• PMID: 30389958
• Gene Name: P2RY4
• Condition: Obstructive azoospermia
• Association: Associated
• Mutation: c.59G?>?A (p.Ser20Asn)
• Population size: 4
• Population details: 4 (2 infertile brothers and 2 fertile family members)
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS

X-linked ADGRG2 mutation and obstructive azoospermia in a large Pakistani family

Khan MJ, Pollock N, Jiang H, Castro C, Nazli R, Ahmed J, Basit S, Rajkovic A, Yatsenko AN.

We performed whole exome sequencing to identify an unknown genetic cause of azoospermia and male infertility in a large Pakistani family. Three infertile males were subjected to semen analysis, hormone testing, testicular histology, ultrasonography, karyotyping, Y-chromosome microdeletion and CFTR testing. The clinical testing suggested a diagnosis of obstructive azoospermia (OA). To identify the cause, we performed whole exome sequencing (WES) for 2 infertile brothers and 2 fertile family members. For segregation analysis and variant confirmation, we performed Sanger sequencing. WES data analysis of the family revealed segregated variants in 3 candidate genes. We considered novel nonsense variant c.2440C > T(p.Arg814*) in X-linked gene ADGRG2 as biologically most plausible. It is predicted to truncate the protein by 204 amino acids (aa) at a key transmembrane domain. Adgrg2-knockout male mice show sperm loss due to obstructive fluid stasis, while ADGRG2 mutations cause OA in the infertile male patients. Our analysis of testicular histology reveals secondary severe reduction of spermatogenesis, consistent with human and knockout mouse phenotypes. The ADGRG2 nonsense mutation is absent in the largest population databases, ExAC and gnomAD. Analysis of the novel nonsense mutation in extended family members confirmed co-segregation of the mutation with OA in all affected males. The likely pathogenic nature of the mutation is supported by its truncation effect on the transmembrane domain and distinctive ultrasound results. The study demonstrates effectiveness of WES in discovering a genetic cause of azoospermia. FAU - Khan, Muhammad Jaseem AU - Khan MJ AD - Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan. FAU - Pollock, Nijole AU - Pollock N AD - Department of OBGYN and Reproductive Sciences, Magee-Womens Research Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. FAU - Jiang, Huaiyang AU - Jiang H AD - Department of OBGYN and Reproductive Sciences, Magee-Womens Research Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. FAU - Castro, Carlos AU - Castro C AD - Department of OBGYN and Reproductive Sciences, Magee-Womens Research Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. FAU - Nazli, Rubina AU - Nazli R AD - Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan. FAU - Ahmed, Jawad AU - Ahmed J AD - Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan. FAU - Basit, Sulman AU - Basit S AD - Center for Genetics and Inherited Diseases, Taibah University, Almadina Almunawarrah, Medina, Saudi Arabia. FAU - Rajkovic, Aleksandar AU - Rajkovic A AD - Department of OBGYN and Reproductive Sciences, Magee-Womens Research Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. AD - Department of Pathology, University of California San Francisco (current appointment), San Francisco, CA, USA.