Construction of Copy Number Variation Map Identifies Small Regions of Overlap and Candidate Genes for Atypical Female Genitalia Development

Abstract

Copy number variations (CNVs) have been implicated in various conditions of differences of sexual development (DSD). Generally, larger genomic aberrations are more often considered disease-causing or clinically relevant, but over time, smaller CNVs have been associated with various forms of DSD. The main objective of this study is to identify small CNVs and the smallest regions of overlap (SROs) in patients with atypical female genitalia (AFG) and build a CNV map of AFG. We queried the DECIPHER database for recurrent duplications and/or deletions detected across the genome of AFG individuals. From these data, we constructed a chromosome map consisting of SROs and investigated such regions for genes that may be associated with the development of atypical female genitalia. Our study identified 180 unique SROs (7.95 kb to 45.34 Mb) distributed among 22 chromosomes. The most SROs were found in chromosomes X, 17, 11, and 22. None were found in chromosome 3. From these SROs, we identified 22 genes as potential candidates. Although none of these genes are currently associated with AFG, a literature review indicated that almost half were potentially involved in the development and/or function of the reproductive system, and only one gene was associated with a disorder that reported an individual patient with ambiguous genitalia. Our data regarding novel SROs requires further functional investigation to determine the role of the identified candidate genes in the development of atypical female genitalia, and this paper should serve as a catalyst for downstream molecular studies that may eventually affect the genetic counseling, diagnosis, and management of these DSD patients.