Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype
Identifieur interne : 005159 ( Main/Exploration ); précédent : 005158; suivant : 005160Rapid identification of mutations in GJC2 in primary lymphoedema using whole exome sequencing combined with linkage analysis with delineation of the phenotype
Auteurs : Pia Ostergaard [Royaume-Uni] ; Michael A. Simpson [Royaume-Uni] ; Glen Brice [Royaume-Uni] ; Sahar Mansour [Royaume-Uni] ; Fiona C. Connell [Royaume-Uni] ; Alexandros Onoufriadis [Royaume-Uni] ; Anne H. Child [Royaume-Uni] ; Jae Hwang [Royaume-Uni] ; Kamini Kalidas [Royaume-Uni] ; Peter S. Mortimer [Royaume-Uni] ; Richard Trembath [Royaume-Uni] ; Steve Jeffery [Royaume-Uni]Source :
- Journal of Medical Genetics [ 0022-2593 ] ; 2011-04.
Descripteurs français
- KwdFr :
- MESH :
- génétique : Connexines, Maladies lymphatiques.
- Analyse de séquence d'ADN, Femelle, Humains, Liaison génétique, Mutation, Mâle, Pedigree, Phénotype.
- Pascal (Inist)
- Wicri :
English descriptors
- KwdEn :
- MESH :
- chemical , genetics : Connexins.
- genetics : Lymphatic Diseases.
- Female, Genetic Linkage, Humans, Male, Mutation, Pedigree, Phenotype, Sequence Analysis, DNA.
Abstract
Background Primary lymphoedema describes a chronic, frequently progressive, failure of lymphatic drainage. This disorder is frequently genetic in origin, and a multigenerational family in which eight individuals developed postnatal lymphoedema of all four limbs was ascertained from the joint Lymphoedema/Genetic clinic at St George's Hospital. Methods Linkage analysis was used to determine a locus, and exome sequencing was employed to look for causative variants. Results Linkage analysis revealed cosegregation of a 16.1 Mb haplotype on chromosome 1q42 that contained 173 known or predicted genes. Whole exome sequencing in a single affected individual was undertaken, and the search for the causative variant was focused to within the linkage interval. This approach revealed two novel non-synonymous single nucleotide substitutions within the chromosome 1 locus, in NVL and GJC2. NVL and GJC2 were sequenced in an additional cohort of individuals with a similar phenotype and non-synonymous variants were found in GJC2 in four additional families. Conclusion This report demonstrates the power of exome sequencing efficiently applied to a traditional positional cloning pipeline in disease gene discovery, and suggests that the phenotype produced by GJC2 mutations is predominantly one of 4 limb lymphoedema.
Url:
DOI: 10.1136/jmg.2010.085563
Affiliations:
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Simpson</name><affiliation wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Medical and Molecular Genetics, King's College London, School of Medicine, Guy's Hospital, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Brice, Glen" sort="Brice, Glen" uniqKey="Brice G" first="Glen" last="Brice">Glen Brice</name><affiliation wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Southwest Thames Regional Genetics Service, St. George's, University of London, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region><settlement type="city">Londres</settlement></placeName><orgName type="university">Université de Londres</orgName></affiliation></author><author><name sortKey="Mansour, Sahar" sort="Mansour, Sahar" uniqKey="Mansour S" first="Sahar" last="Mansour">Sahar Mansour</name><affiliation wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Southwest Thames Regional Genetics Service, St. George's, University of London, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region><settlement type="city">Londres</settlement></placeName><orgName type="university">Université de Londres</orgName></affiliation></author><author><name sortKey="Connell, Fiona C" sort="Connell, Fiona C" uniqKey="Connell F" first="Fiona C" last="Connell">Fiona C. Connell</name><affiliation wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Clinical Genetics Department, Guy's Hospital, NHS Foundation Trust, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Onoufriadis, Alexandros" sort="Onoufriadis, Alexandros" uniqKey="Onoufriadis A" first="Alexandros" last="Onoufriadis">Alexandros Onoufriadis</name><affiliation wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Medical and Molecular Genetics, King's College London, School of Medicine, Guy's Hospital, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Child, Anne H" sort="Child, Anne H" uniqKey="Child A" first="Anne H" last="Child">Anne H. Child</name><affiliation wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Cardiac and Vascular Sciences, St George's, University of London, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region><settlement type="city">Londres</settlement></placeName><orgName type="university">Université de Londres</orgName></affiliation></author><author><name sortKey="Hwang, Jae" sort="Hwang, Jae" uniqKey="Hwang J" first="Jae" last="Hwang">Jae Hwang</name><affiliation wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Medical Genetics, St George's, University of London, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region><settlement type="city">Londres</settlement></placeName><orgName type="university">Université de Londres</orgName></affiliation></author><author><name sortKey="Kalidas, Kamini" sort="Kalidas, Kamini" uniqKey="Kalidas K" first="Kamini" last="Kalidas">Kamini Kalidas</name><affiliation wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Medical Genetics, St George's, University of London, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region><settlement type="city">Londres</settlement></placeName><orgName type="university">Université de Londres</orgName></affiliation></author><author><name sortKey="Mortimer, Peter S" sort="Mortimer, Peter S" uniqKey="Mortimer P" first="Peter S" last="Mortimer">Peter S. Mortimer</name><affiliation wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Cardiac and Vascular Sciences (Dermatology), St George's, University of London, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region><settlement type="city">Londres</settlement></placeName><orgName type="university">Université de Londres</orgName></affiliation></author><author><name sortKey="Trembath, Richard" sort="Trembath, Richard" uniqKey="Trembath R" first="Richard" last="Trembath">Richard Trembath</name><affiliation wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Medical and Molecular Genetics, King's College London, School of Medicine, Guy's Hospital, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Jeffery, Steve" sort="Jeffery, Steve" uniqKey="Jeffery S" first="Steve" last="Jeffery">Steve Jeffery</name><affiliation wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Medical Genetics, St George's, University of London, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region><settlement type="city">Londres</settlement></placeName><orgName type="university">Université de Londres</orgName></affiliation><affiliation wicri:level="1"><country wicri:rule="url">Royaume-Uni</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of Medical Genetics</title><title level="j" type="abbrev">J Med Genet</title><idno type="ISSN">0022-2593</idno><idno type="eISSN">1468-6244</idno><imprint><publisher>BMJ Publishing Group Ltd</publisher><date type="published" when="2011-04">2011-04</date><biblScope unit="volume">48</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="251">251</biblScope></imprint><idno type="ISSN">0022-2593</idno></series><idno type="istex">3FA5E98CD0874AF184905D58C4811A1243E29835</idno><idno type="DOI">10.1136/jmg.2010.085563</idno><idno type="href">jmedgenet-48-251.pdf</idno><idno type="ArticleID">jmedgenet85563</idno><idno type="PMID">21266381</idno><idno type="local">jmedgenet;48/4/251</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-2593</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Connexins (genetics)</term><term>Female</term><term>Genetic Linkage</term><term>Genetic determinism</term><term>Genetic linkage</term><term>Genetic mapping</term><term>Genetics</term><term>Human</term><term>Humans</term><term>Identification</term><term>Lymphatic Diseases (genetics)</term><term>Lymphedema</term><term>Male</term><term>Mutation</term><term>Nucleotide sequence</term><term>Pathogenesis</term><term>Pedigree</term><term>Phenotype</term><term>Sequence Analysis, DNA</term><term>Sequencing</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Analyse de séquence d'ADN</term><term>Connexines (génétique)</term><term>Femelle</term><term>Humains</term><term>Liaison génétique</term><term>Maladies lymphatiques (génétique)</term><term>Mutation</term><term>Mâle</term><term>Pedigree</term><term>Phénotype</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Connexins</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Lymphatic Diseases</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Connexines</term><term>Maladies lymphatiques</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Female</term><term>Genetic Linkage</term><term>Humans</term><term>Male</term><term>Mutation</term><term>Pedigree</term><term>Phenotype</term><term>Sequence Analysis, DNA</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Analyse de séquence d'ADN</term><term>Femelle</term><term>Humains</term><term>Liaison génétique</term><term>Mutation</term><term>Mâle</term><term>Pedigree</term><term>Phénotype</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Carte génétique</term><term>Déterminisme génétique</term><term>Génétique</term><term>Homme</term><term>Identification</term><term>Liaison génétique</term><term>Lymphoedème</term><term>Mutation</term><term>Pathogénie</term><term>Phénotype</term><term>Séquence nucléotide</term><term>Séquençage</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Génétique</term><term>Homme</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Background Primary lymphoedema describes a chronic, frequently progressive, failure of lymphatic drainage. This disorder is frequently genetic in origin, and a multigenerational family in which eight individuals developed postnatal lymphoedema of all four limbs was ascertained from the joint Lymphoedema/Genetic clinic at St George's Hospital. Methods Linkage analysis was used to determine a locus, and exome sequencing was employed to look for causative variants. Results Linkage analysis revealed cosegregation of a 16.1 Mb haplotype on chromosome 1q42 that contained 173 known or predicted genes. Whole exome sequencing in a single affected individual was undertaken, and the search for the causative variant was focused to within the linkage interval. This approach revealed two novel non-synonymous single nucleotide substitutions within the chromosome 1 locus, in NVL and GJC2. NVL and GJC2 were sequenced in an additional cohort of individuals with a similar phenotype and non-synonymous variants were found in GJC2 in four additional families. Conclusion This report demonstrates the power of exome sequencing efficiently applied to a traditional positional cloning pipeline in disease gene discovery, and suggests that the phenotype produced by GJC2 mutations is predominantly one of 4 limb lymphoedema.</div></front></TEI><affiliations><list><country><li>Royaume-Uni</li></country><region><li>Angleterre</li><li>Grand Londres</li></region><settlement><li>Londres</li></settlement><orgName><li>Université de Londres</li></orgName></list><tree><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Ostergaard, Pia" sort="Ostergaard, Pia" uniqKey="Ostergaard P" first="Pia" last="Ostergaard">Pia Ostergaard</name></region><name sortKey="Brice, Glen" sort="Brice, Glen" uniqKey="Brice G" first="Glen" last="Brice">Glen Brice</name><name sortKey="Child, Anne H" sort="Child, Anne H" uniqKey="Child A" first="Anne H" last="Child">Anne H. Child</name><name sortKey="Connell, Fiona C" sort="Connell, Fiona C" uniqKey="Connell F" first="Fiona C" last="Connell">Fiona C. Connell</name><name sortKey="Hwang, Jae" sort="Hwang, Jae" uniqKey="Hwang J" first="Jae" last="Hwang">Jae Hwang</name><name sortKey="Jeffery, Steve" sort="Jeffery, Steve" uniqKey="Jeffery S" first="Steve" last="Jeffery">Steve Jeffery</name><name sortKey="Jeffery, Steve" sort="Jeffery, Steve" uniqKey="Jeffery S" first="Steve" last="Jeffery">Steve Jeffery</name><name sortKey="Kalidas, Kamini" sort="Kalidas, Kamini" uniqKey="Kalidas K" first="Kamini" last="Kalidas">Kamini Kalidas</name><name sortKey="Mansour, Sahar" sort="Mansour, Sahar" uniqKey="Mansour S" first="Sahar" last="Mansour">Sahar Mansour</name><name sortKey="Mortimer, Peter S" sort="Mortimer, Peter S" uniqKey="Mortimer P" first="Peter S" last="Mortimer">Peter S. Mortimer</name><name sortKey="Onoufriadis, Alexandros" sort="Onoufriadis, Alexandros" uniqKey="Onoufriadis A" first="Alexandros" last="Onoufriadis">Alexandros Onoufriadis</name><name sortKey="Simpson, Michael A" sort="Simpson, Michael A" uniqKey="Simpson M" first="Michael A" last="Simpson">Michael A. Simpson</name><name sortKey="Trembath, Richard" sort="Trembath, Richard" uniqKey="Trembath R" first="Richard" last="Trembath">Richard Trembath</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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