Congenital Heart Defects in Patients with Deletions Upstream of<i>SOX9</i>

Sanchez-Castro, Marta; Gordon, Christopher T.; Petit, Florence; Nord, Alexander; Callier, Patrick; Andrieux, Joris; Guérin, Patrice; Pichon, Olivier; David, Albert; Abadie, Véronique; Bonnet, Damien; Visel, Axel; Pennacchio, Len A.; Amiel, Jeanne; Lyonnet, Stanislas; Caignec, Cédric Le

doi:10.1002/humu.22449

Cited by 33 publications

(30 citation statements)

References 19 publications

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“…These individuals, either XX or XY, were investigated because of Pierre-Robin syndrome or cardiac defects. 11,13,28,29 The two duplications that we described are both in tandem, as reported for other DSD cases, 4,5 but a specific predisposing genomic architecture has not been highlighted. This duplication, although without effect in the XY background, appears to be very rare, with no cases containing at least the minimal duplicated RevSex region among the 14 316 individuals collected in the Database of Genomic Variants.…”

Section: Discussionsupporting

confidence: 68%

Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3

et al. 2014

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Duplications in the~2 Mb desert region upstream of SOX9 at 17q24.3 may result in familial 46,XX disorders of sex development (DSD) without any effects on the XY background. A balanced translocation with its breakpoint falling within the same region has also been described in one XX DSD subject. We analyzed, by conventional and molecular cytogenetics, 19 novel SRY-negative unrelated 46,XX subjects both familial and sporadic, with isolated DSD. One of them had a de novo reciprocal t(11;17) translocation. Two cases carried partially overlapping 17q24.3 duplications~500 kb upstream of SOX9, both inherited from their normal fathers. Breakpoints cloning showed that both duplications were in tandem, whereas the 17q in the reciprocal translocation was broken at~800 kb upstream of SOX9, which is not only close to a previously described 46,XX DSD translocation, but also to translocations without any effects on the gonadal development. A further XX male, ascertained because of intellectual disability, carried a de novo cryptic duplication at Xq27.1, involving SOX3. CNVs involving SOX3 or its flanking regions have been reported in four XX DSD subjects. Collectively in our cohort of 19 novel cases of SRY-negative 46,XX DSD, the duplications upstream of SOX9 account for~10.5% of the cases, and are responsible for the disease phenotype, even when inherited from a normal father. Translocations interrupting this region may also affect the gonadal development, possibly depending on the chromatin context of the recipient chromosome. SOX3 duplications may substitute SRY in some XX subjects. European Journal of Human Genetics (2015) 23, 1025-1032; doi:10.1038/ejhg.2014.237; published online 5 November 2014 INTRODUCTION 46,XX disorders of sex development (DSDs) are congenital conditions in which, in the presence of a female karyotype, the development of gonadal and anatomical sex is atypical, ranging from various degrees of ambiguous genitalia to phenotypic males with azoospermia. These conditions are poorly characterized, at least in subjects whose DNA does not contain SRY, the gene triggering testis differentiation in mammals. 1 In fact, in most XX males, SRY is transposed to the tip of Xp as a consequence of a recurrent Xp;Yp translocation, arising predominantly by nonallelic homologous recombination between PRKX and PRKY on a particular Y haplotypic background. 2,3 These males, usually with small testes, are essentially picked up among men with nonobstructive azoospermia.A much less well-understood category is that of the 46,XX DSDs negative for SRY. Recently, six of these cases have been reported

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Section: Discussionsupporting

confidence: 68%

Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3

et al. 2014

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“…We also previously showed that deletions upstream of SOX9 containing regulatory elements are likely responsible for isolated CHD. 24 We performed here a computational approach to search for an enrichment of binding sites of transcription factor genes within our rare CNVs data set that might have altered the expression of genes and thus contributed to the CHD. Our TFBS approach led us to identify a significant enrichment of FOXC1-binding sites in the rare CNVs present in affected children (Table V in the Data Supplement).…”

Section: Discussionmentioning

confidence: 99%

Search for Rare Copy-Number Variants in Congenital Heart Defects Identifies Novel Candidate Genes and a Potential Role for FOXC1 in Patients With Coarctation of the Aorta

Sanchez-Castro¹,

Eldjouzi²,

Charpentier³

et al. 2016

Circ Cardiovasc Genet

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C ongenital heart defects (CHD) are the most common congenital malformations with an incidence of 0.5% to 1% of live births.1 They also are the first cause of mortality during the first year of life of newborns in developed countries.2 Despite therapeutic advances, CHD are associated with a high proportion of long term morbidity. Among CHD, a large subset involves the outflow tract (OFT). This heterogeneous group of malformations represents 20% to 30% of the CHD diagnosed in newborns.3 Transposition of the great arteries (TGA) accounts for 5% to 7% of all CHD 4 and is one of the most common cyanotic disorder diagnosed in the neonatal period with a prevalence of 0.2 per 1000 live births. The most common form of TGA is the dextro-looped type, which consists in a discordant ventriculoarterial connection implying that the aorta incorrectly arises from the right ventricle in an anterior and right-sided position, whereas the pulmonary artery incorrectly arises from the left ventricle in a posterior and left-sided position. By contrast to the normal heart in which both OFTs and great vessels show a dextral (right handed) spiralization, the great vessels in TGA present with a parallel course lacking normal spiralization. Coarctation Background-Congenital heart defects are the most frequent malformations among newborns and a frequent cause of morbidity and mortality. Although genetic variation contributes to congenital heart defects, their precise molecular bases remain unknown in the majority of patients. Methods and Results-We analyzed, by high-resolution array comparative genomic hybridization, 316 children with sporadic, nonsyndromic congenital heart defects, including 76 coarctation of the aorta, 159 transposition of the great arteries, and 81 tetralogy of Fallot, as well as their unaffected parents. We identified by array comparative genomic hybridization, and validated by quantitative real-time polymerase chain reaction, 71 rare de novo (n=8) or inherited (n=63) copy-number variants (CNVs; 50 duplications and 21 deletions) in patients. We identified 113 candidate genes for congenital heart defects within these CNVs, including BTRC, CHRNB3, CSRP2BP, ERBB2, ERMARD, GLIS3, PLN, PTPRJ, RLN3, and TCTE3. No de novo CNVs were identified in patients with transposition of the great arteries in contrast to coarctation of the aorta and tetralogy of Fallot (P=0.002; Fisher exact test). A search for transcription factor binding sites showed that 93% of the rare CNVs identified in patients with coarctation of the aorta contained at least 1 gene with FOXC1-binding sites. This significant enrichment (P<0.0001; permutation test) was not observed for the CNVs identified in patients with transposition of the great arteries and tetralogy of Fallot. We hypothesize that these CNVs may alter the expression of genes regulated by FOXC1. Foxc1 belongs to the forkhead transcription factors family, which plays a critical role in cardiovascular development in mice. Conclusions-These data suggest that deregulation of FOXC1 or its downstream ge...

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“…Mutations both upstream and downstream of the SOX9 gene have been associated with isolated cases of PRS and it is proposed that these mutations lie in SOX9 enhancers and are required for appropriate SOX9 expression during development [11]. Recently a large 1Mb-sized deletion upstream of SOX9 was found in patients with either isolated PRS, isolated congenital heart defect (CHD), or both of these defects from two families [12]. This large deletion includes enhancers that regulate NKX2.5 and GATA4, genes known to be associated with CHD [42, 43].…”

Section: Introductionmentioning

confidence: 99%

Mutations in the noncoding genome

Scacheri

2015

Current Opinion in Pediatrics

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Purpose of review Clinical diagnostic sequencing currently focuses on identifying causal mutations in the exome, where most disease-causing mutations are known to occur. The rest of the genome is mostly comprised of regulatory elements that control gene expression, but these have remained largely unexplored in clinical diagnostics due to the high cost of whole genome sequencing and interpretive challenges. The purpose of this review is to illustrate examples of diseases caused by mutations in regulatory elements and introduce the diagnostic potential for whole genome sequencing. Different classes of functional elements and chromatin structure are described to provide the clinician with a foundation for understanding the basis of these mutations. Recent Findings The utilization of whole genome sequence data, epigenomic maps and iPS cell technologies facilitated the discovery that mutations in the PTF1A enhancer can cause isolated pancreatic agenesis. High resolution array CGH, whole genome sequencing, maps of 3-D chromatin architecture, and mouse models generated using CRISPR-Cas were used to show that disruption of topological-associated domain (TAD) boundary elements cause limb defects. Structural variants that reposition enhancers in somatic cells have also been described in cancer. Summary While not ready for diagnostics, new technologies, epigenomic maps and improved knowledge of chromatin architecture will soon enable a better understanding and diagnostic solutions for currently unexplained genetic disorders.

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Congenital Heart Defects in Patients with Deletions Upstream ofSOX9

Cited by 33 publications

References 19 publications

Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3

Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3

Search for Rare Copy-Number Variants in Congenital Heart Defects Identifies Novel Candidate Genes and a Potential Role for FOXC1 in Patients With Coarctation of the Aorta

Mutations in the noncoding genome

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