Differences in sex development (DSD) — also known as intersex traits — are a set 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 key for medical diagnosis: it also sheds light on the biological foundations of gender identity. A new study published in Orphanet Journal of Rare Diseases has sequenced the whole exome of 39 children with 46,XY DSD in an attempt to locate, at last, the mutations that explain their condition.
Whole-exome sequencing: reading every gene
The team at the Medical University of Silesia, in Poland, applied whole-exome sequencing (WES), a technique that reads the protein-coding regions of the genome, to a group of 39 children with 46,XY DSD, aged between 2 months and 18 years. Of these, 32 had been assigned male at birth, 6 female and 1 was a transgender boy. Before the genetic test, all of them underwent an exhaustive clinical, hormonal and biochemical assessment.
Genetics explains fewer than half of the cases
The results confirm the difficulty of genetic diagnosis in these conditions. A genetic cause explaining the clinical picture was identified in only 8 of the 39 children. In 3, pathogenic variants were found in the AR and DHX37 genes; in another 5, likely pathogenic variants in the AR and HSD17B3 genes. In addition, variants of uncertain significance were found in 7 patients in genes of recognised relevance to sex development, such as NR5A1, MAMLD1, SOS2 or FAM111A.
Androgen insensitivity syndrome, the most common cause
Among the solved cases, the most frequent aetiology was androgen insensitivity syndrome, in which the body does not respond adequately to male hormones. The study also found pathogenic variants in genes unrelated to sex development in 7 patients, which shows the additional clinical usefulness of this technique for detecting other health problems.
Same mutation, different phenotypes: the genetic complexity
One of the most interesting findings was the frequent discordance between genotype and phenotype: very similar clinical pictures could correspond to different genotypes, while the same genetic variant could manifest in very different ways. This reinforces the idea that sex development is the result of a complex genetic network rather than a single determining gene.
Why it matters
Even with a high-throughput technique such as exome sequencing, the molecular cause remains unidentified in a considerable proportion of thoroughly studied patients. The authors recommend reanalysing the genetic data after 12 to 24 months in cases without a definitive diagnosis, as knowledge about the genes involved advances. Every confirmed genetic diagnosis helps to better understand how gender identity takes shape and to offer more precise, personalised clinical support.
Source: Błaszczyk E, et al. Refining the diagnosis of 46,XY disorders of sex development: insight from whole-exome sequencing. Orphanet Journal of Rare Diseases. 2026;21(1):236. doi:10.1186/s13023-026-04453-9.
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