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Whole genome sequencing identifies a cryptic SOX9 regulatory element duplication underlying a case of 46, XX ovotesticular difference of sexual development
Author(s) -
Qian Zhiyu,
Grand Katheryn,
Freedman Andrew,
Nieto Maria C.,
Behlmann Andrea,
Schweiger Bahareh M.,
SanchezLara Pedro A.
Publication year - 2021
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.62373
Subject(s) - gene duplication , whole genome sequencing , biology , genetics , exome sequencing , genome , testis determining factor , dna sequencing , copy number variation , gene , phenotype , y chromosome
Ovotesticular differences of sexual development (OT‐DSD) are rare genetic variances defined by the coexistence of both testicular and ovarian tissues. Various molecular etiologies including SRY translocation or SOX9 pathogenic variants with different modes of inheritance have been associated with 46,XX OT‐DSD. Here we describe a child diagnosed with SRY ‐negative 46,XX OT‐DSD after completing a series of complex clinical genetic analyses, including chromosomal microarray, DSD gene panel (sequencing and deletion/duplication analysis), whole exome sequencing, and whole genome sequencing. Of these, only whole genome sequencing reported a pathogenic duplication in a non‐coding region that contains the RevSex regulatory element, which modifies SOX9 expression and is associated with 46,XX OT‐DSD and complete sex reversal. This is the first clinical RevSex duplication detected by clinical whole genome sequencing. We highlight the utility of whole genome sequencing in shortening the diagnostic odyssey and the importance of optimal counseling through a team‐based multi‐specialty approach for patients with DSDs.