Language
English
Publication Date
7-19-2024
Journal
Journal of Medical Genetics
DOI
10.1136/jmg-2024-109896
PMID
38621993
PMCID
PMC11287555
PubMedCentral® Posted Date
4-15-2024
PubMedCentral® Full Text Version
Post-print
Abstract
Background: As 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.
Methods: In 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.
Results: In 30 of 115 patients (26.1%), we identified four novel genes (ARSH, DMD, MAGEA4 and SHROOM2) affecting at least five unrelated patients and four known genes (USP9Y, UBA1, BCORL1 and KDM6A) 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 in DMD (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.
Conclusion: Our results revealed the role of the DMD gene 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.
Keywords
Animals, Humans, Male, Mice, CRISPR-Cas Systems, Cryptorchidism, Genetic Predisposition to Disease, Muscular Dystrophy, Duchenne, Mutation, Phenotype, RNA Splice Sites, Whole Genome Sequencing, Genetic Diseases, X-Linked; Genetics, Medical; Genomics; Reproductive Health; Child Health
Published Open-Access
yes
Recommended Citation
Chen, Jianhai; Jia, Yangying; Zhong, Jie; et al., "Novel Mutation Leading to Splice Donor Loss in a Conserved Site of DMD Gene Causes Duchenne Muscular Dystrophy With Cryptorchidism" (2024). Faculty and Staff Publications. 5162.
https://digitalcommons.library.tmc.edu/baylor_docs/5162
Included in
Genetic Phenomena Commons, Genetic Processes Commons, Genetic Structures Commons, Medical Genetics Commons, Medical Molecular Biology Commons, Medical Specialties Commons