Identification of novel biallelic LRRC6 variants in male Chinese patients with primary ciliary dyskinesia and infertility

Purpose The aim of this study is to identify the genetic cause of primary ciliary dyskinesia (PCD) and male infertility in two unrelated Han Chinese families. Methods We performed whole-exome sequencing in two unrelated male Han Chinese patients suffering from infertility and PCD to identify the pathogenic variants. Ultrastructural and immunostaining analyses of patient's spermatozoa were performed to characterize the effect of the variants. The pathogenicity of the variants was validated using patient's spermatozoa by western blotting and immunostaining analysis. Intracytoplasmic sperm injection (ICSI) was conducted in the affected families. Results Three variants in leucine-rich repeat containing 6 (LRRC6) [patient 1(compound heterozygote): NM_012472: c.538C > T, (p.R180*) and c.64dupT, (p.S22Ffs*19); patient 2 (homozygote): c.863C > A, (p.P288H)] were identified in two unrelated patients with PCD and male infertility. These variants were predicated deleterious and were absent or rare in human population genome data. LRRC6-mutant spermatozoa showed a highly aberrant morphology and ultrastructure with lacked inner and outer dynein arms. The LRRC6 protein was present along the normal sperm flagella, and was significantly decreased in the mutated spermatozoa. Interestingly, both patients were able to conceive through ICSI and birthed a healthy baby. Conclusion Our results extend the LRRC6 variant spectrum and provide reproductive guidance to families suffering from PCD-linked infertility caused by LRRC6 variants.

Automated summary

The genetic cause of primary ciliary dyskinesia (PCD) and male infertility in two unrelated Han Chinese families was identified through whole-exome sequencing. Variants in the LRRC6 gene were found in two patients with PCD and male infertility. The LRRC6-mutant spermatozoa showed abnormal morphology and ultrastructure, and the LRRC6 protein levels were significantly decreased. Interestingly, both patients were able to conceive through ICSI and gave birth to healthy babies.