</ce:section-title><ce:para view="all" id="para.0055">The evaluation included a careful history and physical examination emphasizing abnormalities associated with Turner syndrome (webbed neck, lymphedema, increased carrying angle, etc.), anthropometric measurements, and appropriate laboratory tests. Twenty-two subjects were evaluated in person by one of us (J.L.R.). Two subjects (SW16 and SW105) were each seen by two geneticists. Four subjects (SW46, SW144, SW145, and SW146) were reported to have no Turner syndrome stigmata. Since we did not personally evaluate these four subjects, we did not include their palate or carrying-angle phenotypes in the statistical analyses.</ce:para><ce:para view="all" id="para.0060">Heights were measured with a stadiometer. Measured or reported parental heights were also recorded. Mid–parental height adjusted for the child's sex (i.e., target height) was calculated by the formula 0.5 × [father's height (cm) −13 + mother's height (cm)] (Tanner et al. <ce:cross-ref refid="bib126">1970</ce:cross-ref>). In seven cases, the deletion was also present in the subject's mother. For these subjects we substituted the mothers' target height (based on mid–parental height of maternal grandparents) for her measured or reported height. Target height LOD score (<ce:italic>Z</ce:italic>) values were calculated from sex-adjusted mid–parental-height data obtained from the National Center for Health Statistics' growth-curve data (Hamill et al. <ce:cross-ref refid="bib109">1979</ce:cross-ref>). Mid–parental height was not calculated for one subject, who was adopted.</ce:para><ce:para view="all" id="para.0065">Cardiac anomalies were documented by ultrasound. Renal anomalies were documented by ultrasound or IVP. Metacarpals were inspected radiographically. The diagnosis of ovarian failure was based on measurements of serum estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels. Ovarian failure was defined by castrate levels of FSH and LH for subjects ⩾10 years of age. Ovarian function in girls <10 years of age was considered indeterminate, and their gonadotropin measurements were repeated periodically during the course of the study.</ce:para><ce:para view="all" id="para.0070">Webbed neck included redundant skin. Since lymphedema can resolve over time, this feature was considered positive either if it was present on exam or if a history of lymphedema was documented in medical records. Palate abnormalities were noted by inspection and included an inverted U shape or an “ogival” form characterized by a narrow vault with bulging of the lateral alveolar ridges. Subjects were photographed with elbows maximally extended and supinated, to measure carrying angle. Miscellaneous Turner syndrome features (strabismus, multiple pigmented nevi, congenitally dislocated hips or scoliosis, and abnormal nails) were clinically assessed. Thyroid abnormalities were documented by measurement of serum thyroxine (T4) and thyroid-stimulating hormone levels, as well as by thyroid-antibody titers.</ce:para></ce:section><ce:section id="sc2.4" view="all"><ce:section-title>Statistical Analysis</ce:section-title><ce:para view="all" id="para.0075">Our approach to phenotype mapping of Turner syndrome, a chromosome disorder, was analogous to association studies for Mendelian or complex traits (Lander and Schork <ce:cross-ref refid="bib113">1994</ce:cross-ref>). We analyzed subjects' deletions with a set of markers distributed along the short arm of the X chromosome. For each marker, we divided subjects into two groups: those with or without deletion of that marker. Each trait was considered as either a dichotomous variable (e.g., ovarian failure [yes or no]) or a numerically continuous variable (e.g., height).</ce:para><ce:section id="sc2.4.1" view="all"><ce:section-title>Dichotomous variables</ce:section-title><ce:para view="all" id="para.0080">For each marker, we compared the proportion of individuals with a given trait, in the group with the marker deleted, versus the proportion of individuals with the same trait, in the group without the marker deleted. The comparison between the proportions was based on a simple <ce:italic>Z</ce:italic> value for the difference of two binomial proportions. We did not use Yates's correction for continuity, which is often suggested for binomial probabilities with small sample sizes (expected frequencies less than five), in order to avoid missing associations.</ce:para></ce:section><ce:section id="sc2.4.2" view="all"><ce:section-title>Numerically continuous variables</ce:section-title><ce:para view="all" id="para.0085">We used an unpaired <ce:italic>t</ce:italic>-test to compare the mean of all individuals with the marker deleted versus the mean of all individuals without the marker deleted, for each marker. The strength of the association was estimated from the <ce:italic>Z</ce:italic> value <ce:italic>t</ce:italic> score. The <ce:italic>P</ce:italic> value associated with a specific test would be appropriate for testing one specific marker. However, we tested a series of markers. Thus, the proper <ce:italic>P</ce:italic> value is actually the observed <ce:italic>P</ce:italic> value times the number of markers tested. Furthermore, because we analyzed multiple traits, we applied an additional Bonferroni correction for simultaneous multiple inferences. Therefore, the <ce:italic>P</ce:italic> value that we reported for a specific marker (of a set of <ce:italic>m</ce:italic> markers) and a specific trait (of a set of <ce:italic>k</ce:italic> traits) equals the observed <ce:italic>P</ce:italic> value times <ce:italic>mk.</ce:italic> For our tests (one tailed) at α=.05, comparing six markers and five traits, the threshold required for an observed <ce:italic>P</ce:italic> value to be considered statistically significant was <ce:italic>P</ce:italic><.0017 (Z<ce:inf loc="post">.0017</ce:inf>=2.93; t<ce:inf loc="post">.0017,25</ce:inf>=3.2).</ce:para></ce:section></ce:section></ce:section><ce:section id="sc3" view="all"><ce:section-title>Results</ce:section-title><ce:section id="sc3.1" view="all"><ce:section-title>Subjects</ce:section-title><ce:para view="all" id="para.0090">Subjects who participated in this study are listed in <ce:cross-ref refid="tbl1">table 1</ce:cross-ref><ce:float-anchor refid="tbl1"></ce:float-anchor>, along with karyotype results from clinical records and chronological age at the time of evaluation for this study. Subjects were Caucasian (23), African American (2), Hispanic (2), and Asian (1) and had an age range of 1.3–45.2 years. SW16/105, SW96/97, and SW145/146 were sib pairs. SW144 was the mother of SW145 and SW146; SW175 was the mother of SW174. Other subjects were unrelated.</ce:para></ce:section><ce:section id="sc3.2" view="all"><ce:section-title>Molecular Cytogenetics</ce:section-title><ce:para view="all" id="para.0095">Markers spaced at ∼10-Mb intervals along the 60-Mb X-chromosome short arm (<ce:cross-ref refid="tbl2">table 2</ce:cross-ref><ce:float-anchor refid="tbl2"></ce:float-anchor>) were tested initially. Additional markers were then tested to resolve clustered breakpoints but were not included in statistical analyses. DXYS14, situated <100 kb from the Xp/Yp subtelomeric repeats, distinguished terminal versus interstitial deletions.</ce:para><ce:para view="all" id="para.0100">The molecular-cytogenetic breakpoints are depicted graphically in <ce:cross-ref refid="fig1">figure 1</ce:cross-ref><ce:float-anchor refid="fig1"></ce:float-anchor>. Karyotypes were generally accurate. We did find that subjects SW144, SW145, and SW146 had either a terminal Xp deletion or a cryptic X translocation, rather than an interstitial Xp deletion. Conversely, subject SW190 had an interstitial Xp deletion that was thought, on the basis of karyotyping, to be terminal. The largest group of breakpoints clustered within a few megabases of the X centromere. We were able to resolve several cytogenetically similar breakpoints by using molecular markers. For example, the Xp11.2 breakpoints of SW71, SW85, and SW103 could be distinguished by our FISH probes.</ce:para><ce:para view="all" id="para.0105">The X-inactivation pattern in peripheral blood leukocytes from 21 subjects was also examined, by means of the androgen-receptor gene–methylation assay (see <ce:cross-ref refid="sc2">Subjects and Methods</ce:cross-ref>). This assay measures the presence of methylated cytosine residues flanking a highly polymorphic trinucleotide repeat in the X-linked androgen-receptor gene. The presence of methylation reflects inactivation of an androgen-receptor allele and its chromosome. Twenty subjects were informative for the androgen-receptor polymorphism. Of these 20, 18 showed completely skewed inactivation, with evidence for methylation of only one androgen-receptor allele (presumably the allele borne by the deleted X chromosome, because of selection against cells in which the normal X is inactivated [Migeon <ce:cross-ref refid="bib8">1998</ce:cross-ref>]) (data not shown). The two subjects without complete skewing, SW174 and SW175, had a very small deletion.</ce:para></ce:section><ce:section id="sc3.3" view="all"><ce:section-title>Phenotype Mapping</ce:section-title><ce:para view="all" id="para.0110"><ce:cross-ref refid="tbl3">Table 3</ce:cross-ref><ce:float-anchor refid="tbl3"></ce:float-anchor> shows the presence or absence in our subjects of five Turner syndrome–associated phenotypes: short stature, high-arched palate, increased carrying angle, thyroid antibodies, and ovarian failure. All subjects were evaluated as described in <ce:cross-ref refid="sc2">Subjects and Methods</ce:cross-ref>. In general, but not always, the phenotype was similar in relatives with the identical deletion. For example, ovarian failure was apparently absent in SW97 and was present in her sister, SW96. Siblings SW16 and SW105 were discordant for thyroid autoimmunity and the presence of a high-arched palate. Phenotypic features that we did not personally evaluate or that were not objectively documented in medical records were not scored. Missing data were not used in statistical analyses.</ce:para><ce:para view="all" id="para.0115">Certain Turner syndrome–associated abnormalities were present in so few subjects that we did not attempt statistical analysis of the loci involved. These included horseshoe kidney (1 subject), aortic coarctation (0), webbed neck (0), and lymphedema (2). Other minor Turner syndrome stigmata, including multiple pigmented nevi, short 4th or 5th metacarpal, abnormal nails, strabismus, congenitally dislocated hips, and scoliosis, were seen in a number of subjects but showed no apparent relationship to the size or position of deletions (data not shown). We focused our statistical analysis on the following five phenotypic traits: short stature, high-arched palate, increased carrying angle, thyroid antibodies, and ovarian failure.</ce:para><ce:para view="all" id="para.0120">We tested the association between these traits and the presence or absence of specified Xp markers (DXYS14, DXS7470, PDHA1, GK, DXS1110, and SYP) that are spaced at ∼10-Mb intervals (Nelson et al. <ce:cross-ref refid="bib9">1995</ce:cross-ref>).<ce:cross-ref refid="tbl4">Table 4</ce:cross-ref><ce:float-anchor refid="tbl4"></ce:float-anchor> shows the results for stature (adjusted for mid–parental or target height). No comparison was made for the most distal marker (DXYS14), since only one subject did not have this marker deleted. Subjects with deletion of DXS7470 or PDHA1 tended to have lower mean heights than were seen in subjects not deleted for these markers, although the differences were not statistically significant. By contrast, the mean stature of subjects deleted for GK was almost 2 SDs less than that of subjects not deleted for this marker. This difference was statistically significant. No breakpoints fell between GK and DXS1110, so the statistical results for these two markers were identical. The decrease in mean stature SDs that was associated with deletion of SYP, although still statistically significant, was less than that associated with deletion of GK/DXS1110.</ce:para><ce:para view="all" id="para.0125">We performed similar analyses for ovarian failure, abnormal palate, and autoimmune thyroid disease. In these cases, the phenotypes were considered as dichotomous variables. The results are shown in <ce:cross-refs refid="tbl5 tbl6 tbl7">tables 5–7</ce:cross-refs><ce:float-anchor refid="tbl5"></ce:float-anchor><ce:float-anchor refid="tbl6"></ce:float-anchor><ce:float-anchor refid="tbl7"></ce:float-anchor>. There was statistically significant evidence for a locus or loci for gonadal dysgenesis and abnormal palate in the same interval spanning GK–DXS1110. The data also indicate a possible locus for autoimmune thyroid disease within the same interval, although the strength of this association did not achieve statistical significance. By contrast, we did not find any association between increased carrying angle and deletion of any marker (data not shown).<ce:cross-ref refid="fig2">Figure 2</ce:cross-ref><ce:float-anchor refid="fig2"></ce:float-anchor> shows a graphic summary of the associations between these five traits and the presence or absence of the six markers.</ce:para></ce:section></ce:section><ce:section id="sc4" view="all"><ce:section-title>Discussion</ce:section-title><ce:para view="all" id="para.0130">Our key finding is that a locus (or loci) for short stature, ovarian failure, and high-arched palate maps to one region of the X chromosome, Xp11.2-p22.1. Our data also suggest a possible locus for autoimmune thyroid disease in this same region, although this result was not statistically significant. The critical region comprises approximately one-fifth of the X chromosome and is consistent with previous inferences from karyotype/phenotype correlations (Ferguson-Smith <ce:cross-ref refid="bib2">1965</ce:cross-ref>; Fraccaro et al. <ce:cross-ref refid="bib107">1977</ce:cross-ref>; Kalousek et al. <ce:cross-ref refid="bib6">1979</ce:cross-ref>; Fryns et al. <ce:cross-ref refid="bib3">1981</ce:cross-ref>; Goldman et al. <ce:cross-ref refid="bib4">1982</ce:cross-ref>; Simpson <ce:cross-ref refid="bib14">1988</ce:cross-ref>; Jacobs et al. <ce:cross-ref refid="bib5">1990</ce:cross-ref>; Massa et al. <ce:cross-ref refid="bib116">1992</ce:cross-ref>; Temtamy et al. <ce:cross-ref refid="bib15">1992</ce:cross-ref>; Ogata and Matsuo <ce:cross-ref refid="bib10">1995</ce:cross-ref>).</ce:para><ce:para view="all" id="para.0135">Our data suggest that a stature determinant is situated between markers PDHA1 (Xp22.1) and SYP (Xp11.2). Weaker associations between stature and deletion of markers that are more distal (e.g., DXS7470) or more proximal (e.g., SYP) can be explained by the fact that deletions were contiguous and spanned more than one interval. For example, all subjects missing SYP were also missing the markers, GK/DXS1110, that were maximally associated with short stature. Conversely, not every subject missing GK/DXS1110 was also missing SYP. Those subjects missing GK/DXS1110 but not SYP would weaken the association between stature and SYP.</ce:para><ce:para view="all" id="para.0140">A more distal short-stature gene, <ce:italic>SHOX,</ce:italic> has recently been identified in the Xp-Yp pseudoautosomal region (Rao et al. <ce:cross-ref refid="bib122">1997</ce:cross-ref>). Only one of our subjects was not deleted for the pseudoautosomal region, and she had normal stature. FISH with a cosmid probe (not shown) confirmed the presence of two copies of <ce:italic>SHOX</ce:italic> in this subject. By comparison, the mean height SDs of subjects missing DXYS14 (<ce:italic>SHOX</ce:italic>) was −2.2.</ce:para><ce:para view="all" id="para.0145">Interestingly, the association of short stature and deletion of Xp22.1-p11.2 was not statistically significant when stature was not adjusted for mid–parental height (data not shown). Other studies have shown that correlation with mid–parental height is preserved in Turner syndrome (Brook et al. <ce:cross-ref refid="bib103">1977</ce:cross-ref>). Thus, this haploinsufficient effect of Xp loci can be modified by genetic background. Subjects with the largest Xp deletions had height deficits essentially equivalent to that typically seen in 45,X Turner syndrome, suggesting that Xq loci play little or no role in growth failure. However, most of our subjects were ascertained because of short stature, and therefore the effect of Xp deletions on stature may be overestimated.</ce:para><ce:para view="all" id="para.0150">Data from previous studies indicate that ovarian failure is frequent in women with deletions of either Xp or Xq. Some have interpreted this finding to imply that the primary Turner syndrome ovarian defect involves meiotic-chromosome pairing (Ogata and Matsuo <ce:cross-ref refid="bib10">1995</ce:cross-ref>). To the contrary, autopsy studies have indicated that germ cells are deficient in 45,X fetuses even prior to the pachytene stage, when chromosomes pair (Speed <ce:cross-ref refid="bib124">1986</ce:cross-ref>). Our data suggest a phenotypic difference between distal deletions, associated with preserved ovarian function, and proximal deletions, associated with ovarian failure. The correlation is imperfect, since at least one subject missing almost all of Xp still had functioning ovaries. Until long-term follow-up studies have been conducted, we cannot rule out the possibility that our subjects with preserved ovarian function will suffer premature menopause. Another limitation of our data is that ovarian failure, defined as castrate levels of gonadotropins, cannot be reliably determined in young children, such as were three of our subjects.</ce:para><ce:para view="all" id="para.0155">One candidate gene within the critical region for ovarian failure is <ce:italic>ZFX,</ce:italic> which maps to Xp21.2. <ce:italic>ZFX</ce:italic> encodes a transcription factor of unknown function (Page et al. <ce:cross-ref refid="bib11">1987</ce:cross-ref>); inactivation of the orthologous gene in mice causes growth retardation and reduced germ-cell number (Luoh et al. <ce:cross-ref refid="bib115">1997</ce:cross-ref>). The hypothesis that <ce:italic>ZFX</ce:italic> haploinsufficiency contributes to ovarian failure could be tested by mutational analysis of 46,XX women with premature ovarian failure.</ce:para><ce:para view="all" id="para.0160">The localization of a high arched–palate determinant to Xp11.2-p22.1 was unexpected. High-arched palate, seen in many chromosome disorders, is generally considered a nonspecific aneuploidy effect. It may be that haploinsufficiency of one or a few genes is the major etiologic factor for high-arched palate associated with Turner syndrome, as appears to be the case for short stature. By contrast, there does not appear to be a major Xp locus for increased carrying angle of the elbow. The absence of a locus for cubitus valgus was surprising, since this classic trait is a relatively specific feature of monosomy X. It is possible that a gene(s) outside the critical region—for example, <ce:italic>SHOX</ce:italic>—contributes to this trait. Our finding that some Turner syndrome traits were associated with deletion of the critical region whereas others were not argues that the associations were not due to occult 45,X mosaicism.</ce:para><ce:para view="all" id="para.0165">Autoimmune thyroid disease is present in approximately one-third of our 45,X Turner syndrome patients (J. L. Ross, unpublished observation). This phenotype may be difficult to assess, because antibodies tend to develop with increasing age, and different antibodies (peroxidase, microsomal, or thyroglobulin) are measured by various laboratories. Our data suggest that haploinsufficiency of a locus in Xp11.2-p22.1, perhaps the same locus as that causing growth retardation, ovarian failure, or high-arched palate, also contributes to immune dysregulation. One speculative hypothesis is that these features are all manifestations of selective impairment of cellular growth during development.</ce:para><ce:para view="all" id="para.0170">Other typical Turner syndrome features, such as aortic coarctation or webbed neck, that are relatively common in 45,X patients were notably absent from our subjects. Lymphedema has been reported in 60% of 45,X newborns but in only 10% of Turner syndrome patients with other karyotypes (Sybert <ce:cross-ref refid="bib125">1995</ce:cross-ref>). In our series, only one subject each had lymphedema or horseshoe kidney. One reason for the paucity of these features could be that deletion of Xq is required for their complete expression.</ce:para><ce:para view="all" id="para.0175">We considered the possibility that imprinting or X inactivation might play a role in the phenotypic variability of our subjects. Imprinting could confound apparent relationships between deletions and phenotypes, unless the parental origins of the deleted chromosomes were factored into analyses. However, several previous reports, including a recent study describing a putative imprinted Turner syndrome cognitive locus (Skuse et al. <ce:cross-ref refid="bib123">1997</ce:cross-ref>), indicate that imprinting plays no role in Turner syndrome physical features (Mathur et al. <ce:cross-ref refid="bib117">1991</ce:cross-ref>). In other studies, we also failed to find any phenotypic differences due to parent-of-origin effects in 30 45,X subjects (J.L. Ross, H. Kushner, A.R. Zinn, unpublished data). Therefore, imprinting is unlikely to be important in the present study of Turner syndrome physical features. X-inactivation differences are also unlikely to have contributed to phenotypic variability of our subjects. All subjects tested, except for two with very small deletions, showed completely skewed inactivation, as is the general rule for partial monosomy X (Belmont <ce:cross-ref refid="bib1">1996</ce:cross-ref>). The deletions in these two related women are 5–9 Mb in size (B. Franco, personal communication), which is consistent with inferential data from clinical manifestations of X-linked disorders in female carriers, which suggest that terminal Xp deletions ≤∼15 Mb in size do not cause highly skewed X inactivation (Schaefer et al. <ce:cross-ref refid="bib13">1993</ce:cross-ref>).</ce:para><ce:para view="all" id="para.0180">We approached phenotype mapping of Turner syndrome with the hypothesis that at least some features are due to haploinsufficiency of discrete loci on the X chromosome (Epstein <ce:cross-ref refid="bib105">1988</ce:cross-ref>). Although this approach had been tried previously, earlier studies lacked precise phenotype descriptions, accurate molecular-cytogenetic definition of deletions, and sufficient numbers of subjects to permit statistical analysis. In our study, we attempted to address each of these shortcomings. One limitation to our data is that breakpoints were not uniformly distributed: 8 of 28 subjects were missing >80% of Xp. This distribution may reflect clinical ascertainment through the presence of major Turner syndrome features, which are more likely with larger deletions. Alternatively, there could be a propensity for the X chromosome to break near the centromere, because of repetitive sequences or other chromatin features.</ce:para><ce:para view="all" id="para.0185">Because of the difficulties in data collection, our statistical analysis also has limitations. First, the number of subjects in each comparison (deleted and undeleted) is small. Second, since some of our subjects are related, the statistical independence assumption underlying the <ce:italic>t</ce:italic> and binomial-comparisons tests does not hold. However, we did not eliminate redundant or minimally informative markers—for example, 6K/DXS1110 or DXYS14—so our correction for multiple inferences was conservative. As more subjects become available, we will not have to include related individuals, and the power to detect phenotypic differences between groups thereby will be increased.</ce:para><ce:para view="all" id="para.0190">Our data should be helpful for genetic-counseling in cases of partial monosomy X, heretofore a prognostic quandary. The results also provide the basis for future investigations aimed at molecular identification of Turner syndrome genes. The availability of additional subjects should allow us to refine the map location of Xp genes associated with specific traits and to determine whether the associations are manifestations of haploinsufficiency for a single gene or gene cluster. Guided by this information, mutational analysis of karyotypically normal individuals with Turner syndrome traits may reveal the culprit genes. The statistical approach that we have used should be useful for phenotype mapping not only of Turner syndrome but also of other aneuploidy syndromes, such as trisomy 21, for which accurate molecular-cytogenetic and phenotypic data are available (Epstein et al. <ce:cross-ref refid="bib106">1991</ce:cross-ref>; Korenberg et al. <ce:cross-ref refid="bib110">1994</ce:cross-ref>).</ce:para></ce:section></ce:sections><ce:acknowledgment><ce:section-title>Acknowledgments</ce:section-title><ce:para view="all" id="para.0195">This work was supported by National Institutes of Health grant R01 NS35554. We thank Bing Ouyang and Lillian Sellati for performing molecular-cytogenetic analyses, Dr. Gudrun Rappold for the <ce:italic>SHOX</ce:italic> probe, Dr. Nancy Schneider and Debra Cohen for karyotyping, and Karen Kowal for assistance with phenotype evaluations. We especially thank the many physicians who referred patients for this study, especially Drs. G. S. 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Genet</sb:maintitle></sb:title><sb:volume-nr>9</sb:volume-nr></sb:series><sb:date>1993</sb:date></sb:issue><sb:pages><sb:first-page>90</sb:first-page><sb:last-page>93</sb:last-page></sb:pages></sb:host></sb:reference></ce:bib-reference></ce:bibliography-sec></ce:bibliography></tail></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Evidence for a Turner Syndrome Locus or Loci at Xp11.2-p22.1</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Evidence for a Turner Syndrome Locus or Loci at Xp11.2-p22.1</title></titleInfo><name type="personal"><namePart type="given">Andrew R.</namePart><namePart type="family">Zinn</namePart><affiliation>E-mail: Andrew.Zinn@email.swmed.edu</affiliation><affiliation>Eugene McDermott Center for Human Growth and Development and Department of Internal Medicine, The University of Texas Southwestern Medical School</affiliation><description>Address for correspondence and reprints: Dr. Andrew R. Zinn, University of Texas Southwestern Medical School, 6000 Harry Hines Boulevard, Dallas, TX 75235-8591.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Vijay S.</namePart><namePart type="family">Tonk</namePart><affiliation>Departments of Pediatrics and Pathology, Texas Tech University Health Sciences Center, Lubbock</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Zhong</namePart><namePart type="family">Chen</namePart><affiliation>Genzyme Genetics, Santa Fe</affiliation><description>Present affiliation: Department of Pediatrics, University of Utah, Salt Lake City.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Wendy L.</namePart><namePart type="family">Flejter</namePart><affiliation>Department of Pediatrics, University of Utah, Salt Lake City</affiliation><description>Present affiliation: Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">H. Allen</namePart><namePart type="family">Gardner</namePart><affiliation>Oshawa General Hospital, Oshawa, Ontario, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rudy</namePart><namePart type="family">Guerra</namePart><affiliation>Department of Statistical Science, Southern Methodist University, Dallas</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Harvey</namePart><namePart type="family">Kushner</namePart><affiliation>Biomedical Computing Thomas Jefferson University, Philadelphia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Stuart</namePart><namePart type="family">Schwartz</namePart><affiliation>Department of Genetics and Center for Human Genetics, Case Western Reserve University and University Hospitals of Case Western Reserve University, Cleveland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Virginia P.</namePart><namePart type="family">Sybert</namePart><affiliation>Departments of Genetics and Dermatology, University of Washington, Seattle</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Daniel L.</namePart><namePart type="family">Van Dyke</namePart><affiliation>Department of Medical Genetics, Henry Ford Hospital, Detroit</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Judith L.</namePart><namePart type="family">Ross</namePart><affiliation>Department of Pediatrics, Thomas Jefferson University, Philadelphia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="Full-length article"></genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">1998</dateIssued><copyrightDate encoding="w3cdtf">1998</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>SummaryTurner syndrome is the complex human phenotype associated with complete or partial monosomy X. Principle features of Turner syndrome include short stature, ovarian failure, and a variety of other anatomic and physiological abnormalities, such as webbed neck, lymphedema, cardiovascular and renal anomalies, hypertension, and autoimmune thyroid disease. We studied 28 apparently nonmosaic subjects with partial deletions of Xp, in order to map loci responsible for various components of the Turner syndrome phenotype. Subjects were carefully evaluated for the presence or absence of Turner syndrome features, and their deletions were mapped by FISH with a panel of Xp markers. Using a statistical method to examine genotype/phenotype correlations, we mapped one or more Turner syndrome traits to a critical region in Xp11.2-p22.1. These traits included short stature, ovarian failure, high-arched palate, and autoimmune thyroid disease. The results are useful for genetic counseling of individuals with partial monosomy X. Study of additional subjects should refine the localization of Turner syndrome loci and provide a rational basis for exploration of candidate genes.</abstract><note type="content">Figure 1: Graphic representation of deletions. Bars represent material present in deleted X chromosomes. Positions of molecular-cytogenetic markers are indicated.</note><note type="content">Figure 2: Strength of associations between deleted markers and five phenotypic traits: adjusted height, ovarian failure (ovary), high-arched palate (palate), thyroid autoantibodies (thyroid), and increased carrying angle of the elbow (carrying angle). A score of “0” indicates that there is no association. Scores >∼3 are statistically significant (see Subjects and Methods).</note><note type="content">Table 1: Reported Karyotypes and Chronological Ages of Subjects at the Time of Evaluation</note><note type="content">Table 2: Molecular-Cytogenetic Markers</note><note type="content">Table 3: Phenotypic Data</note><note type="content">Table 4: Mean ± SD Z-Score for Mid–Parental Height or Target Height</note><note type="content">Table 5: Ovarian-Failure Trait</note><note type="content">Table 6: High Arched–Palate Trait</note><note type="content">Table 7: Autoimmune Thyroid–Disease Trait</note><subject><genre>article-category</genre><topic>Original Articles</topic></subject><subject lang="en"><topic>Aneuploidy</topic><topic>Gonadal dysgenesis</topic><topic>Haploinsufficiency</topic><topic>Sex-chromosome abnormalities</topic><topic>Turner syndrome</topic><topic>X chromosome</topic></subject><relatedItem type="host"><titleInfo><title>The American Journal of Human Genetics</title></titleInfo><titleInfo type="abbreviated"><title>AJHG</title></titleInfo><genre type="journal">journal</genre><originInfo><dateIssued encoding="w3cdtf">199812</dateIssued></originInfo><identifier type="ISSN">0002-9297</identifier><identifier type="PII">S0002-9297(07)X6052-X</identifier><part><date>199812</date><detail type="volume"><number>63</number><caption>vol.</caption></detail><detail type="issue"><number>6</number><caption>no.</caption></detail><extent unit="issue pages"><start>i</start><end>ii</end></extent><extent unit="issue pages"><start>1573</start><end>1950</end></extent><extent unit="pages"><start>1757</start><end>1766</end></extent></part></relatedItem><identifier type="istex">A9C4E5A4FBB921A5AFB0F9BBF7DD7D252CC9A373</identifier><identifier type="DOI">10.1086/302152</identifier><identifier type="PII">S0002-9297(07)61621-8</identifier><identifier type="ArticleID">61621</identifier><accessCondition type="use and reproduction" contentType="copyright">©1998 The American Society of Human Genetics</accessCondition><recordInfo><recordContentSource>ELSEVIER</recordContentSource><recordOrigin>The American Society of Human Genetics, ©1998</recordOrigin></recordInfo></mods></metadata></istex></record>Pour manipuler ce document sous Unix (Dilib)
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