Point-of-care whole-exome sequencing of idiopathic male infertility

• Published in: Genetics in medicine Vol. 20; no. 11; pp. 1365 - 1373
• Main Authors: Fakhro, Khalid A, Elbardisi, Haitham, Arafa, Mohamed, Robay, Amal, Rodriguez-Flores, Juan L, Al-Shakaki, Alya, Syed, Najeeb, Mezey, Jason G, Abi Khalil, Charbel, Malek, Joel A, Al-Ansari, Abdulla, Al Said, Sami, Crystal, Ronald G
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2018; Elsevier Limited
• Subjects: Adult; Azoospermia - epidemiology; Azoospermia - genetics; Azoospermia - physiopathology; Biomedical and Life Sciences; Biomedicine; Cell Cycle Proteins - genetics; Consanguinity; Endodeoxyribonucleases - genetics; Genetic Association Studies; Genetic Predisposition to Disease; Human Genetics; Humans; Infertility, Male - epidemiology; Infertility, Male - genetics; Infertility, Male - physiopathology; Laboratory Medicine; Male; Middle East; Mutation; Nuclear Proteins - genetics; Pedigree; Polymorphism, Single Nucleotide - genetics; Protein Serine-Threonine Kinases - genetics; RNA-Binding Proteins - genetics; Spermatogenesis - genetics; Transcription Factors - genetics; Whole Exome Sequencing; Middle East; male infertility; nonobstructive azoospermia; whole-exome sequencing; disease genetics; spermatogenic failure
• DOI: 10.1038/gim.2018.10
• ISSN: 1098-3600; 1530-0366

Purpose Nonobstructive azoospermia (NOA) affects 1% of the male population; however, despite state-of-the-art clinical assessment, for most patients the cause is unknown. We capitalized on an analysis of multiplex families in the Middle East to identify highly penetrant genetic causes. Methods We used whole-exome sequencing (WES) in 8 consanguineous families and combined newly discovered genes with previously reported ones to create a NOA gene panel, which was used to identify additional variants in 75 unrelated idiopathic NOA subjects and 74 fertile controls. Results In five of eight families, we identified rare deleterious recessive variants in CCDC155 , NANOS2 , SPO11 , TEX14 , and WNK3 segregating with disease. These genes, which are novel to human NOA, have remarkable testis-specific expression, and murine functional evidence supports roles for them in spermatogenesis. Among 75 unrelated NOA subjects, we identified 4 (~5.3%) with additional recessive variants in these newly discovered genes and 6 with deleterious variants in previously reported NOA genes, yielding an overall genetic etiology for 13.3% subjects versus 0 fertile controls ( p  = 0.001). Conclusion NOA affects millions of men, many of whom remain idiopathic despite extensive laboratory evaluation. The genetic etiology for a substantial fraction of these patients (>50% familial and >10% sporadic) may be discovered by WES at the point of care.