MYRF Variants in Patients With 46,XY Differences/Disorders of Sex Development and Literature Review.

46,XY differences/disorders of sex development (DSD) are genetically heterogeneous conditions characterized by atypical development of the reproductive system. MYRF, a gene encoding a transcription factor, has been identified as a potential causative gene for DSD and cardiac urogenital syndrome (CUGS). This study aims to delineate the clinical manifestations of patients with 46,XY DSD and MYRF mutations, encompassing both from our cohort and cases reported in the literature. Patients with 46,XY DSD were recruited from Peking Union Medical College Hospital and identified through a comprehensive review of published literature. Whole-exome sequencing was conducted to elucidate the genetic etiology. Comprehensive clinical data, including physical examination findings, hormonal profiles, and imaging results, were retrospectively gathered from medical records and published sources. Three of our patients with 46,XY DSD were found to harbor heterozygous loss-of-function mutations in the MYRF gene, including the recurrent variant c.789dup and two novel variants c.1915C>T and c.2154del. The patients exhibited underdeveloped testicular tissue, inadequate masculinization, and the persistence of Müllerian ducts. A review of the literature indentified 31 MYRF-linked 46,XY DSD patients and two 46,XX DSD patients. Among these, 11 cases presented with isolated testicular dysgenesis, 20 cases exhibited severe cardiopulmonary issues, and the majority of patients had congenital diaphragmatic hernia. Genetic analysis revealed 26 distinct MYRF variants among these patients, including 10 missense, 8 frameshift, 5 nonsense, and 3 splice site alterations, affecting critical domains of the MYRF gene. Our study broadens the spectrum of MYRF mutations in 46,XY DSD patients and highlighting the gene's indispensable role in gonadal development. However, a clear genotype-phenotype correlation in MYRF-related DSD remain elusive.