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

BACKGROUND

Dual molecular diagnoses involving concurrent monogenic variants and imprinting disorders are increasingly recognized in complex phenotypes, yet systematic approaches to elucidate such convergence remain limited.

METHODS

We report a 46,XY proband with disorders of sex development (DSD), global developmental delay, and clinical features suggestive of Prader-Willi syndrome (PWS). We performed whole-exome sequencing (WES) to identify sequence-level variants. Upon detection of copy-neutral loss of heterozygosity (CN-LOH), we used methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) to assess imprinting status and performed single-nucleotide polymorphism (SNP) microarray to characterize the extent and allelic architecture.

RESULTS

WES identified a maternally inherited heterozygous deletion spanning exons 2-7 of NR5A1, classified as likely pathogenic based on its predicted loss-of-function impact on this dosage-sensitive transcription factor. WES also detected a 13.95 Mb CN-LOH at 15q21.1q21.3. MS-MLPA revealed a methylation profile consistent with maternal uniparental disomy of chromosome 15 (UPD(15)), confirming PWS. SNP microarray detected a larger 32.7 Mb CN-LOH across 15q14-q21.3. The combined data support maternal UPD(15) involving mixed heterodisomy and isodisomy, likely arising from meiotic nondisjunction followed by trisomy rescue.

CONCLUSIONS

An integrated genomic strategy resolved dual etiologies-NR5A1 haploinsufficiency and maternal UPD(15)-underlying complex neurodevelopmental and reproductive features. Demonstrating how integrated analysis of sequence variation, epigenetic regulation, and genome-wide allelic architecture can uncover coexisting monogenic and imprinting mechanisms, this case highlights a diagnostic strategy warranting further evaluation in broader cohorts.