MYOCD-associated congenital megabladder: novel variants and insights into prenatal phenotypic diversity

Myocardin, encoded by MYOCD , is a key transcriptional coactivator of serum response factor that is essential for smooth muscle cell differentiation and contractility. Loss-of-function variants in MYOCD have been reported to cause congenital megabladder (MGBL), a rare and severe developmental defect. To date, only six pathogenic variants across five families have been documented worldwide. Four unrelated Chinese families presenting with fetal urinary tract malformations were recruited. Amniocentesis or chorionic villus sampling was performed, followed by conventional cytogenetic karyotyping, chromosomal microarray analysis, and trio-based exome sequencing (trio-ES). The ClinGen gene curation framework was employed to evaluate the clinical validity of the relationship between MYOCD and MGBL. Trio-ES identified four novel heterozygous variants in the MYOCD gene, including two nonsense variants [p.(Gln434Ter) and p.(Gln307Ter)], one canonical splice-site variant (c.1125 + 1G > A), and one frameshift variant [p.(Gly191ValfsTer42)]. Marked phenotypic variability was observed, ranging from isolated prenatal bilateral hydronephrosis with postnatal survival to severe MGBL leading to pregnancy termination or intrauterine fetal demise. By integrating evidence from our study and previously reports, the MYOCD –MGBL association was classified as “Definitive” under the ClinGen framework. This study expands the mutational and phenotypic spectrum of MYOCD -related MGBL and highlights substantial prenatal phenotypic heterogeneity. The findings underscore the complexity of prenatal diagnosis and the importance of careful genetic counseling.