Novel mutation leading to splice donor loss in a conserved site ofDMDgene causes Duchenne muscular dystrophy with cryptorchidism

Abstract

BackgroundAs one of the most common congenital abnormalities in male births, cryptorchidism has been found to have a polygenic aetiology according to previous studies of common variants. However, little is known about genetic predisposition of rare variants for cryptorchidism, since rare variants have larger effective size on diseases than common variants.MethodsIn this study, a cohort of 115 Chinese probands with cryptorchidism was analysed using whole-genome sequencing, alongside 19 parental controls and 2136 unaffected men. Additionally, CRISPR-Cas9 editing of a conserved variant was performed in a mouse model, with MRI screening used to observe the phenotype.ResultsIn 30 of 115 patients (26.1%), we identified four novel genes (ARSH,DMD,MAGEA4andSHROOM2) affecting at least five unrelated patients and four known genes (USP9Y,UBA1,BCORL1andKDM6A) with the candidate rare pathogenic variants affecting at least two cases. Burden tests of rare variants revealed the genome-wide significances for newly identified genes (p<2.5×10−6) under the Bonferroni correction. Surprisingly, novel and known genes were mainly found on X chromosome (seven on X and one on Y) and all rare X-chromosomal segregating variants exhibited a maternal inheritance rather than de novo origin. CRISPR-Cas9 mouse modelling of a splice donor loss variant inDMD(NC_000023.11:g.32454661C>G), which resides in a conserved site across vertebrates, replicated bilateral cryptorchidism phenotypes, confirmed by MRI at 4 and 10 weeks. The movement tests further revealed symptoms of Duchenne muscular dystrophy (DMD) in transgenic mice.ConclusionOur results revealed the role of theDMDgene mutation in causing cryptorchidism. The results also suggest that maternal-X inheritance of pathogenic defects could have a predominant role in the development of cryptorchidism.

Evolutionarily new genes in humans with disease phenotypes reveal functional enrichment patterns shaped by adaptive innovation and sexual selection.

“…In recent years, increasing availability of large-scale sequencing of whole exomes and whole genomes have greatly promoted the identification of deleterious variants underlying rare disorders (Richards et al 2015). Statistical and medical studies have demonstrated that rare diseases are often caused by rare variants, which have more significant effects on disease phenotypes than common variants (Richards et al 2015; Wang et al 2021; Chen et al 2022; Greene et al 2023; Jia et al 2023; Weiner et al 2023; Chen et al 2024a). The effect of genebased rare variant burden—the aggregate impact of rare (including de novo germline) protein-altering variants—has been confirmed in many genetic disorders (Purcell et al 2014; Zuk et al 2014; Guo et al 2018; Halvorsen et al 2020; Jiang et al 2021).…”