ESPE Abstracts

Differences of sex development (DSD) occurs when the development of chromosomal sex, gonadal or internal/external genitalia is atypical. It has an incidence of 1: 1000-4500 live born children. New chromosomal array technologies (SNP-array) can analyze the genome of the individual providing information of copy number variation (CNV) of specific chromosomal regions helping to identified pathogenic variants that could explain the etiology of the DSD. This study aims to analyze the presence of CNVs using genomic array platforms in DSD patients with syndromic feature in a cohort followed at the outpatient clinic of tertiary hospital. Two SNP-array platforms were used (Illumina® Infinium CytoSNP-850K BeadChip® and Affymetrics® CytoScan HD 750K). Twenty-two DSD patients with syndromic features encompassing several systems, in addition to the genital abnormalities, were included in the study. A total of 229 CNVs were identified: 126 deletions, 66 duplications and 37 loss of heterozygous state. Reported CNV length varied from 2.8 Kb to 12.7 Mb. Nine CNVs in six different patients were considered pathogenic or probably pathogenic after in silico analysis. Two patients had the final diagnose of 46,XX SRY + DSD associates with copy gain of 7 Mb Yp fragment. Two deletions, a 1.7Mb in 3q29 region in one patient and a 9 Mb in Xp22.33 in other patient, were revealed by the array in addition to the Yp fragment. Four others pathogenic CNVs were found in three patients that can justify the syndromic features and genital ambiguity: a 11.6 Mb deletion at 10q25.3-26.2 in one patient; a 10.9 Mb deletion at 13q33.1 in other patient; a duplication (6.5Mb) and deletion (12.7) in chromosome 14q11.2-q12 and 21p11.2-q21.3, respectively in another patient. Genes related with gonadal development were deleted in one patient (FGFR2 and EMX2) and in other patient (EFNB2). In one patient, a 12Kb deletion in chromosome 10 encompassing the PITX3 was found responsible for congenital cataract. The SNP-array technique allowed to establish the molecular cause of DSD in two patients 46,XX DSD SRY+ (10%). In three other patients, pathogenic CNVs that contained candidate genes related to DSD (10q25.3-26.2, 13q33.1-q34) and a contiguous gene deletion syndrome with atypical genital but without a known candidate gene (14q11.2-q12 duplication and 21p11.2-q21.3 deletion), were identified and may justified the presence of 46,XY DSD phenotype. Copy number variation (CNV) of specific chromosomal regions containing pathogenic variants could explain the etiology of DSD.