Submicroscopic copy number variants in Indian children with gene panel negative 46, XY Gonadal Dysgenesis: An...

46, XY disorders of sex development (DSD) are a group of highly heterogeneous conditions in which the molecular etiology remains unknown in a significant proportion of patients, even with massive parallel sequencing. Clinically significant copy number variants (CNVs) are identified in 20-30% of cases, particularly among those with gonadal dysgenesis (GD) and no molecular diagnosis.

Fourteen patients with 46, XY DSD due to GD in whom no pathogenic/likely pathogenic variants were found on next-generation sequencing using a targeted panel of 155 genes were screened for clinically significant CNVs using Affymetrix Comparative Genomic Hybridization (CGH). Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER) and ClinVar were searched for matching genotypes and phenotypes, and chromosomal regions were screened for genes with known or potential association with GD.

Significant CNVs were identified in 6 (43%) of 14 patients with 46, XY GD. A previously unreported 19p13.3 duplication was found in three patients. This CNV was associated with GD based on overlapping CNV regions from previous studies and databases; and the inclusion of CIRBP, a candidate gene implicated in GD. CNVs involving WT1 (11p15) and SOX8 (16p13.3) were also identified.

CGH was helpful in pointing toward the molecular etiology in a significant proportion of patients with "idiopathic" 46, XY GD. However, establishing causality will require additional evidence including functional studies.