Conundrum resolved by optical genome mapping in a 46,XY girl with difference in sex development and skeletal...

In individuals with a 46,XY karyotype, heterozygous SOX9 genetic variants have been associated with autosomal dominant male-to-female sex reversal accompanied by campomelic dysplasia. This report describes a child with Pierre-Robin sequence, skeletal abnormalities, and 46,XY differences of sex development. Exome sequencing was first performed with noninformative results and no variants were detected in the SOX9 gene. Because skeletal anomalies suggested campomelic dysplasia, karyotype analysis was obtained despite normal female external genitalia. The karyotype analysis revealed a 46,XY complement with a de novo translocation between chromosomes 5 and 17 [46,XY,t(5;17)(q22;q23.1)dn]. Genome sequencing and optical genome mapping characterized the precise translocation breakpoint upstream of the SOX9 gene. Use of high-resolution techniques was crucial to identifying the relevant genetic variant and confirming the diagnosis. Ultimately, this case demonstrates the value of optical genome mapping in identifying a cryptic rearrangement affecting the SOX9 regulatory elements that cannot be detected by exome sequencing, underscoring its utility in differences of sex development diagnosis.