A Novelmutation Of MSX2 Associated With Non-syndromic Cryptorchidism In A Chinese Family By Whole-exome Sequencing

Objective: Cryptorchidism,or undescended testis,is a common urogenital systemmalformation in the male newborn period,and prolonged treatment will increase the risk of infertility and testicular tumor.The genetic basis of cryptorchidism isdiversitied,and the mechanism is still incompletely understood.Familial non-syndromic cryptorchidism provided the ideal assumption to study the hereditary cryptorchidism,however,the phenomen of familial non-syndromic cryptorchidism is less common and the genetic studies of familial cryptorchidism were seldom reported.The study of genetic variants from familial cryptorchidism aims to further understand the mechanism of inherited and the potential causative gene of cryptorchidism.Method:Whole-exome sequencing was performed on two affected brothers with cryptorchidism and their parents,and candidate variantsshared by both affected brothers were identifiedwith a minor allele frequency < 1% based on the reference databases;Further prediction was done by GO analysis and protein-protein interaction’s network,and validation was used by Sanger sequencing.Result:After filtering candidate variants by multiple steps,we identified 72 rare and potential pathogenic variants(67 genes)were associated with cryptorchidism in the autosomal dominant model.Go analysis suggested a potential role of candidate genes involved in cytoskeletal-dependent functions,including cellular macromolecule localization,cell adhesion,development,cytoskeleton,biological adhesion.Parts of candidate genes were associated with muscle development and hormone signaling pathway,MSX2,RYR3 and NCOA6 were overlapped with previous observations on structural and functional.Conclusion: Inheritance pattern of cryptorchidism is likely to be autosomal dominant through whole-exome sequencing in our familial cryptorchidism.Our data suggest that deleterious variant of muscle-and cytoskeleton-related genes were associated with cryptorchidism,and it may be regulated by multiple genes.The study of our familial cryptorchidism identified a list of rare candidate genes,and it is helpful for the study of cryptorchidism in human.MSX2 is the most potential causative gene for cryptorchidism in this family,but further studies for validation are required.