Findings from aCGH in patients with congenital diaphragmatic hernia (CDH): A possible locus for Fryns syndrome

Kantarci, Sibel; Casavant, David; Prada, Carlos E.; Russell, Meaghan; Byrne, Janice L. B.; Haug, Louise Wilkins; Jennings, Rebecca B.; Manning, Simon M.; Boyd, Theonia K.; Fryns, Jean‐Pierre; Holmes, Lewis B.; Donahoe, Patricia K.; Lee, C.; Kimonis, Virginia; Pober, Barbara R.

doi:10.1002/ajmg.a.31025

Cited by 70 publications

(90 citation statements)

References 34 publications

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“…Deletions of these four CDH-critical regions have previously been shown to be associated with abnormal diaphragm development and these regions are not novel. 10,11,13,16,17 However, our detection of further patients with CDH and deletions of these regions strengthens the concept that haploinsufficiency for a gene or genes in these regions leads to diaphragm defects. We hypothesize that loss of function of a gene(s) in these regions can cause CDH, either through chromosome deletion or through possible gene mutation.…”

Section: Discussionsupporting

confidence: 68%

“…This patient is the second of two patients with CDH and overlapping deletions of 1q41 -1q42 to be reported and the critical region is 5 Mb in size. 13 In the 15 patients with nonsyndromic CDH, no other copy number changes consistent with chromosome aberrations were identified.…”

Section: Array Cgh Datamentioning

confidence: 92%

“…12 A third study by a third group of authors reported a deletion of 1q41-1q42 in a patient with CDH and other anomalies. 13 In the present study, we sought to further explore array CGH for identifying and mapping chromosome aberrations in a large panel of CDH patients to provide additional genomic information on regions likely to contain genes of relevance to CDH etiology.…”

Section: Introductionmentioning

confidence: 99%

“…There is one other recent report of a patient with a similar phenotype studied with array CGH who was found to have a smaller submicroscopic deletion of 1q41 -1q42. 13 G-banded chromosome studies have also reported additional overlapping 1q42 deletions in CDH patients. A female with CDH and multiple malformations had a karytoype of 46,XX,del(1)(pter-42.11::q42.3-qter) de novo, with normal FISH studies for the 1q telomeres.…”

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confidence: 99%

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Array comparative genomic hybridization in patients with congenital diaphragmatic hernia: mapping of four CDH-critical regions and sequencing of candidate genes at 15q26.1–15q26.2

et al. 2006

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Congenital diaphragmatic hernia (CDH) is a common birth defect with a high mortality and morbidity. There have been few studies that have assessed copy number changes in CDH. We present array comparative genomic hybridization data for 29 CDH patients to identify and map chromosome aberrations in this disease. Three patients with 15q26.1-15q26.2 deletions had heterogeneous breakpoints that overlapped with the critical 4 Mb region previously delineated for CDH, confirming 15q26.1-15q26.2 as a critical region for CDH. The three other most compelling CDH-critical regions for genomic deletions based on these data and a literature review are located at chromosomes 8p23.1, 4p16.3 -4pter, and 1q41-1q42.1. Based on these recurrent deletions at 15q26.1-15q26.2, we hypothesized that loss-of-function mutations in a gene or genes from this region could cause CDH and sequenced six candidate genes from this region in more than 100 patients with CDH. For three of these genes (CHD2, ARRDC4, and RGMA), we identified missense changes and that were not identified in normal controls; however, none of these alterations appeared unambiguously causal with CDH. These data suggest that CDH caused by chromosome deletions at 15q26.2 may arise because of a contiguous gene deletion syndrome or may have a multifactorial etiology. In addition, there is evidence for substantial genetic heterogeneity in CDH and diaphragmatic hernias can be non-penetrant in patients who have deletions involving CDH-critical regions.

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Section: Discussionsupporting

confidence: 68%

Section: Array Cgh Datamentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Array comparative genomic hybridization in patients with congenital diaphragmatic hernia: mapping of four CDH-critical regions and sequencing of candidate genes at 15q26.1–15q26.2

et al. 2006

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“…One strategy for gene detection utilized array comparative genomic hybridization to identify and define chromosome deletions in patients with CDH and multiple anomalies. 5,6 These deleted chromosome regions can be assumed to contain gene(s) necessary for normal diaphragm development, and genes from these 'DH-critical' regions can subsequently be selected for sequencing in isolated CDH patients. Although several CDH critical regions at 15q26.2, 8p23.1, 4p16.3 and 1q41 -1q42 have been mapped using this strategy, no CDH-causative gene has yet been identified.…”

Section: Introductionmentioning

confidence: 99%

Candidate genes for congenital diaphragmatic hernia from animal models: sequencing of FOG2 and PDGFRα reveals rare variants in diaphragmatic hernia patients

Bleyl

Moshrefi

Shaw³

et al. 2007

Eur J Hum Genet

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Congenital diaphragmatic hernia (CDH) is a common, life threatening birth defect. Although there is strong evidence implicating genetic factors in its pathogenesis, few causative genes have been identified, and in isolated CDH, only one de novo, nonsense mutation has been reported in FOG2 in a female with posterior diaphragmatic eventration. We report here that the homozygous null mouse for the Pdgfra gene has posterolateral diaphragmatic defects and thus is a model for human CDH. We hypothesized that mutations in this gene could cause human CDH. We sequenced PDGFRa and FOG2 in 96 patients with CDH, of which 53 had isolated CDH (55.2%), 36 had CDH and additional anomalies (37.5%), and 7 had CDH and known chromosome aberrations (7.3%). For FOG2, we identified novel sequence alterations predicting p.M703L and p.T843A in two patients with isolated CDH that were absent in 526 and 564 control chromosomes respectively. These altered amino acids were highly conserved. However, due to the lack of available parental DNA samples we were not able to determine if the sequence alterations were de novo. For PDGFRa, we found a single variant predicting p.L967V in a patient with CDH and multiple anomalies that was absent in 768 control chromosomes. This patient also had one cell with trisomy 15 on skin fibroblast culture, a finding of uncertain significance. Although our study identified sequence variants in FOG2 and PDGFRa, we have not definitively established the variants as mutations and we found no evidence that CDH commonly results from mutations in these genes.

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Genomic Approaches to Surgical Diseases

Donahoe

2006

Arch Surg

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Findings from aCGH in patients with congenital diaphragmatic hernia (CDH): A possible locus for Fryns syndrome

Cited by 70 publications

References 34 publications

Array comparative genomic hybridization in patients with congenital diaphragmatic hernia: mapping of four CDH-critical regions and sequencing of candidate genes at 15q26.1–15q26.2

Array comparative genomic hybridization in patients with congenital diaphragmatic hernia: mapping of four CDH-critical regions and sequencing of candidate genes at 15q26.1–15q26.2

Candidate genes for congenital diaphragmatic hernia from animal models: sequencing of FOG2 and PDGFRα reveals rare variants in diaphragmatic hernia patients

Genomic Approaches to Surgical Diseases

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