Browsing by Subject "CHD7"

Now showing 1 - 4 of 4
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    Evidence for replicative mechanism in a CHD7 rearrangement in a patient with CHARGE syndrome
    (Wiley, 2013-12) Vatta, Matteo; Niu, Zhiyv; Lupski, James R.; Putnam, Philip; Spoonamore, Katherine G.; Fang, Ping; Eng, Christine M.; Willis, Alecia S.; Medical & Molecular Genetics, School of Medicine
    Haploinsufficiency of CHD7 (OMIM# 608892) is known to cause CHARGE syndrome (OMIM# 214800). Molecular testing supports a definitive diagnosis in approximately 65-70% of cases. Most CHD7 mutations arise de novo, and no mutations affecting exon-7 have been reported to date. We report on an 8-year-old girl diagnosed with CHARGE syndrome that was referred to our laboratory for comprehensive CHD7 gene screening. Genomic DNA from the subject with a suspected diagnosis of CHARGE was isolated from peripheral blood lymphocytes and comprehensive Sanger sequencing, along with deletion/duplication analysis of the CHD7 gene using multiplex ligation-dependent probe amplification (MLPA), was performed. MLPA analysis identified a reduced single probe signal for exon-7 of the CHD7 gene consistent with potential heterozygous deletion. Long-range PCR breakpoint analysis identified a complex genomic rearrangement (CGR) leading to the deletion of exon-7 and breakpoints consistent with a replicative mechanism such as fork stalling and template switching (FoSTeS) or microhomology-mediated break-induced replication (MMBIR). Taken together this represents the first evidence for a CHD7 intragenic CGR in a patient with CHARGE syndrome leading to what appears to be also the first report of a mutation specifically disrupting exon-7. Although likely rare, CGR may represent an overlooked mechanism in subjects with CHARGE syndrome that can be missed by current sequencing and dosage assays.
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    Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency
    (PNAS, 2014-12-16) Balasubramanian, Ravikumar; Choi, Jin-Ho; Francescatto, Ludmila; Willer, Jason; Horton, Edward R.; Asimacopoulos, Eleni P.; Stankovic, Konstantina M.; Plummer, Lacey; Buck, Cassandra L.; Quinton, Richard; Nebesio, Todd D.; Mericq, Veronica; Merino, Paulina M.; Meyer, Brian F.; Monies, Dorota; Gusella, James F.; Al Tassanj, Nada; Katsanis, Nicholas; Crowley Jr., William F.; Department of Pediatrics, IU School of Medicine
    Inactivating mutations in chromodomain helicase DNA binding protein 7 (CHD7) cause CHARGE syndrome, a severe multiorgan system disorder of which Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a minor feature. Recent reports have described predominantly missense CHD7 alleles in IGD patients, but it is unclear if these alleles are relevant to causality or overall genetic burden of Kallmann syndrome (KS) and normosmic form of IGD. To address this question, we sequenced CHD7 in 783 well-phenotyped IGD patients lacking full CHARGE features; we identified nonsynonymous rare sequence variants in 5.2% of the IGD cohort (73% missense and 27% splice variants). Functional analyses in zebrafish using a surrogate otolith assay of a representative set of these CHD7 alleles showed that rare sequence variants observed in controls showed no altered function. In contrast, 75% of the IGD-associated alleles were deleterious and resulted in both KS and normosmic IGD. In two families, pathogenic mutations in CHD7 coexisted with mutations in other known IGD genes. Taken together, our data suggest that rare deleterious CHD7 alleles contribute to the mutational burden of patients with both KS and normosmic forms of IGD in the absence of full CHARGE syndrome. These findings (i) implicate a unique role or preferential sensitivity for CHD7 in the ontogeny of GnRH neurons, (ii) reiterate the emerging genetic complexity of this family of IGD disorders, and (iii) demonstrate how the coordinated use of well-phenotyped cohorts, families, and functional studies can inform genetic architecture and provide insights into the developmental biology of cellular systems.
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    Inappropriate p53 Activation During Development Induces Features of CHARGE Syndrome
    (Nature Publishing Group, 2014-10-09) Van Nostrand, Jeanine L.; Brady, Colleen A.; Jung, Heiyoun; Fuentes, Daniel R.; Kozak, Margaret M.; Johnson, Thomas M.; Lin, Chieh-Yu; Lin, Chien-Jung; Swiderski, Donald L.; Vogel, Hannes; Bernstein, Jonathan A.; Attié-Bitach, Tania; Chang, Ching-Pin; Wysocka, Joanna; Martin, Donna M.; Attardi, Laura D.; Department of Medicine, IU School of Medicine
    CHARGE syndrome is a multiple anomaly disorder in which patients present with a variety of phenotypes, including ocular coloboma, heart defects, choanal atresia, retarded growth and development, genitourinary hypoplasia and ear abnormalities. Despite 70-90% of CHARGE syndrome cases resulting from mutations in the gene CHD7, which encodes an ATP-dependent chromatin remodeller, the pathways underlying the diverse phenotypes remain poorly understood. Surprisingly, our studies of a knock-in mutant mouse strain that expresses a stabilized and transcriptionally dead variant of the tumour-suppressor protein p53 (p53(25,26,53,54)), along with a wild-type allele of p53 (also known as Trp53), revealed late-gestational embryonic lethality associated with a host of phenotypes that are characteristic of CHARGE syndrome, including coloboma, inner and outer ear malformations, heart outflow tract defects and craniofacial defects. We found that the p53(25,26,53,54) mutant protein stabilized and hyperactivated wild-type p53, which then inappropriately induced its target genes and triggered cell-cycle arrest or apoptosis during development. Importantly, these phenotypes were only observed with a wild-type p53 allele, as p53(25,26,53,54)(/-) embryos were fully viable. Furthermore, we found that CHD7 can bind to the p53 promoter, thereby negatively regulating p53 expression, and that CHD7 loss in mouse neural crest cells or samples from patients with CHARGE syndrome results in p53 activation. Strikingly, we found that p53 heterozygosity partially rescued the phenotypes in Chd7-null mouse embryos, demonstrating that p53 contributes to the phenotypes that result from CHD7 loss. Thus, inappropriate p53 activation during development can promote CHARGE phenotypes, supporting the idea that p53 has a critical role in developmental syndromes and providing important insight into the mechanisms underlying CHARGE syndrome.
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    Persistent left superior vena cava: an overlooked feature of CHARGE syndrome?
    (PAGEpress, 2015-12-19) Goldenberg, Paula; Shikany, Amy; Parrott, Ashley; Ware, Stephanie M.; Hinton, Robert B.; Medical and Molecular Genetics, School of Medicine
    CHARGE is a well-characterized syndrome (OMIM 2148400) associated with multiple congenital anomalies including cardiovascular malformations. Mutations in CHD7 are the most common cause of CHARGE syndrome. Persistent left superior vena cava (LSVC) has been described in patients with CHARGE syndrome in one study of LSVC associations. A retrospective chart review was conducted for all patients with CHARGE syndrome, diagnosed by Blake criterion features and/or the presence of a pathogenic CHD7 mutation. Echocardio - grams were performed on a clinical basis for all patients and were systematically reviewed and classified. Persistent LSVC was present in 50% of patients with CHARGE syndrome (4/8) and was seen in 3 out of 33 patients seen by cardiovascular genetics with 22q11.2 deletion syndrome. Persistent LSVC is a common finding in patients with CHARGE syndrome and its presence may increase the index of suspicion in patients with other characteristic congenital anomalies.