A Possible Exacerbation of Semen Findings by Additive Contribution of 2 Genetic Factors
2Institute of Animal Science, ARO-The Volcani Center, Israel
3Department of Molecular Genetics, Weizmann Institute of Science, Israel
Introduction:
Complete microdeletions of the azoospermia factor (AZF) regions, AZFb or AZFa, are manifested by testicular meiotic arrest or even Sertoli cells only, and the infertile men are azoospermic. In contrast, complete AZFc microdeletion causes severe oligozoospermia and even azoospermia. and those azoospermic men have 75% chance of finding sperm cells in testicular extraction, and they show much poorer ICSI-related outcomes than the oligozoospermic.
Objective:
To identify additive effect of genetic factors involved in men infertility.
Methods:
Two infertile members from a consanguineous Jewish family underwent exome sequencing. The suspected causative variations were validated by Sanger sequencing, screening 250 infertile men (228 oligozoospermic and 22 azoospermic) and 26 controls from similar suspected ethnicity, as well as screening an in-house sequence database of 500 Israelis. Testis scRNA-seq data analysis verified the spermatogenic expression stage. Y-chromosome and karyotype were also performed.
Results:
One azoospermic participant had a complete AZFc microdeletion, whereas the other participant suffered severe oligoteratoasthenozoospermia (sOAT) and had no microdeletion. Both participants were identified as homozygous to a likely causative new rare nonsense variant in a gene previously identified as being involved in sOAT in human and mouse. The genetic variant is included in one of the two transcripts expressed in the testis, and is not found in our cohort of additional infertile men.
Discussion:
We identified a likely sOAT causative new variant that seems to be exacerbated by the AZFc microdeletion. Contribution of two genetic factors to the semen phenotype is demonstrated for the first time.