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Validation and application of a novel integrated genetic screening method to a cohort of 1,112 men with idiopathic azoospermia or severe oligozoospermia
Author(s) -
Oud Ma S.,
Ramos Liliana,
O'Bryan Moira K.,
McLachlan Robert I.,
Okutman Özlem,
Viville Stephane,
Vries Petra F.,
Smeets Dominique F.C.M.,
Lugtenberg Dorien,
HehirKwa Jayne Y.,
Gilissen Christian,
de Vorst Maartje,
Vissers Lisenka E.L.M.,
Hoischen Alexander,
Meijerink Aukje M.,
Fleischer Kathrin,
Veltman Joris A.,
Noordam Michiel J.
Publication year - 2017
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23312
Subject(s) - azoospermia , male infertility , biology , infertility , genetics , frameshift mutation , human genetics , gene , mutation , pregnancy
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.