• PMID: 31479588
• Gene Name: DMRT1
• Condition: Sertoli cell only syndrome
• Association: Associated
• Mutation: c.671A>G p.(Asn224Ser)
• Population size: 16
• Population details: 23 non-obstructive azoospermia
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS

Sequence analysis of 37 candidate genes for male infertility: challenges in variant assessment and validating genes

Araujo TF, Friedrich C, Grangeiro CHP, Martelli LR, Grzesiuk JD, Emich J, Wyrwoll MJ, Kliesch S, Simões AL, Tüttelmann F.

BACKGROUND: The routine genetic analysis for diagnosing male infertility has not changed over the last twenty years, and currently available tests can only determine the etiology of 4% of unselected infertile patients. Thus, to create new diagnostic assays, we must better understand the molecular and genetic mechanisms of male infertility. Although next-generation sequencing allows for simultaneous analysis of hundreds of genes and the discovery of novel candidates related to male infertility, so far only a few gene candidates have enough sound evidence to support the gene-disease relationship. OBJECTIVE: Since complementary studies are required to validate genes, we aimed to analyze the presence of potentially pathogenic rare variants in a set of candidate genes related to azoospermia in a hitherto understudied South American population. SUBJECTS AND METHODS: We performed whole exome sequencing in a group of 16 patients with non-obstructive azoospermia from Ribeirão Preto, Brazil. Based on a recent systematic review of monogenic causes of male infertility, we selected a set of 37 genes related to azoospermia, Sertoli-Cell-Only histology, and spermatogenic arrest to analyze. The identified variants were confirmed by Sanger sequencing, and their functional consequence was predicted by in silico programs. RESULTS: We identified potential pathogenic variants in seven genes in six patients. Two variants, c.671A>G (p.(Asn224Ser)) in DMRT1 and c.91C>T (p.(Arg31Cys)) in REC8, have already been described in association with azoospermia. We also found new variants in genes that already have moderate evidence of being linked to spermatogenic failure (TEX15, KLHL10), in genes with limited evidence (DNMT3B, TEX14) and in one novel promising candidate gene that has no evidence so far (SYCE1L). DISCUSSION: Although this study included a small number of patients, the process of rationally selecting genes allowed us to detect rare potentially pathogenic variants, providing supporting evidence for validating candidate genes associated with azoospermia. CI - © 2020 The Authors. Andrology published by Wiley Periodicals, Inc. on behalf of American Society of Andrology and European Academy of Andrology. FAU - Araujo, T F AU - Araujo TF AD - Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, SP, Brazil. FAU - Friedrich, C AU - Friedrich C AD - Institute of Human Genetics, University of Münster, Münster, Germany. FAU - Grangeiro, C H P AU - Grangeiro CHP AD - Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, SP, Brazil. FAU - Martelli, L R AU - Martelli LR AD - Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, SP, Brazil. FAU - Grzesiuk, J D AU - Grzesiuk JD AD - Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, SP, Brazil. FAU - Emich, J AU - Emich J AD - Institute of Human Genetics, University of Münster, Münster, Germany. FAU - Wyrwoll, M J AU - Wyrwoll MJ AD - Institute of Human Genetics, University of Münster, Münster, Germany. FAU - Kliesch, S AU - Kliesch S AD - Centre of Reproductive Medicine and Andrology, Department of Clinical and Surgical Andrology, University Hospital Münster, Münster, Germany. FAU - Simões, A L AU - Simões AL AD - Department of Genetics, Ribeirão Preto Medical School, University of São Paulo (USP), Ribeirão Preto, SP, Brazil.