Bi-allelic loss-of-function mutations cause meiotic arrest and non-obstructive azoospermia.

BACKGROUND

The genetic causes of human idiopathic non-obstructive azoospermia (NOA) with meiotic arrest remain unclear.

METHODS

Two Chinese families with infertility participated in the study. In family 1, two brothers were affected by idiopathic NOA. In family 2, the proband was diagnosed with idiopathic NOA, and his elder sister suffered from infertility. Whole-exome sequencing (WES) was conducted in the two patients in family 1, the proband in family 2 and 362 additional sporadic patients with idiopathic NOA. Sanger sequencing was used to verify the WES results. Periodic acid-Schiff (PAS), immunohistochemistry (IHC) and meiotic chromosomal spread analyses were carried out to evaluate the stage of spermatogenesis arrested in the affected cases.

RESULTS

We identified compound heterozygous loss of function (LoF) variants of (c.C1582T:p.R528X and c.231_232del:p.L78Sfs9, respectively) in both affected cases with NOA from family 1. In family 2, homozygous LoF variant in (c.1194delA:p.L400Cfs7) was identified in the siblings with infertility. PAS, IHC and meiotic chromosomal spread analyses demonstrated that the spermatogenesis was arrested at zygotene stage in the three patients with NOA. Consistent with the autosomal recessive mode of inheritance, all of these variants were inherited from heterozygous parental carriers. Intriguingly, WES of 362 sporadic NOA cases revealed one additional NOA case with a bi-allelic LoF variant (c.1464delT:p.D489Tfs*13).

CONCLUSION

To the best of our knowledge, this is the first report identifying as the causative gene for human NOA. Furthermore, our study showed an autosomal recessive mode of inheritance in the NOA caused by deficiency.