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

Publication Type	Academic Article
Authors	Fakhro K, Elbardisi H, Arafa M, Robay A, Rodriguez-Flores J, Al-Shakaki A, Syed N, Mezey J, Abi Khalil C, Malek J, Al-Ansari A, Al Said S, Crystal R
Journal	Genet Med
Volume	20
Issue	11
Pagination	1365-1373
Date Published	04/12/2018
ISSN	1530-0366
Keywords	Azoospermia, Genetic Association Studies, Genetic Predisposition to Disease, Infertility, Male
Abstract	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.
DOI	10.1038/gim.2018.10
PubMed ID	29790874