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

Congenital diaphragmatic hernia (CDH), characterized by malformation of the diaphragm and hypoplasia of the lungs, is one of the most common and severe birth defects, and is associated with high morbidity and mortality rates. There is growing evidence demonstrating that genetic factors contribute to CDH, although the pathogenesis remains largely elusive. Single-nucleotide polymorphisms have been studied in recent whole-exome sequencing efforts, but larger copy number variants (CNVs) have not yet been studied on a large scale in a case control study. To capture CNVs within CDH candidate regions, we developed and tested a targeted array comparative genomic hybridization platform to identify CNVs within 140 regions in 196 patients and 987 healthy controls, and identified six significant CNVs that were either unique to patients or enriched in patients compared with controls. These CDH-associated CNVs reveal high-priority candidate genes including HLX, LHX1, and HNF1B. We also discuss CNVs that are present in only one patient in the cohort but have additional evidence of pathogenicity, including extremely rare large and/or de novo CNVs. The candidate genes within these predicted disease-causing CNVs form functional networks with other known CDH genes and play putative roles in DNA binding/transcription regulation and embryonic development. These data substantiate the importance of CNVs in the etiology of CDH, identify CDH candidate genes and pathways, and highlight the importance of ongoing analysis of CNVs in the study of CDH and other structural birth defects.

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Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 and ALYREF as new candidate risk genes

10.1101/2021.06.01.21257928 ◽

2021 ◽

Author(s):

Lu Qiao ◽

Le Xu ◽

Lan Yu ◽

Julia Wynn ◽

Rebecca Hernan ◽

...

Keyword(s):

Congenital Diaphragmatic Hernia ◽

Diaphragmatic Hernia ◽

Rare Variants ◽

De Novo ◽

Disease Genes ◽

Risk Genes ◽

Association Analyses ◽

Significant Enrichment ◽

Coding Variants

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (Lon Peptidase 1, Mitochondrial) and ALYREF (Aly/REF Export Factor) as novel candidate CDH genes based on de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 cases and 11,220 ancestry-matched population controls and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in familial cases. Approximately 3% of our CDH cohort was heterozygous with ultra-rare predicted damaging variants in LONP1 who have a range of clinical phenotypes including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium specific deletion of Lonp1 die immediately after birth and have reduced lung growth and branching that may at least partially explain the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

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Decreased Lung Fibroblast Growth Factor 18 and Elastin in Human Congenital Diaphragmatic Hernia and Animal Models

American Journal of Respiratory and Critical Care Medicine ◽

10.1164/rccm.200601-050oc ◽

2007 ◽

Vol 175 (10) ◽

pp. 1066-1077 ◽

Cited By ~ 34

Author(s):

Olivier Boucherat ◽

Alexandra Benachi ◽

Anne-Marie Barlier-Mur ◽

Marie-Laure Franco-Montoya ◽

Jelena Martinovic ◽

...

Keyword(s):

Growth Factor ◽

Animal Models ◽

Congenital Diaphragmatic Hernia ◽

Fibroblast Growth Factor ◽

Diaphragmatic Hernia ◽

Lung Fibroblast ◽

Fibroblast Growth

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Diaphragm defects occur in a CDH hernia model independently of myogenesis and lung formation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00257.2002 ◽

2002 ◽

Vol 283 (6) ◽

pp. L1310-L1314 ◽

Cited By ~ 70

Author(s):

Randal P. Babiuk ◽

John J. Greer

Keyword(s):

Animal Models ◽

Congenital Diaphragmatic Hernia ◽

Lung Tissue ◽

Diaphragmatic Hernia ◽

Clinical Problem ◽

Mouse Embryos ◽

Diaphragm Muscle ◽

Primary Defect ◽

Muscle Precursor ◽

Lung Agenesis

Congenital diaphragmatic hernia (CDH) is a significant clinical problem in which a portion of the diaphragmatic musculature fails to form, resulting in a hole in the diaphragm. Here we use animal models of CDH to test two hypotheses regarding the pathogenesis. First, the origin of the defect results from the malformation of the amuscular mesenchymal component of the primordial diaphragm rather than with the process of myogenesis. Second, the defect in the primordial diaphragmatic tissue is not secondary to defects in the developing lung. In c- met(−/−) mouse embryos, in which diaphragm muscle fibers do not form because of a defect in muscle precursor migration, the amuscular substratum forms fully. We show that a defect characteristic of CDH can be induced in the amuscular membrane. In Fgf10(−/−) mouse embryos that have lung agenesis we show that the primordial diaphragm does not depend on signals from lung tissue for proper development and that diaphragmatic malformation is a primary defect in CDH. These data suggest that the pathogenesis of CDH involves mechanisms fundamentally different from previously proposed hypotheses.

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