Identification of De Novo Copy Number Variants Associated with Human Disorders of Sexual Development

摘要: Disorders of sexual development (DSD), ranging in severity from genital abnormalities to complete sex reversal, are among the most common human birth defects with incidence rates reaching almost 3%. Although causative alterations key genes controlling gonad have been identified, majority DSD cases remain unexplained. To improve diagnosis, we screened 116 children born idiopathic using a clinically validated array-based comparative genomic hybridization platform. 8951 controls without urogenital were used compare our cohort affected patients. Clinically relevant imbalances found 21.5% analyzed Most anomalies (74.2%) evaded detection by routinely ordered karyotype and scattered across genome gene-enriched subtelomeric loci. Among these defects, confirmed de novo duplication deletion events noted on 1p36.33, 9p24.3 19q12-q13.11 for ambiguous genitalia, 10p14 Xq28 cryptorchidism 12p13 16p11.2 hypospadias. These variants significantly associated genitourinary (P = 6.08×10−12). The causality observed 5p15.3, 9p24.3, 22q12.1 was supported presence overlapping chromosomal rearrangements several unrelated In addition known determining including SRY DMRT1, novel candidate such as FGFR2, KANK1, ADCY2 ZEB2 encompassed. identification risk germline may impact diagnosis genetic counseling contribute elucidation molecular mechanisms underlying pathogenesis development.