Sometimes a person’s clinical picture can only be explained by accepting an uncomfortable idea: that two different genetic causes may be acting at once. That is what the authors of a case report published in Human Molecular Genetics, one of the reference journals in human genetics, have demonstrated. Their patient, a child with a difference of sex development (DSD), developmental delay and features of a well-known syndrome, hid in his genome not one but two simultaneous explanations for his condition.
What are differences of sex development
Differences of sex development (DSD) are a group of congenital conditions in which chromosomal, gonadal or anatomical development does not follow the typically male or female pattern. Understanding their genetic basis is not only useful for medical diagnosis: it also helps to understand the biological foundations underlying the development of gender identity. When genetic diagnosis becomes complicated, medicine faces patients who do not fit simple explanations.
One patient, two mysteries
The case described by the authors is that of a child with a 46,XY karyotype — the usual chromosomal pattern in males — who presented DSD, global developmental delay and features compatible with Prader-Willi syndrome, a rare genetic disorder affecting growth, appetite and neurological development. That combination of symptoms did not point to a single cause: it pointed to two at once.
Whole-exome sequencing, the first step
The team applied whole-exome sequencing, a technique that reads all the protein-coding regions of the genome. They found a heterozygous deletion inherited from the mother in the NR5A1 gene, a key gene in gonadal development. The deletion, spanning exons 2 to 7, was classified as likely pathogenic: NR5A1 encodes a dosage-sensitive transcription factor, and losing one of its copies alters sex development.
The second clue: chromosome 15
But sequencing also detected an unexpected signal on chromosome 15: a copy-neutral loss of heterozygosity (CN-LOH) of almost 14 megabases. Using a methylation-specific technique (MS-MLPA), the team confirmed that the patient had inherited both copies of chromosome 15 from his mother (maternal uniparental disomy, UPD15), the classic mechanism of Prader-Willi syndrome. A SNP microarray extended the affected region to 32.7 megabases and revealed a mix of heterodisomy and isodisomy, consistent with a meiotic error followed by trisomy rescue.
Why this case matters
The conclusion is twofold. First, the patient had two independent molecular diagnoses: NR5A1 haploinsufficiency explained the difference of sex development, while maternal disomy of chromosome 15 explained Prader-Willi syndrome. Second, only the integrated combination of sequencing, methylation analysis and genome-wide allelic architecture allowed the case to be resolved.
The study shows how complex the genetics of sex development really is: two distinct molecular mechanisms can coexist in the same patient, and neither one alone tells the whole story. For those working on DSD diagnosis, the lesson is clear: when symptoms point in several directions, the whole genome — not a single gene — is where the answers should be sought.
Source: Dong R et al. Integrated multi-platform genetic profiling reveals dual molecular pathology in 46,XY disorders of sex development through NR5A1 haploinsufficiency and maternal chromosome 15 UPD. Human Molecular Genetics, 2026, vol. 35, art. ddag055. DOI: 10.1093/hmg/ddag055.
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