Modest Impact on Risk for Autism Spectrum Disorder of Rare Copy Number Variants at 15q11.2, Specifically Breakpoints 1 to 2
Identifieur interne : 000301 ( France/Analysis ); précédent : 000300; suivant : 000302Modest Impact on Risk for Autism Spectrum Disorder of Rare Copy Number Variants at 15q11.2, Specifically Breakpoints 1 to 2
Auteurs : Pauline Chaste [États-Unis, France] ; Stephan J. Sanders [États-Unis] ; Kommu N. Mohan [Inde, États-Unis] ; Lambertus Klei [États-Unis] ; Youeun Song [États-Unis] ; Michael T. Murtha ; Vanessa Hus ; Jennifer K. Lowe [États-Unis] ; A. Jeremy Willsey [États-Unis] ; Daniel Moreno-De-Luca [États-Unis] ; Timothy W. Yu [États-Unis] ; Eric Fombonne [États-Unis] ; Daniel Geschwind [États-Unis] ; Dorothy E. Grice [États-Unis] ; David H. Ledbetter ; Catherine Lord ; Shrikant M. Mane ; Donna M. Martin ; Eric M. Morrow [États-Unis] ; Christopher A. Walsh [États-Unis] ; James S. Sutcliffe ; Matthew W. State [États-Unis] ; Christa Lese Martin ; Bernie Devlin [États-Unis] ; Arthur L. Beaudet [États-Unis] ; Edwin H. Cook Jr. [États-Unis] ; Soo-Jeong Kim [États-Unis]Source :
- Autism Research [ 1939-3792 ] ; 2014-06.
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Abstract
The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants (CNVs). Among the rearrangements observed in this region, CNVs from the interval between the common breakpoints 1 and 2 (BP1 and BP2) have been reported cosegregating with autism spectrum disorder (ASD). Although evidence supporting an association between BP1‐BP2 CNVs and autism accumulates, the magnitude of the effect of BP1‐BP2 CNVs remains elusive, posing a great challenge to recurrence‐risk counseling. To gain further insight into their pathogenicity for ASD, we estimated the penetrance of the BP1‐BP2 CNVs for ASD as well as their effects on ASD‐related phenotypes in a well‐characterized ASD sample (n = 2525 families). Transmission disequilibrium test revealed significant preferential transmission only for the duplicated chromosome in probands (20T:9NT). The penetrance of the BP1‐BP2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyses suggest a greater effect of the CNVs on ASD‐related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP1‐BP2 CNVs as risk factors for autism. However, their effect is modest, more akin to that seen for common variants. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1‐BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status. Autism Res 2014, 7: 355–362. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.
Url:
DOI: 10.1002/aur.1378
Affiliations:
- France, Inde, États-Unis
- Californie, Connecticut, Illinois, Massachusetts, Oregon, Pennsylvanie, Rhode Island, Texas, Washington (État), État de New York, Île-de-France
- Boston, Chicago, Créteil, Houston, Los Angeles, Pittsburgh, Portland, Providence (Rhode Island), San Francisco, Seattle
- Université Brown, Université de Washington
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Yu</name><affiliation wicri:level="3"><country>États-Unis</country><placeName><settlement type="city">Boston</settlement><region type="state">Massachusetts</region></placeName><wicri:orgArea>Division of Genetics, Children's Hospital Boston, Harvard Medical School, Massachusetts</wicri:orgArea></affiliation></author><author><name sortKey="Fombonne, Eric" sort="Fombonne, Eric" uniqKey="Fombonne E" first="Eric" last="Fombonne">Eric Fombonne</name><affiliation wicri:level="3"><country>États-Unis</country><placeName><settlement type="city">Portland</settlement><region type="state">Oregon</region></placeName><wicri:orgArea>Department of Psychiatry, Oregon Health & Science University, Oregon</wicri:orgArea></affiliation></author><author><name sortKey="Geschwind, Daniel" sort="Geschwind, Daniel" uniqKey="Geschwind D" first="Daniel" last="Geschwind">Daniel Geschwind</name><affiliation wicri:level="3"><country>États-Unis</country><placeName><settlement type="city">Los Angeles</settlement><region type="state">Californie</region></placeName><wicri:orgArea>Neurogenetics Program, Department of Neurology and Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, California</wicri:orgArea></affiliation></author><author><name sortKey="Grice, Dorothy E" sort="Grice, Dorothy E" uniqKey="Grice D" first="Dorothy E." last="Grice">Dorothy E. Grice</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">État de New York</region></placeName><wicri:cityArea>Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York</wicri:cityArea></affiliation></author><author><name sortKey="Ledbetter, David H" sort="Ledbetter, David H" uniqKey="Ledbetter D" first="David H." last="Ledbetter">David H. Ledbetter</name><affiliation><wicri:noCountry code="subField">Danville</wicri:noCountry></affiliation></author><author><name sortKey="Lord, Catherine" sort="Lord, Catherine" uniqKey="Lord C" first="Catherine" last="Lord">Catherine Lord</name><affiliation><wicri:noCountry code="subField">Plains</wicri:noCountry></affiliation></author><author><name sortKey="Mane, Shrikant M" sort="Mane, Shrikant M" uniqKey="Mane S" first="Shrikant M." last="Mane">Shrikant M. Mane</name><affiliation><wicri:noCountry code="subField">Orange</wicri:noCountry></affiliation></author><author><name sortKey="Martin, Donna M" sort="Martin, Donna M" uniqKey="Martin D" first="Donna M." last="Martin">Donna M. Martin</name><affiliation><wicri:noCountry code="subField">Arbor</wicri:noCountry></affiliation></author><author><name sortKey="Morrow, Eric M" sort="Morrow, Eric M" uniqKey="Morrow E" first="Eric M." last="Morrow">Eric M. Morrow</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Rhode Island</region></placeName><wicri:cityArea>Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence</wicri:cityArea></affiliation><affiliation wicri:level="4"><orgName type="university">Université Brown</orgName><country>États-Unis</country><placeName><settlement type="city">Providence (Rhode Island)</settlement><region type="state">Rhode Island</region></placeName></affiliation></author><author><name sortKey="Walsh, Christopher A" sort="Walsh, Christopher A" uniqKey="Walsh C" first="Christopher A." last="Walsh">Christopher A. Walsh</name><affiliation wicri:level="3"><country>États-Unis</country><placeName><settlement type="city">Boston</settlement><region type="state">Massachusetts</region></placeName><wicri:orgArea>Howard Hughes Medical Institute and Division of Genetics, Children's Hospital Boston, and Neurology and Pediatrics, Center for Life Sciences, Harvard Medical School, Massachusetts</wicri:orgArea></affiliation></author><author><name sortKey="Sutcliffe, James S" sort="Sutcliffe, James S" uniqKey="Sutcliffe J" first="James S." last="Sutcliffe">James S. Sutcliffe</name><affiliation><wicri:noCountry code="subField">Nashville</wicri:noCountry></affiliation></author><author><name sortKey="State, Matthew W" sort="State, Matthew W" uniqKey="State M" first="Matthew W." last="State">Matthew W. State</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><placeName><region type="state">Connecticut</region></placeName><wicri:cityArea>Department of Genetics, Yale University School of Medicine, New Haven</wicri:cityArea></affiliation><affiliation wicri:level="3"><country>États-Unis</country><placeName><settlement type="city">San Francisco</settlement><region type="state">Californie</region></placeName><wicri:orgArea>Department of Psychiatry, University of California, California</wicri:orgArea></affiliation></author><author><name sortKey="Martin, Christa Lese" sort="Martin, Christa Lese" uniqKey="Martin C" first="Christa Lese" last="Martin">Christa Lese Martin</name><affiliation><wicri:noCountry code="subField">Danville</wicri:noCountry></affiliation></author><author><name sortKey="Devlin, Bernie" sort="Devlin, Bernie" uniqKey="Devlin B" first="Bernie" last="Devlin">Bernie Devlin</name><affiliation wicri:level="3"><country>États-Unis</country><placeName><settlement type="city">Pittsburgh</settlement><region type="state">Pennsylvanie</region></placeName><wicri:orgArea>Department of Psychiatry, University of Pittsburgh School of Medicine, Pennsylvania</wicri:orgArea></affiliation></author><author><name sortKey="Beaudet, Arthur L" sort="Beaudet, Arthur L" uniqKey="Beaudet A" first="Arthur L." last="Beaudet">Arthur L. Beaudet</name><affiliation wicri:level="3"><country>États-Unis</country><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName><wicri:orgArea>Department of Human and Molecular Genetics, Baylor College of Medicine, Texas</wicri:orgArea></affiliation></author><author><name sortKey="Cook Jr, Edwin H" sort="Cook Jr, Edwin H" uniqKey="Cook Jr E" first="Edwin H." last="Cook Jr.">Edwin H. Cook Jr.</name><affiliation wicri:level="3"><country>États-Unis</country><placeName><settlement type="city">Chicago</settlement><region type="state">Illinois</region></placeName><wicri:orgArea>Institute for Juvenile Research, Department of Psychiatry, University of Illinois, Illinois</wicri:orgArea></affiliation></author><author><name sortKey="Kim, Soo Eong" sort="Kim, Soo Eong" uniqKey="Kim S" first="Soo-Jeong" last="Kim">Soo-Jeong Kim</name><affiliation wicri:level="4"><orgName type="university">Université de Washington</orgName><country>États-Unis</country><placeName><settlement type="city">Seattle</settlement><region type="state">Washington (État)</region></placeName></affiliation><affiliation wicri:level="1"><country wicri:rule="url">États-Unis</country></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Autism Research</title><title level="j" type="alt">AUTISM RESEARCH</title><idno type="ISSN">1939-3792</idno><idno type="eISSN">1939-3806</idno><imprint><biblScope unit="vol">7</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="355">355</biblScope><biblScope unit="page" to="362">362</biblScope><biblScope unit="page-count">8</biblScope><date type="published" when="2014-06">2014-06</date></imprint><idno type="ISSN">1939-3792</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1939-3792</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adult</term><term>Child</term><term>Child Development Disorders, Pervasive (genetics)</term><term>Chromosome Deletion</term><term>Chromosomes, Human, Pair 15 (genetics)</term><term>DNA Copy Number Variations (genetics)</term><term>Female</term><term>Genetic Predisposition to Disease (genetics)</term><term>Humans</term><term>Male</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adulte</term><term>Chromosomes humains de la paire 15 (génétique)</term><term>Délétion de segment de chromosome</term><term>Enfant</term><term>Femelle</term><term>Humains</term><term>Mâle</term><term>Prédisposition génétique à une maladie (génétique)</term><term>Troubles généralisés du développement de l'enfant (génétique)</term><term>Variations de nombre de copies de segment d'ADN (génétique)</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Child Development Disorders, Pervasive</term><term>Chromosomes, Human, Pair 15</term><term>DNA Copy Number Variations</term><term>Genetic Predisposition to Disease</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Chromosomes humains de la paire 15</term><term>Prédisposition génétique à une maladie</term><term>Troubles généralisés du développement de l'enfant</term><term>Variations de nombre de copies de segment d'ADN</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adult</term><term>Child</term><term>Chromosome Deletion</term><term>Female</term><term>Humans</term><term>Male</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Adulte</term><term>Délétion de segment de chromosome</term><term>Enfant</term><term>Femelle</term><term>Humains</term><term>Mâle</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract">The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants (CNVs). Among the rearrangements observed in this region, CNVs from the interval between the common breakpoints 1 and 2 (BP1 and BP2) have been reported cosegregating with autism spectrum disorder (ASD). Although evidence supporting an association between BP1‐BP2 CNVs and autism accumulates, the magnitude of the effect of BP1‐BP2 CNVs remains elusive, posing a great challenge to recurrence‐risk counseling. To gain further insight into their pathogenicity for ASD, we estimated the penetrance of the BP1‐BP2 CNVs for ASD as well as their effects on ASD‐related phenotypes in a well‐characterized ASD sample (n = 2525 families). Transmission disequilibrium test revealed significant preferential transmission only for the duplicated chromosome in probands (20T:9NT). The penetrance of the BP1‐BP2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyses suggest a greater effect of the CNVs on ASD‐related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP1‐BP2 CNVs as risk factors for autism. However, their effect is modest, more akin to that seen for common variants. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1‐BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status. Autism Res 2014, 7: 355–362. © 2014 International Society for Autism Research, Wiley Periodicals, Inc.</div></front></TEI><affiliations><list><country><li>France</li><li>Inde</li><li>États-Unis</li></country><region><li>Californie</li><li>Connecticut</li><li>Illinois</li><li>Massachusetts</li><li>Oregon</li><li>Pennsylvanie</li><li>Rhode Island</li><li>Texas</li><li>Washington (État)</li><li>État de New York</li><li>Île-de-France</li></region><settlement><li>Boston</li><li>Chicago</li><li>Créteil</li><li>Houston</li><li>Los Angeles</li><li>Pittsburgh</li><li>Portland</li><li>Providence (Rhode Island)</li><li>San Francisco</li><li>Seattle</li></settlement><orgName><li>Université Brown</li><li>Université de Washington</li></orgName></list><tree><noCountry><name sortKey="Hus, Vanessa" sort="Hus, Vanessa" uniqKey="Hus V" first="Vanessa" last="Hus">Vanessa Hus</name><name sortKey="Ledbetter, David H" sort="Ledbetter, David H" uniqKey="Ledbetter D" first="David H." last="Ledbetter">David H. Ledbetter</name><name sortKey="Lord, Catherine" sort="Lord, Catherine" uniqKey="Lord C" first="Catherine" last="Lord">Catherine Lord</name><name sortKey="Mane, Shrikant M" sort="Mane, Shrikant M" uniqKey="Mane S" first="Shrikant M." last="Mane">Shrikant M. Mane</name><name sortKey="Martin, Christa Lese" sort="Martin, Christa Lese" uniqKey="Martin C" first="Christa Lese" last="Martin">Christa Lese Martin</name><name sortKey="Martin, Donna M" sort="Martin, Donna M" uniqKey="Martin D" first="Donna M." last="Martin">Donna M. Martin</name><name sortKey="Murtha, Michael T" sort="Murtha, Michael T" uniqKey="Murtha M" first="Michael T." last="Murtha">Michael T. Murtha</name><name sortKey="Sutcliffe, James S" sort="Sutcliffe, James S" uniqKey="Sutcliffe J" first="James S." last="Sutcliffe">James S. Sutcliffe</name></noCountry><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Chaste, Pauline" sort="Chaste, Pauline" uniqKey="Chaste P" first="Pauline" last="Chaste">Pauline Chaste</name></region><name sortKey="Beaudet, Arthur L" sort="Beaudet, Arthur L" uniqKey="Beaudet A" first="Arthur L." last="Beaudet">Arthur L. Beaudet</name><name sortKey="Chaste, Pauline" sort="Chaste, Pauline" uniqKey="Chaste P" first="Pauline" last="Chaste">Pauline Chaste</name><name sortKey="Cook Jr, Edwin H" sort="Cook Jr, Edwin H" uniqKey="Cook Jr E" first="Edwin H." last="Cook Jr.">Edwin H. Cook Jr.</name><name sortKey="Devlin, Bernie" sort="Devlin, Bernie" uniqKey="Devlin B" first="Bernie" last="Devlin">Bernie Devlin</name><name sortKey="Fombonne, Eric" sort="Fombonne, Eric" uniqKey="Fombonne E" first="Eric" last="Fombonne">Eric Fombonne</name><name sortKey="Geschwind, Daniel" sort="Geschwind, Daniel" uniqKey="Geschwind D" first="Daniel" last="Geschwind">Daniel Geschwind</name><name sortKey="Grice, Dorothy E" sort="Grice, Dorothy E" uniqKey="Grice D" first="Dorothy E." last="Grice">Dorothy E. Grice</name><name sortKey="Kim, Soo Eong" sort="Kim, Soo Eong" uniqKey="Kim S" first="Soo-Jeong" last="Kim">Soo-Jeong Kim</name><name sortKey="Kim, Soo Eong" sort="Kim, Soo Eong" uniqKey="Kim S" first="Soo-Jeong" last="Kim">Soo-Jeong Kim</name><name sortKey="Klei, Lambertus" sort="Klei, Lambertus" uniqKey="Klei L" first="Lambertus" last="Klei">Lambertus Klei</name><name sortKey="Lowe, Jennifer K" sort="Lowe, Jennifer K" uniqKey="Lowe J" first="Jennifer K." last="Lowe">Jennifer K. Lowe</name><name sortKey="Mohan, Kommu N" sort="Mohan, Kommu N" uniqKey="Mohan K" first="Kommu N." last="Mohan">Kommu N. Mohan</name><name sortKey="Moreno E Uca, Daniel" sort="Moreno E Uca, Daniel" uniqKey="Moreno E Uca D" first="Daniel" last="Moreno-De-Luca">Daniel Moreno-De-Luca</name><name sortKey="Morrow, Eric M" sort="Morrow, Eric M" uniqKey="Morrow E" first="Eric M." last="Morrow">Eric M. Morrow</name><name sortKey="Morrow, Eric M" sort="Morrow, Eric M" uniqKey="Morrow E" first="Eric M." last="Morrow">Eric M. Morrow</name><name sortKey="Sanders, Stephan J" sort="Sanders, Stephan J" uniqKey="Sanders S" first="Stephan J." last="Sanders">Stephan J. Sanders</name><name sortKey="Sanders, Stephan J" sort="Sanders, Stephan J" uniqKey="Sanders S" first="Stephan J." last="Sanders">Stephan J. Sanders</name><name sortKey="Song, Youeun" sort="Song, Youeun" uniqKey="Song Y" first="Youeun" last="Song">Youeun Song</name><name sortKey="State, Matthew W" sort="State, Matthew W" uniqKey="State M" first="Matthew W." last="State">Matthew W. State</name><name sortKey="State, Matthew W" sort="State, Matthew W" uniqKey="State M" first="Matthew W." last="State">Matthew W. State</name><name sortKey="Walsh, Christopher A" sort="Walsh, Christopher A" uniqKey="Walsh C" first="Christopher A." last="Walsh">Christopher A. Walsh</name><name sortKey="Willsey, A Jeremy" sort="Willsey, A Jeremy" uniqKey="Willsey A" first="A. Jeremy" last="Willsey">A. Jeremy Willsey</name><name sortKey="Willsey, A Jeremy" sort="Willsey, A Jeremy" uniqKey="Willsey A" first="A. Jeremy" last="Willsey">A. Jeremy Willsey</name><name sortKey="Yu, Timothy W" sort="Yu, Timothy W" uniqKey="Yu T" first="Timothy W." last="Yu">Timothy W. Yu</name></country><country name="France"><region name="Île-de-France"><name sortKey="Chaste, Pauline" sort="Chaste, Pauline" uniqKey="Chaste P" first="Pauline" last="Chaste">Pauline Chaste</name></region></country><country name="Inde"><noRegion><name sortKey="Mohan, Kommu N" sort="Mohan, Kommu N" uniqKey="Mohan K" first="Kommu N." last="Mohan">Kommu N. Mohan</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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