Integrated multi-platform genetic profiling reveals dual molecular pathology in 46, XY disorders of sex development through NR5A1 Haploinsufficiency and maternal chromosome 15 UPD.

Dual diagnosis: NR5A1 haploinsufficiency and maternal uniparental disomy of chromosome 15

The authors report a 46,XY proband with disorder of sex development, global developmental delay and features suggestive of Prader-Willi syndrome. WES identified a maternally inherited heterozygous deletion of NR5A1 exons 2-7, classified as likely pathogenic, alongside copy-neutral loss of heterozygosity at 15q. MS-MLPA and SNP microarray confirmed maternal uniparental disomy of chromosome 15 (mixed heterodisomy and isodisomy) consistent with Prader-Willi syndrome, likely from meiotic nondisjunction followed by trisomy rescue. An integrated genomic strategy resolved both converging etiologies.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A case illustrating the value of integrated genomic analysis (sequence, methylation, allelic architecture) to unmask dual diagnoses, increasingly recognized in complex phenotypes. Detecting copy-neutral loss of heterozygosity was the key, a reminder not to stop at the first causal variant. An approach to validate in larger cohorts.

Analysis by Dr Thibaut Benquey