Human molecular genetics · 2026
Integrated multi-platform genetic profiling reveals dual molecular pathology in 46, XY disorders of sex development through NR5A1 Haploinsufficiency and maternal chromosome 15 UPD.
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Dong Rui, Liu Chen, Gao Min, Yu Kunkun, Zhang Lei, Wang Xiaochen, Li Kaisheng, Li Hongying, Zhang Kaihui, Liu Guohua
Аннотация
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.
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.