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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

Lookup NU author(s): Professor Joris VeltmanORCiD


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© 2017 Wiley Periodicals, Inc. 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.

Publication metadata

Author(s): Oud MS, Ramos L, O'Bryan MK, Mclachlan RI, Okutman O, Viville S, de Vries PF, Smeets DF, Lugtenberg D, Hehir-Kwa JY, Gilissen C, van de Vorst M, Vissers LE, Hoischen A, Meijerink AM, Fleischer K, Veltman JA, Noordam MJ

Publication type: Article

Publication status: Published

Journal: Human Mutation

Year: 2017

Volume: 38

Issue: 11

Pages: 1592-1605

Print publication date: 01/11/2017

Online publication date: 11/08/2017

Acceptance date: 08/08/2017

ISSN (print): 1059-7794

ISSN (electronic): 1098-1004

Publisher: John Wiley and Sons Inc.


DOI: 10.1002/humu.23312


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