Endocrine Abstracts

Background: Deletions within the 9p24.3 region are frequently associated with 46,XY gonadal dysgenesis (46,XY GD), but the definitive causative gene remains to be clearly identified. DMRT1, located within this region, plays a highly conserved role in the sex development across metazoans and is a strong candidate for GD. However, previous characterisations of 9p24.3 deletions often lacked precise breakpoint resolution and often involved neighbouring DMRT genes. Here we present two unrelated patients (one previously described(1), one novel) with partial GD and DMRT1 microdeletions.

Case Presentations & Methods: Case 1: Previously described by Ledig et al. (1). Initial presentation at 2 years and 2 months; 46,XY karyotype; phallus 3.5 cm; prominent glans (1.2 cm in diameter); asymmetric labioscrotal folds; right-sided palpable gonad. Introitus with an almost female appearance; no uterus.Case 2: Initial presentation at 12 weeks; 46,XY karyotype; phallus 3.5 cm; penoscrotal hypospadias. Laparoscopy showed small bilateral gonads as well as remnants of fallopian tubes, and a uterus with left-sided predominance. Array comparative genomic hybridization and whole-exome sequencing identified a suspected microdeletion in the DMRT1 gene. Long-read whole-genome sequencing (WGS) enabled the precise characterisation of the extent of the deletion and the breakpoints, as well as the exclusion of potential other known genetic causes of DSD.

Results: Long-read WGS confirmed distinct DMRT1 microdeletions in both patients. Detailed breakpoint analysis revealed a deletion of exons 3 and 4 in case 1 and of exon 4 in case 2. Involvement of other exons or surrounding DMRT genes was ruled out. WGS also excluded other known genetic causes of DSD. In both patients, deletion breakpoints were located within repetitive Alu elements, suggesting non-allelic homologous recombination as the cause of the deletions.

Conclusion: Our findings strengthen the evidence that DMRT1 haploinsufficiency is a primary cause of 46,XY GD. Through comparison with nearly identical deletions associated solely with azoospermia (2), our study underscores that loss of DMRT1 can lead to GD but exhibits highly variable penetrance. Other (epi)genetic or environmental factors are likely to contribute significantly to the expression of the phenotype.