Combined optical genome mapping and cnv-seq identify complex Y-chromosome rearrangements and ectopy in 46,XX testicular disorder of sex development.

OBJECTIVE

To define the genomic architecture of Y‑chromosome ectopy in a child with 46,XX testicular disorders of sex development (DSD) and illustrate the complementary roles of low‑coverage CNV sequencing (CNV‑seq) and optical genome mapping (OGM).

METHODS

A one‑and‑a‑half‑year‑old child with male phenotype, unfused scrotum, and hypospadias underwent clinical assessment and Doppler ultrasound, karyotyping, whole‑exome sequencing (WES), CNV‑seq, and OGM. CNV‑seq data were aligned to GRCh37; OGM maps were aligned to GRCh38 with T2T‑CHM13 consulted for Y display. Coordinates were harmonized for interpretation. FISH and long‑range PCR targeting the full SRY locus were not performed.

RESULT: Ultrasound showed bilateral scrotal testes, with no uterus or ovarian tissue. Karyotype was 46,XX, inv(9)(p12q13). CNV-seq identified called losses at Xp22.33 (287,328-3,605,487) and within Yp11.31-p11.2 (2,649,472-6,065,425) and Yp11.2 (7,270,527-9,599,178). OGM resolved a derivative X containing an insertion of Yp sequence at Xp22.33, with three re-join events in Yp11.2, including a deleted interval (~ 6.2-7.3 Mb) and a local inversion (~ 7.3-9.9 Mb); the call was ogm[GRCh38] der(X)(Ypter_Yp11.2::Yp11.2::Xp22.33_Xqter)(Ypter_6248448::9915169_7362950::3618476_Xqter). Harmonized coordinates indicate that the retained Yp11.3 interval includes SRY and is inserted into der(Xp22.33), supporting SRYpositive 46,XX testicular DSD on a coordinate basis. The Xp22.33 deletion supports counseling regarding SHOX haploinsufficiency-related growth surveillance.

CONCLUSION

CNV-seq and OGM deliver nonredundant, genomewide dosage and architectural resolution that localizes the insertion site, defines breakpoint orientation, and provides counseling-relevant information beyond karyotype and WES. The coordinate-based inference of SRY and PAR1 involvement demonstrates a practical framework for integrating structural genomics into DSD diagnostics.