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

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

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List of pathogenic (P) copy number variations detected by CMA in patients presenting with gonadal dysgenesis or a referring diagnosis of ambiguous genitalia.

<p>List of pathogenic (P) copy number variations detected by CMA in patients presenting with gonadal dysgenesis or a referring diagnosis of ambiguous genitalia.</p

Submicroscopic imbalances revealed by CMA screening of children affected with syndromic and non-syndromic disorders of sex development.

<p>Footnote: UCS: Uncertain Clinical Significance.</p

Overlapping Chromosomal Rearrangements in DSD patients.

<p><b>A</b>. <b>Delineation of a minimal human 9p sex reversal deletion.</b> Schematic representation of the overlapping CMA detected 9p deletions in three unrelated 46,XY patients presenting with gonadal dysgenesis. A minimal common 260 Kb region was defined. Map showing the BAC clones covering the critical sex determination region and the normal flanking clones (RP11-459D20 and GS-43N6). A UCSC genome browser view (<i>May 2006</i> Human Assembly) of the <i>RefSeq</i> genes encompassing the minimal 9p24.3 sex-reversing region was presented. <b>B</b>. <b>Structural variation shared by unrelated patients presenting with distinct urogenital defects, may affect master regulator(s) of human genital development.</b> A common genomic interval of 65 Kb in the cytoband 5p15.31 was deleted in patient 6 with genital ambiguity and duplicated in patient 5 with hypospadias. CMA detection of the 65 Kb duplication in patient 5 and a UCSC genome browser view (<i>May 2006</i> Human Assembly) of the encompassed <i>ADCY2</i> gene were presented.</p

List of pathogenic (P) copy number variations in patients presenting with cryptorchidism.

<p>List of pathogenic (P) copy number variations in patients presenting with cryptorchidism.</p

<i>De novo</i> CMA detected events are more enriched in GU patients than in individuals without urogenital abnormalities.

<p><i>Footnotes</i>: Two-tailed Fisher's exact test was used to evaluate the association of CMA detected <i>de novo</i> events with urogenital defects. *: GU cases (n = 90 out of the total of 116 analyzed GU children) and non GU controls (n = 8951) run only on CMA V.6.1 and CMA Oligo V6, since <i>de novo</i> events were specifically observed in GU patients screened with these two qualitatively comparable platforms (n = 10; see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015392#pone-0015392-t006" target="_blank">Table 6</a>); <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015392#pone.0015392-Ou1" target="_blank">[21]</a>. See Statistical Analysis in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0015392#s2" target="_blank">Methods</a> for details.</p

Comprehensive map of non-polymorphic copy number changes detected by CMA in patients with disorders of sex development.

<p>On the right, CMA detected imbalances were shown for each clinical condition (asterisks). To gain insight into the genomic distribution of the identified imbalances, all published single gene mutations associated with cryptorchidism (blue), hypospadias (green) and ambiguous genitalia (red) were reviewed and indicated on the left side of the chromosomes. References are available upon request.</p