Genome sequencing of Pakistani families with male infertility identifies deleterious genotypes in SPAG6, CCDC9, TKTL1, TUBA3C, and M1AP

Author:

Khan Muhammad Riaz1,Akbari Arvand2,Nicholas Thomas J.3,Castillo‐Madeen Helen2,Ajmal Muhammad1,Haq Taqweem Ul1,Laan Maris4,Quinlan Aaron R.3,Ahuja Jasvinder S.2ORCID,Shah Aftab Ali1,Conrad Donald F.256ORCID

Affiliation:

1. Department of Biotechnology Faculty of Biological Sciences University of Malakand Chakdara Khyber Pakhtunkhwa Pakistan

2. Center for Embryonic Cell & Gene Therapy Oregon Health & Science University Portland Oregon USA

3. Department of Human Genetics University of Utah Salt Lake City Utah USA

4. Chair of Human Genetics Institute of Biomedicine and Translational Medicine University of Tartu Tartu Estonia

5. Division of Genetics Oregon National Primate Research Center Beaverton Oregon USA

6. Department of Molecular and Medical Genetics Oregon Health & Science University Portland Oregon USA

Abstract

AbstractBackgroundThere are likely to be hundreds of monogenic forms of human male infertility. Whole genome sequencing (WGS) is the most efficient way to make progress in mapping the causative genetic variants, and ultimately improve clinical management of the disease in each patient. Recruitment of consanguineous families is an effective approach to ascertain the genetic forms of many diseases.ObjectivesTo apply WGS to large consanguineous families with likely hereditary male infertility and identify potential genetic cases.Materials and methodsWe recruited seven large families with clinically diagnosed male infertility from rural Pakistan, including five with a history of consanguinity. We generated WGS data on 26 individuals (3–5 per family) and analyzed the resulting data with a computational pipeline to identify potentially causal single nucleotide variants, indels, and copy number variants.ResultsWe identified plausible genetic causes in five of the seven families, including a homozygous 10 kb deletion of exon 2 in a well‐established male infertility gene (M1AP), and biallelic missense substitutions (SPAG6, CCDC9, TUBA3C) and an in‐frame hemizygous deletion (TKTL1) in genes with emerging relevance.Discussion and conclusionThe rate of genetic findings using the current approach (71%) was much higher than what we recently achieved using whole‐exome sequencing (WES) of unrelated singleton cases (20%). Furthermore, we identified a pathogenic single‐exon deletion in M1AP that would be undetectable by WES. Screening more families with WGS, especially in underrepresented populations, will further reveal the types of variants underlying male infertility and accelerate the use of genetics in the patient management.

Funder

Eesti Teadusagentuur

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Publisher

Wiley

Subject

Urology,Endocrinology,Reproductive Medicine,Endocrinology, Diabetes and Metabolism

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