A Novel Approach Using Microarray Testing as a Screening Method with Clinical Validation Using Whole-Genome Sequencing and Karyotyping for Identifying 46,XX Testicular Differences of Sex Development

TL;DR

A man with a typical male appearance was found to have a rare genetic condition through consumer genetic testing, leading to a diagnosis of 46,XX testicular differences of sex development.

Contribution

This is the first reported case of 46,XX testicular DSD diagnosed via direct-to-consumer microarray testing followed by clinical validation.

Findings

Microarray testing revealed missing Y chromosome haplogroup data in a male-phenotype individual.

Whole-genome sequencing and karyotyping confirmed the presence of Y-derived genomic material in a 46,XX karyotype.

The case highlights the potential of DTC genetic testing to identify rare chromosomal disorders.

Abstract

Background: Microarray testing is commonly used as a screening method for phenotypic traits and common diseases and for genome-wide association studies (GWASs). Despite the known limitations, microarray services can potentially be used as a prescreening tool for chromosomal disorders, which affect approximately 0.4–0.6% of the world population, followed by further clinical diagnostic methods when appropriate. Case Presentation: Here we present a case study of a male subject in his 40s who underwent direct-to-consumer (DTC) genetic testing that utilized microarray, which revealed the absence of Y chromosome haplogroup data despite possessing a typical male phenotype. Subsequent medical consultation, whole-genome sequencing (WGS), and chromosomal analysis confirmed a diagnosis of 46,XX testicular differences of sex development (DSD, formerly XX male syndrome) characterized by the presence of Y chromosome-derived genomic material, including the SRY gene. An initial microarray test gave an indeterminate result for the Y chromosome call rate and an X chromosome heterozygosity result that aligned with the female average. These indeterminate results, coupled with the subject’s male phenotype, led to further testing—WGS, karyotyping, fluorescence in situ hybridization using an SRY Probe, and endocrine testing. From these results, the subject was diagnosed with 46,XX testicular DSD. Conclusions: To our knowledge, this represents the first reported case where 46,XX testicular DSD was diagnosed starting from a DTC test which led to medical consultation and comprehensive genomic and cytogenetic analysis. This case underscores the potential diagnostic value of consumer-initiated DTC microarray screening in the era of genomic medicine and for supporting social needs such as gender confirmation for sports.

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