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Congenital diaphragmatic hernia interval on chromosome 8p23.1 characterized by genetics and protein interaction networks.

ABSTRACT: Chromosome 8p23.1 is a common hotspot associated with major congenital malformations, including congenital diaphragmatic hernia (CDH) and cardiac defects. We present findings from high-resolution arrays in patients who carry a loss (n?=?18) or a gain (n?=?1) of sub-band 8p23.1. We confirm a region involved in both diaphragmatic and heart malformations. Results from a novel CNVConnect algorithm, prioritizing protein-protein interactions between products of genes in the 8p23.1 hotspot and products of previously known CDH causing genes, implicated GATA4, NEIL2, and SOX7 in diaphragmatic defects. Sequence analysis of these genes in 226 chromosomally normal CDH patients, as well as in a small number of deletion 8p23.1 patients, showed rare unreported variants in the coding region; these may be contributing to the diaphragmatic phenotype. We also demonstrated that two of these three genes were expressed in the E11.5-12.5 primordial mouse diaphragm, the developmental stage at which CDH is thought to occur. This combination of bioinformatics and expression studies can be applied to other chromosomal hotspots, as well as private microdeletions or microduplications, to identify causative genes and their interaction networks.

SUBMITTER: Longoni M

PROVIDER: S-EPMC3761361 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Congenital diaphragmatic hernia interval on chromosome 8p23.1 characterized by genetics and protein interaction networks.

Longoni Mauro M Lage Kasper K Russell Meaghan K MK Loscertales Maria M Abdul-Rahman Omar A OA Baynam Gareth G Bleyl Steven B SB Brady Paul D PD Breckpot Jeroen J Chen Chih P CP Devriendt Koenraad K Gillessen-Kaesbach Gabriele G Grix Arthur W AW Rope Alan F AF Shimokawa Osamu O Strauss Bernarda B Wieczorek Dagmar D Zackai Elaine H EH Coletti Caroline M CM Maalouf Faouzi I FI Noonan Kristin M KM Park Ji H JH Tracy Adam A AA Lee Charles C Donahoe Patricia K PK Pober Barbara R BR

American journal of medical genetics. Part A 20121119 12

Chromosome 8p23.1 is a common hotspot associated with major congenital malformations, including congenital diaphragmatic hernia (CDH) and cardiac defects. We present findings from high-resolution arrays in patients who carry a loss (n = 18) or a gain (n = 1) of sub-band 8p23.1. We confirm a region involved in both diaphragmatic and heart malformations. Results from a novel CNVConnect algorithm, prioritizing protein-protein interactions between products of genes in the 8p23.1 hotspot and products ...[more]

PMID: 23165946

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Project description:Congenital diaphragmatic hernia (CDH) is a congenital structural anomaly in which the diaphragm has not developed properly. It may occur either as an isolated anomaly or with additional anomalies. It is thought to be a multifactorial disease in which genetic factors could either substantially contribute to or directly result in the developmental defect. Patients with aneuploidies, pathogenic variants or de novo Copy Number Variations (CNVs) impacting specific genes and loci develop CDH typically in the form of a monogenetic syndrome. These patients often have other associated anatomical malformations. In patients without a known monogenetic syndrome, an increased genetic burden of de novo coding variants contributes to disease development. In early years, genetic evaluation was based on karyotyping and SNP-array. Today, genomes are commonly analyzed with next generation sequencing (NGS) based approaches. While more potential pathogenic variants are being detected, analysis of the data presents a bottleneck-largely due to the lack of full appreciation of the functional consequence and/or relevance of the detected variant. The exact heritability of CDH is still unknown. Damaging de novo alterations are associated with the more severe and complex phenotypes and worse clinical outcome. Phenotypic, genetic-and likely mechanistic-variability hampers individual patient diagnosis, short and long-term morbidity prediction and subsequent care strategies. Detailed phenotyping, clinical follow-up at regular intervals and detailed registries are needed to find associations between long-term morbidity, genetic alterations, and clinical parameters. Since CDH is a relatively rare disorder with only a few recurrent changes large cohorts of patients are needed to identify genetic associations. Retrospective whole genome sequencing of historical patient cohorts using will yield valuable data from which today's patients and parents will profit Trio whole genome sequencing has an excellent potential for future re-analysis and data-sharing increasing the chance to provide a genetic diagnosis and predict clinical prognosis. In this review, we explore the pitfalls and challenges in the analysis and interpretation of genetic information, present what is currently known and what still needs further study, and propose strategies to reap the benefits of genetic screening.

Dataset Information

Congenital diaphragmatic hernia interval on chromosome 8p23.1 characterized by genetics and protein interaction networks.

Publications

Congenital diaphragmatic hernia interval on chromosome 8p23.1 characterized by genetics and protein interaction networks.

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