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 SHOC1 (c.C1582T:p.R528X and c.231_232del:p.L78Sfs*9, respectively) in both affected cases with NOA from family 1. In family 2, homozygous LoF variant in SHOC1 (c.1194delA:p.L400Cfs*7) 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 SHOC1 variants were inherited from heterozygous parental carriers. Intriguingly, WES of 362 sporadic NOA cases revealed one additional NOA case with a bi-allelic SHOC1 LoF variant (c.1464delT:p.D489Tfs*13).
Conclusion To the best of our knowledge, this is the first report identifying SHOC1 as the causative gene for human NOA. Furthermore, our study showed an autosomal recessive mode of inheritance in the NOA caused by SHOC1 deficiency.
- Loss of function mutation
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CY, CY and LZ contributed equally.
Contributors ZL, ZZ and FZ designed the research; CCY, CY and LYZ performed the research; PL, RHT, HXC, YG, YHH, ELZ and JZ performed the bioinformatics analysis; HFS, JXZ, YH and LZ analysed the data; CCY, CY, ZYJ and LYZ wrote and revised the paper.
Funding This work was supported by the National Key Research and Development Program of China (2017YFC1002003), National Natural Science Foundation of China (81871215) and Shanghai Sailing Program (20YF1439500 and 20YF1453700).
Competing interests None declared.
Patient consent for publication Obtained.
Ethics approval This study was approved by the Institutional Ethical Review Committee of Shanghai General Hospital, Shanghai Jiao Tong University (Permit Number 2018KY052), and an informed consent of clinical data and testicular tissues for research was obtained from the donors.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
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