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

Scott Department of Urology, Baylor College of Medicine, Houston, Texas, United States of America.
PLoS ONE (Impact Factor: 3.23). 10/2010; 5(10):e15392. DOI: 10.1371/journal.pone.0015392
Source: PubMed


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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    • "Importantly, over the past years several studies have been showing that a significant portion of the genes involved in severe spermatogenic failure (SSF) are spread throughout the genome rather than restricted to the sex chromosomes (reviewed in Lima & Lopes, 2014). One particular genomic region (9p), harboring the double sex and mab-3-related transcription factor (DMRT) gene cluster, has been linked with disorders of sex development (Veitia et al., 1997; Raymond et al., 1999; ~ Ounap et al., 2004; Tannour-Louet et al., 2010). It appears that isolated genetic defects in DMRT1, one of the genes in the cluster, may be the cause of alterations in gonadal development in some cases (Ledig et al., 2010, 2012) but not all, as no inactivating mutations or deletions were found in this gene in a study of patients with gonadal dysgenesis (Machado et al., 2012). "
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    ABSTRACT: The double sex and mab-3-related transcription factor 1 (DMRT1) gene has long been linked to sex-determining pathways across vertebrates and is known to play an essential role in gonadal development and maintenance of spermatogenesis in mice. In humans, the genomic region harboring the DMRT gene cluster has been implicated in disorders of sex development and recently DMRT1 deletions were shown to be associated with non-obstructive azoospermia (NOA). In this work, we have employed different methods to screen a cohort of Portuguese NOA patients for DMRT1 exonic insertions and deletions [by multiplex ligation probe assay (MLPA); n = 68] and point mutations (by Sanger sequencing; n = 155). We have found three novel patient-specific non-coding variants in heterozygosity that were absent from 357 geographically matched controls. One of these is a complex variant with a putative regulatory role (c.-223_-219CGAAA>T), located in the promoter region within a conserved sequence involved in Dmrt1 repression. Moreover, while DMRT1 domains are highly conserved across vertebrates and show reduced levels of diversity in human populations, two rare synonymous substitutions (rs376518776 and rs34946058) and two rare non-coding variants that potentially affect DMRT1 expression and splicing (rs144122237 and rs200423545) were overrepresented in patients when compared with 376 Portuguese controls (301 fertile and 75 normozoospermic). Overall our previous and present results suggest a role of changes in DMRT1 dosage in NOA potentially also through a process of gene misregulation, even though DMRT1 deleterious variants seem to be rare. © 2015 American Society of Andrology and European Academy of Andrology.
    Andrology 07/2015; 3(5). DOI:10.1111/andr.12063 · 2.30 Impact Factor
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    • "While GU defects frequently occur as isolated defects, they present together with multiple GU defects, usually known as CAKUTs (congenital anomalies of the kidney and urinary tract), that occur in 1∶500 live births [19]. Emerging evidence suggests that genetic and genomic changes can result in susceptibility to abnormal GU tract development [20]. "
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    ABSTRACT: Normal development of the genitourinary (GU) tract is a complex process that frequently goes awry. In male children the most frequent congenital GU anomalies are cryptorchidism (1-4%), hypospadias (1%) and micropenis (0.35%). Bladder exstrophy and epispadias complex (BEEC) (1∶47000) occurs less frequently but significantly impacts patients' lives. Array comparative genomic hybridization (aCGH) identified seven individuals with overlapping deletions in the 2p15 region (66.0 kb-5.6 Mb). Six of these patients have GU defects, while the remaining patient has no GU defect. These deletions encompass the transcription factor OTX1. Subjects 2-7 had large de novo CNVs (2.39-6.31 Mb) and exhibited features similar to those associated with the 2p15p16.1 and 2p15p14 microdeletion syndromes, including developmental delay, short stature, and variable GU defects. Subject-1 with BEEC had the smallest deletion (66 kb), which deleted only one copy of OTX1. Otx1-null mice have seizures, prepubescent transient growth retardation and gonadal defects. Two subjects have short stature, two have seizures, and six have GU defects, mainly affecting the external genitalia. The presence of GU defects in six patients in our cohort and eight of thirteen patients reported with deletions within 2p14p16.1 (two with deletion of OTX1) suggest that genes in 2p15 are important for GU development. Genitalia defects in these patients could result from the effect of OTX1 on pituitary hormone secretion or on the regulation of SHH signaling, which is crucial for development of the bladder and genitalia.
    PLoS ONE 09/2014; 9(9):e107028. DOI:10.1371/journal.pone.0107028 · 3.23 Impact Factor
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    • "This array-CGH platform has the highest resolution compared to other platforms for detection of copy number changes that have previously been applied to patients with XY GD. In addition to single reports [18] [27], also three studies with larger groups of patients presenting with various forms of DSD have been described [23] [28] [29], resulting in the identification of known and potentially causative aberrations in approximately a third of the patients (36%, 22% and 21.5% respectively). Using a customized 1 M array-CGH platform, we investigated a selected group of patients with complete GD for novel copy number changes potentially causing gene haploinsufficiency or overexpression . "
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    ABSTRACT: Half of all patients with a disorder of sex development (DSD) do not receive a specific molecular diagnosis. Comparative genomic hybridization (CGH) can detect copy number changes causing gene haploinsufficiency or over-expression that can lead to impaired gonadal development and gonadal DSD. The purpose of this study was to identify novel candidate genes for 46,XY gonadal dysgenesis (GD) using a customized 1M array-CGH platform with whole-genome coverage and probe enrichment targeting 78 genes involved in sex development. Fourteen patients with 46,XY gonadal DSD were enrolled in the study. Nine individuals were analyzed by array CGH. All patients were included in a follow up sequencing study of candidate genes. Three novel candidate regions for 46,XY GD were identified in two patients. An interstitial duplication of the SUPT3H gene and a deletion of C2ORF80 were detected in a pair of affected siblings. Sequence analysis of these genes in all patients revealed no additional mutations. A large duplication highlighting PIP5K1B, PRKACG and FAM189A2 as candidates for 46,XY GD, were also detected. All five genes are expressed in testicular tissues, and one is shown to cause gonadal DSD in mice. However detailed functional information is lacking for these genes.
    European journal of medical genetics 09/2013; 56(12). DOI:10.1016/j.ejmg.2013.09.003 · 1.47 Impact Factor
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