Validation and application of a novel integrated genetic screening method to a cohort of 1,112 men with idiopathic azoospermia or severe oligozoospermia.
Identifieur interne : 000082 ( Main/Exploration ); précédent : 000081; suivant : 000083Validation and application of a novel integrated genetic screening method to a cohort of 1,112 men with idiopathic azoospermia or severe oligozoospermia.
Auteurs : Manon S. Oud [Pays-Bas] ; Liliana Ramos [Pays-Bas] ; Moira K. O'Bryan [Australie] ; Robert I. Mclachlan [Australie] ; Özlem Okutman [France] ; Stephane Viville [France] ; Petra F. De Vries [Pays-Bas] ; Dominique F C M. Smeets [Pays-Bas] ; Dorien Lugtenberg [Pays-Bas] ; Jayne Y. Hehir-Kwa [Pays-Bas] ; Christian Gilissen [Pays-Bas] ; Maartje Van De Vorst [Pays-Bas] ; Lisenka E L M. Vissers [Pays-Bas] ; Alexander Hoischen [Pays-Bas] ; Aukje M. Meijerink [Pays-Bas] ; Kathrin Fleischer [Pays-Bas] ; Joris A. Veltman [Pays-Bas] ; Michiel J. Noordam [Pays-Bas]Source :
- Human mutation [ 1098-1004 ] ; 2017.
Abstract
Microdeletions of the Y chromosome (YCMs), Klinefelter syndrome (47,XXY), and CFTR mutations are known genetic causes of severe male infertility, but the majority of cases remain idiopathic. Here, we describe a novel method using single molecule Molecular Inversion Probes (smMIPs), to screen infertile men for mutations and copy number variations affecting known disease genes. We designed a set of 4,525 smMIPs targeting the coding regions of causal (n = 6) and candidate (n = 101) male infertility genes. After extensive validation, we screened 1,112 idiopathic infertile men with non-obstructive azoospermia or severe oligozoospermia. In addition to five chromosome YCMs and six other sex chromosomal anomalies, we identified five patients with rare recessive mutations in CFTR as well as a patient with a rare heterozygous frameshift mutation in SYCP3 that may be of clinical relevance. This results in a genetic diagnosis in 11-17 patients (1%-1.5%), a yield that may increase significantly when more genes are confidently linked to male infertility. In conclusion, we developed a flexible and scalable method to reliably detect genetic causes of male infertility. The assay consolidates the detection of different types of genetic variation while increasing the diagnostic yield and detection precision at the same or lower price compared with currently used methods.
DOI: 10.1002/humu.23312
PubMed: 28801929
Affiliations:
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Oud</name><affiliation wicri:level="3"><nlm:affiliation>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Ramos, Liliana" sort="Ramos, Liliana" uniqKey="Ramos L" first="Liliana" last="Ramos">Liliana Ramos</name><affiliation wicri:level="3"><nlm:affiliation>Department of Gynaecology and Obstetrics, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Gynaecology and Obstetrics, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="O Bryan, Moira K" sort="O Bryan, Moira K" uniqKey="O Bryan M" first="Moira K" last="O'Bryan">Moira K. 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De Vries</name><affiliation wicri:level="3"><nlm:affiliation>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Smeets, Dominique F C M" sort="Smeets, Dominique F C M" uniqKey="Smeets D" first="Dominique F C M" last="Smeets">Dominique F C M. 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Hehir-Kwa</name><affiliation wicri:level="3"><nlm:affiliation>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Gilissen, Christian" sort="Gilissen, Christian" uniqKey="Gilissen C" first="Christian" last="Gilissen">Christian Gilissen</name><affiliation wicri:level="3"><nlm:affiliation>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Van De Vorst, Maartje" sort="Van De Vorst, Maartje" uniqKey="Van De Vorst M" first="Maartje" last="Van De Vorst">Maartje Van De Vorst</name><affiliation wicri:level="3"><nlm:affiliation>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Vissers, Lisenka E L M" sort="Vissers, Lisenka E L M" uniqKey="Vissers L" first="Lisenka E L M" last="Vissers">Lisenka E L M. Vissers</name><affiliation wicri:level="3"><nlm:affiliation>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Hoischen, Alexander" sort="Hoischen, Alexander" uniqKey="Hoischen A" first="Alexander" last="Hoischen">Alexander Hoischen</name><affiliation wicri:level="3"><nlm:affiliation>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Meijerink, Aukje M" sort="Meijerink, Aukje M" uniqKey="Meijerink A" first="Aukje M" last="Meijerink">Aukje M. Meijerink</name><affiliation wicri:level="3"><nlm:affiliation>Department of Gynaecology and Obstetrics, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Gynaecology and Obstetrics, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Fleischer, Kathrin" sort="Fleischer, Kathrin" uniqKey="Fleischer K" first="Kathrin" last="Fleischer">Kathrin Fleischer</name><affiliation wicri:level="3"><nlm:affiliation>Department of Gynaecology and Obstetrics, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Gynaecology and Obstetrics, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Veltman, Joris A" sort="Veltman, Joris A" uniqKey="Veltman J" first="Joris A" last="Veltman">Joris A. Veltman</name><affiliation wicri:level="3"><nlm:affiliation>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Noordam, Michiel J" sort="Noordam, Michiel J" uniqKey="Noordam M" first="Michiel J" last="Noordam">Michiel J. Noordam</name><affiliation wicri:level="1"><nlm:affiliation>Department of Genetics and Cell Biology, Maastricht UMC+, Maastricht, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Genetics and Cell Biology, Maastricht UMC+, Maastricht</wicri:regionArea><wicri:noRegion>Maastricht</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2017">2017</date><idno type="RBID">pubmed:28801929</idno><idno type="pmid">28801929</idno><idno type="doi">10.1002/humu.23312</idno><idno type="wicri:Area/PubMed/Corpus">000191</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000191</idno><idno type="wicri:Area/PubMed/Curation">000191</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000191</idno><idno type="wicri:Area/PubMed/Checkpoint">000191</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000191</idno><idno type="wicri:Area/Ncbi/Merge">004C81</idno><idno type="wicri:Area/Ncbi/Curation">004C81</idno><idno type="wicri:Area/Ncbi/Checkpoint">004C81</idno><idno type="wicri:Area/Main/Merge">000077</idno><idno type="wicri:Area/Main/Curation">000082</idno><idno type="wicri:Area/Main/Exploration">000082</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Validation and application of a novel integrated genetic screening method to a cohort of 1,112 men with idiopathic azoospermia or severe oligozoospermia.</title><author><name sortKey="Oud, Manon S" sort="Oud, Manon S" uniqKey="Oud M" first="Manon S" last="Oud">Manon S. Oud</name><affiliation wicri:level="3"><nlm:affiliation>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Ramos, Liliana" sort="Ramos, Liliana" uniqKey="Ramos L" first="Liliana" last="Ramos">Liliana Ramos</name><affiliation wicri:level="3"><nlm:affiliation>Department of Gynaecology and Obstetrics, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Gynaecology and Obstetrics, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="O Bryan, Moira K" sort="O Bryan, Moira K" uniqKey="O Bryan M" first="Moira K" last="O'Bryan">Moira K. O'Bryan</name><affiliation wicri:level="1"><nlm:affiliation>The Development and Stem Cells Program of Monash Biomedicine Discovery Institute, Monash University, Clayton, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>The Development and Stem Cells Program of Monash Biomedicine Discovery Institute, Monash University, Clayton</wicri:regionArea><wicri:noRegion>Clayton</wicri:noRegion></affiliation></author><author><name sortKey="Mclachlan, Robert I" sort="Mclachlan, Robert I" uniqKey="Mclachlan R" first="Robert I" last="Mclachlan">Robert I. Mclachlan</name><affiliation wicri:level="1"><nlm:affiliation>Hudson Institute of Medical Research, Monash University, Clayton, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Hudson Institute of Medical Research, Monash University, Clayton</wicri:regionArea><wicri:noRegion>Clayton</wicri:noRegion></affiliation></author><author><name sortKey="Okutman, Ozlem" sort="Okutman, Ozlem" uniqKey="Okutman O" first="Özlem" last="Okutman">Özlem Okutman</name><affiliation wicri:level="3"><nlm:affiliation>Laboratory of Genetic Diagnostics, UF3472-Genetics of Infertility, University Hospital Strasbourg, Strasbourg, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Laboratory of Genetic Diagnostics, UF3472-Genetics of Infertility, University Hospital Strasbourg, Strasbourg</wicri:regionArea><placeName><region type="region">Grand Est</region><region type="old region">Alsace (région administrative)</region><settlement type="city">Strasbourg</settlement></placeName></affiliation></author><author><name sortKey="Viville, Stephane" sort="Viville, Stephane" uniqKey="Viville S" first="Stephane" last="Viville">Stephane Viville</name><affiliation wicri:level="3"><nlm:affiliation>Laboratory of Genetic Diagnostics, UF3472-Genetics of Infertility, University Hospital Strasbourg, Strasbourg, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Laboratory of Genetic Diagnostics, UF3472-Genetics of Infertility, University Hospital Strasbourg, Strasbourg</wicri:regionArea><placeName><region type="region">Grand Est</region><region type="old region">Alsace (région administrative)</region><settlement type="city">Strasbourg</settlement></placeName></affiliation></author><author><name sortKey="De Vries, Petra F" sort="De Vries, Petra F" uniqKey="De Vries P" first="Petra F" last="De Vries">Petra F. De Vries</name><affiliation wicri:level="3"><nlm:affiliation>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Smeets, Dominique F C M" sort="Smeets, Dominique F C M" uniqKey="Smeets D" first="Dominique F C M" last="Smeets">Dominique F C M. Smeets</name><affiliation wicri:level="3"><nlm:affiliation>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Lugtenberg, Dorien" sort="Lugtenberg, Dorien" uniqKey="Lugtenberg D" first="Dorien" last="Lugtenberg">Dorien Lugtenberg</name><affiliation wicri:level="3"><nlm:affiliation>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Hehir Kwa, Jayne Y" sort="Hehir Kwa, Jayne Y" uniqKey="Hehir Kwa J" first="Jayne Y" last="Hehir-Kwa">Jayne Y. Hehir-Kwa</name><affiliation wicri:level="3"><nlm:affiliation>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Gilissen, Christian" sort="Gilissen, Christian" uniqKey="Gilissen C" first="Christian" last="Gilissen">Christian Gilissen</name><affiliation wicri:level="3"><nlm:affiliation>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Van De Vorst, Maartje" sort="Van De Vorst, Maartje" uniqKey="Van De Vorst M" first="Maartje" last="Van De Vorst">Maartje Van De Vorst</name><affiliation wicri:level="3"><nlm:affiliation>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Vissers, Lisenka E L M" sort="Vissers, Lisenka E L M" uniqKey="Vissers L" first="Lisenka E L M" last="Vissers">Lisenka E L M. Vissers</name><affiliation wicri:level="3"><nlm:affiliation>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Hoischen, Alexander" sort="Hoischen, Alexander" uniqKey="Hoischen A" first="Alexander" last="Hoischen">Alexander Hoischen</name><affiliation wicri:level="3"><nlm:affiliation>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Meijerink, Aukje M" sort="Meijerink, Aukje M" uniqKey="Meijerink A" first="Aukje M" last="Meijerink">Aukje M. Meijerink</name><affiliation wicri:level="3"><nlm:affiliation>Department of Gynaecology and Obstetrics, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Gynaecology and Obstetrics, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Fleischer, Kathrin" sort="Fleischer, Kathrin" uniqKey="Fleischer K" first="Kathrin" last="Fleischer">Kathrin Fleischer</name><affiliation wicri:level="3"><nlm:affiliation>Department of Gynaecology and Obstetrics, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Gynaecology and Obstetrics, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Veltman, Joris A" sort="Veltman, Joris A" uniqKey="Veltman J" first="Joris A" last="Veltman">Joris A. Veltman</name><affiliation wicri:level="3"><nlm:affiliation>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboudumc, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Noordam, Michiel J" sort="Noordam, Michiel J" uniqKey="Noordam M" first="Michiel J" last="Noordam">Michiel J. Noordam</name><affiliation wicri:level="1"><nlm:affiliation>Department of Genetics and Cell Biology, Maastricht UMC+, Maastricht, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Genetics and Cell Biology, Maastricht UMC+, Maastricht</wicri:regionArea><wicri:noRegion>Maastricht</wicri:noRegion></affiliation></author></analytic><series><title level="j">Human mutation</title><idno type="eISSN">1098-1004</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Microdeletions of the Y chromosome (YCMs), Klinefelter syndrome (47,XXY), and CFTR mutations are known genetic causes of severe male infertility, but the majority of cases remain idiopathic. Here, we describe a novel method using single molecule Molecular Inversion Probes (smMIPs), to screen infertile men for mutations and copy number variations affecting known disease genes. We designed a set of 4,525 smMIPs targeting the coding regions of causal (n = 6) and candidate (n = 101) male infertility genes. After extensive validation, we screened 1,112 idiopathic infertile men with non-obstructive azoospermia or severe oligozoospermia. In addition to five chromosome YCMs and six other sex chromosomal anomalies, we identified five patients with rare recessive mutations in CFTR as well as a patient with a rare heterozygous frameshift mutation in SYCP3 that may be of clinical relevance. This results in a genetic diagnosis in 11-17 patients (1%-1.5%), a yield that may increase significantly when more genes are confidently linked to male infertility. In conclusion, we developed a flexible and scalable method to reliably detect genetic causes of male infertility. The assay consolidates the detection of different types of genetic variation while increasing the diagnostic yield and detection precision at the same or lower price compared with currently used methods.</div></front></TEI><affiliations><list><country><li>Australie</li><li>France</li><li>Pays-Bas</li></country><region><li>Alsace (région administrative)</li><li>Grand Est</li><li>Gueldre</li></region><settlement><li>Nimègue</li><li>Strasbourg</li></settlement></list><tree><country name="Pays-Bas"><region name="Gueldre"><name sortKey="Oud, Manon S" sort="Oud, Manon S" uniqKey="Oud M" first="Manon S" last="Oud">Manon S. Oud</name></region><name sortKey="De Vries, Petra F" sort="De Vries, Petra F" uniqKey="De Vries P" first="Petra F" last="De Vries">Petra F. De Vries</name><name sortKey="Fleischer, Kathrin" sort="Fleischer, Kathrin" uniqKey="Fleischer K" first="Kathrin" last="Fleischer">Kathrin Fleischer</name><name sortKey="Gilissen, Christian" sort="Gilissen, Christian" uniqKey="Gilissen C" first="Christian" last="Gilissen">Christian Gilissen</name><name sortKey="Hehir Kwa, Jayne Y" sort="Hehir Kwa, Jayne Y" uniqKey="Hehir Kwa J" first="Jayne Y" last="Hehir-Kwa">Jayne Y. Hehir-Kwa</name><name sortKey="Hoischen, Alexander" sort="Hoischen, Alexander" uniqKey="Hoischen A" first="Alexander" last="Hoischen">Alexander Hoischen</name><name sortKey="Lugtenberg, Dorien" sort="Lugtenberg, Dorien" uniqKey="Lugtenberg D" first="Dorien" last="Lugtenberg">Dorien Lugtenberg</name><name sortKey="Meijerink, Aukje M" sort="Meijerink, Aukje M" uniqKey="Meijerink A" first="Aukje M" last="Meijerink">Aukje M. Meijerink</name><name sortKey="Noordam, Michiel J" sort="Noordam, Michiel J" uniqKey="Noordam M" first="Michiel J" last="Noordam">Michiel J. Noordam</name><name sortKey="Ramos, Liliana" sort="Ramos, Liliana" uniqKey="Ramos L" first="Liliana" last="Ramos">Liliana Ramos</name><name sortKey="Smeets, Dominique F C M" sort="Smeets, Dominique F C M" uniqKey="Smeets D" first="Dominique F C M" last="Smeets">Dominique F C M. Smeets</name><name sortKey="Van De Vorst, Maartje" sort="Van De Vorst, Maartje" uniqKey="Van De Vorst M" first="Maartje" last="Van De Vorst">Maartje Van De Vorst</name><name sortKey="Veltman, Joris A" sort="Veltman, Joris A" uniqKey="Veltman J" first="Joris A" last="Veltman">Joris A. Veltman</name><name sortKey="Vissers, Lisenka E L M" sort="Vissers, Lisenka E L M" uniqKey="Vissers L" first="Lisenka E L M" last="Vissers">Lisenka E L M. Vissers</name></country><country name="Australie"><noRegion><name sortKey="O Bryan, Moira K" sort="O Bryan, Moira K" uniqKey="O Bryan M" first="Moira K" last="O'Bryan">Moira K. O'Bryan</name></noRegion><name sortKey="Mclachlan, Robert I" sort="Mclachlan, Robert I" uniqKey="Mclachlan R" first="Robert I" last="Mclachlan">Robert I. Mclachlan</name></country><country name="France"><region name="Grand Est"><name sortKey="Okutman, Ozlem" sort="Okutman, Ozlem" uniqKey="Okutman O" first="Özlem" last="Okutman">Özlem Okutman</name></region><name sortKey="Viville, Stephane" sort="Viville, Stephane" uniqKey="Viville S" first="Stephane" last="Viville">Stephane Viville</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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