Genetic characteristics of patients with MYH3-associated congenital skeletal malformations
Objective To determine the genetic etiology of 5 patients with congenital skeletal malformations of dif-ferent severity by whole exome sequencing,and to summarize the clinical characteristics and analyze the genotype-phenotype.Methods The clinical and imaging data of 5 patients were collected.The peripheral blood of the proband's family was col-lected and DNA was extracted.Whole exome sequencing of patients were performed and variants were classified following the interpretation standards and guidelines of the American College of Medical Genetics and Genomics.(ACMG)and the Associa-tion for Molecular Pathology.Putative pathogenic variants were verified by Sanger sequencing.Results All five patients car-ried missense variants in the MYH3 gene.Two missense mutations were maternal,c.941T>G(p.Ile314Ser)in patient 2 and c.3842T>G(p.Leu1281Trp)in patient 3;and three missense mutations were de novo:c.853C>G(p.His285Asp)in patient 1,c.2621T>C(p.Leu874Pro)in patient 4 and c.854A>G(p.His285Arg)in patient 5.Conclusion We found five mutation sites of MYH3.The phenotypes of congenital skeletal diseases caused by different variants of MYH3 have extensive heterogeneity.This result expanded the variation spectrum of MYH3 in the Chinese population.