Peer-reviewed article
Genetic and Clinical Characteristics of 185 Japanese Children With 46,XY Differences of Sex Development.
Hayashi M, Narumi S, Sato T, Amano N, Suwanai AS et al. ·
Summary
Written by AI, not yet AICS's view · claude-haiku-4-5-20251001This is a genetic and clinical study of 185 Japanese children with a chromosomal condition affecting sex development. The researchers identified genetic causes in about 26% of cases by sequencing 25 genes. Children with more severe genital underdevelopment were more likely to have an identifiable genetic disorder. The study characterizes which genes are involved and how often each occurs in this population.
Key points
- 51 of 185 patients (26%) had pathogenic variants in genes related to 46,XY DSD
- Most common gene involved was AR (11%), followed by SRD5A2 (4.5%) and NR5A1 (4.0%)
- Monogenic disorders were found in 57% of patients with Müllerian derivatives versus 26% without
- Monogenic disorders were found in 91% of patients with female-typical genitalia versus 19% with ambiguous genitalia
Limitations
This is a descriptive genetic study focused on etiology and does not evaluate any intervention or treatment approach. The findings apply to Japanese populations and may not generalise to other ethnic groups.
Abstract
Context 46,XY differences of sex development (DSD) are heterogeneous in etiology. The detailed phenotypes of 46,XY DSD patients with monogenic disorders have not been fully elucidated. Objectives To estimate the proportion of monogenic disorders in 46,XY DSD and to characterize the clinical phenotypes of patients with monogenic disorders. Methods A total of 185 Japanese patients (178 families) were enrolled. We sequenced 25 genes related to 46,XY DSD and assessed the pathogenicity of the identified sequence variants according to the American College of Medical Genetics and Genomics guidelines, supplemented by in silico and/or in vitro analyses. We analyzed the clinical phenotypes of patients with monogenic disorders, with particular attention to the external or internal genitalia. Results We identified 51 patients (47 families) with any monogenic disorders (26%), who possessed pathogenic variants in AR (11%), SRD5A2 (4.5%), NR5A1 (4.0%), SRY (2.8%), WT1 (1.1%), STAR (1.1%), CYP17A1 (0.56%), HSD3B2 (0.56%), or MAP3K1 (0.56%). The proportion of monogenic disorders was significantly higher in subjects with detected Müllerian derivatives (57%) than in those undetected (26%) (P = .029), and in subjects with female-typical genitalia (91%) than in those with ambiguous genitalia (19%) (P < .001). Conclusion The proportion of monogenic disorders in Japanese 46,XY DSD patients was approximately 26%. Monogenic disorders were frequent among patients with severe undermasculinization of the external or internal genitalia.