De novo frameshift mutation inCOUP-TFII(NR2F2) in human congenital diaphragmatic hernia

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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De Novo Duplication of 11p15 Associated With Congenital Diaphragmatic Hernia

Frontiers in Pediatrics ◽

10.3389/fped.2018.00116 ◽

2018 ◽

Vol 6 ◽

Author(s):

Gabriel C. Dworschak ◽

Hartmut Engels ◽

Jessica Becker ◽

Lukas Soellner ◽

Thomas Eggermann ◽

...

Keyword(s):

Congenital Diaphragmatic Hernia ◽

Diaphragmatic Hernia ◽

De Novo

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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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Likely damaging de novo variants in congenital diaphragmatic hernia patients are associated with worse clinical outcomes

Genetics in Medicine ◽

10.1038/s41436-020-0908-0 ◽

2020 ◽

Vol 22 (12) ◽

pp. 2020-2028 ◽

Cited By ~ 1

Author(s):

Lu Qiao ◽

Julia Wynn ◽

Lan Yu ◽

Rebecca Hernan ◽

Xueya Zhou ◽

...

Keyword(s):

Congenital Diaphragmatic Hernia ◽

Clinical Outcomes ◽

Diaphragmatic Hernia ◽

De Novo

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Congenital Diaphragmatic Hernia in a Fetus with a De novo Terminal Deletion of Chromosome 15q26.1

Hereditary Genetics ◽

10.4172/2161-1041.1000101 ◽

2012 ◽

Vol 01 (01) ◽

Author(s):

Ruth C ◽

Starcevic J ◽

Bartholomew ML

Keyword(s):

Congenital Diaphragmatic Hernia ◽

Diaphragmatic Hernia ◽

De Novo ◽

Terminal Deletion

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Management of Congenital Diaphragmatic Hernia (CDH): Role of Molecular Genetics

International Journal of Molecular Sciences ◽

10.3390/ijms22126353 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6353

Author(s):

Giulia Cannata ◽

Chiara Caporilli ◽

Federica Grassi ◽

Serafina Perrone ◽

Susanna Esposito

Keyword(s):

Congenital Diaphragmatic Hernia ◽

Diaphragmatic Hernia ◽

De Novo ◽

Current Knowledge ◽

Lung Hypoplasia ◽

Cellular Mechanisms ◽

Major Life ◽

Mortality And Morbidity ◽

Functional Studies ◽

Life Threatening

Congenital diaphragmatic hernia (CDH) is a relatively common major life-threatening birth defect that results in significant mortality and morbidity depending primarily on lung hypoplasia, persistent pulmonary hypertension, and cardiac dysfunction. Despite its clinical relevance, CDH multifactorial etiology is still not completely understood. We reviewed current knowledge on normal diaphragm development and summarized genetic mutations and related pathways as well as cellular mechanisms involved in CDH. Our literature analysis showed that the discovery of harmful de novo variants in the fetus could constitute an important tool for the medical team during pregnancy, counselling, and childbirth. A better insight into the mechanisms regulating diaphragm development and genetic causes leading to CDH appeared essential to the development of new therapeutic strategies and evidence-based genetic counselling to parents. Integrated sequencing, development, and bioinformatics strategies could direct future functional studies on CDH; could be applied to cohorts and consortia for CDH and other birth defects; and could pave the way for potential therapies by providing molecular targets for drug discovery.

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Genome-wide enrichment of damaging de novo variants in patients with isolated and complex congenital diaphragmatic hernia

Human Genetics ◽

10.1007/s00439-017-1774-y ◽

2017 ◽

Vol 136 (6) ◽

pp. 679-691 ◽

Cited By ~ 16

Author(s):

Mauro Longoni ◽

Frances A. High ◽

Hongjian Qi ◽

Maliackal P. Joy ◽

Regis Hila ◽

...

Keyword(s):

Congenital Diaphragmatic Hernia ◽

Diaphragmatic Hernia ◽

De Novo ◽

Genome Wide

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Clinical exome sequencing data reveal high diagnostic yields for congenital diaphragmatic hernia plus (CDH+) and new phenotypic expansions involving CDH

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-107317 ◽

2021 ◽

pp. jmedgenet-2020-107317

Author(s):

Tiana M Scott ◽

Ian M Campbell ◽

Andres Hernandez-Garcia ◽

Seema R Lalani ◽

Pengfei Liu ◽

...

Keyword(s):

Congenital Diaphragmatic Hernia ◽

Exome Sequencing ◽

Diaphragmatic Hernia ◽

De Novo ◽

Diagnostic Yield ◽

Fanconi Anaemia ◽

Compound Heterozygous ◽

Pathogenic Variants ◽

Clinical Exome Sequencing ◽

Made In

BackgroundCongenital diaphragmatic hernia (CDH) is a life-threatening birth defect that often co-occurs with non-hernia-related anomalies (CDH+). While copy number variant (CNV) analysis is often employed as a diagnostic test for CDH+, clinical exome sequencing (ES) has not been universally adopted.MethodsWe analysed a clinical database of ~12 000 test results to determine the diagnostic yields of ES in CDH+ and to identify new phenotypic expansions.ResultsAmong the 76 cases with an indication of CDH+, a molecular diagnosis was made in 28 cases for a diagnostic yield of 37% (28/76). A provisional diagnosis was made in seven other cases (9%; 7/76). Four individuals had a diagnosis of Kabuki syndrome caused by frameshift variants in KMT2D. Putatively deleterious variants in ALG12 and EP300 were each found in two individuals, supporting their role in CDH development. We also identified individuals with de novo pathogenic variants in FOXP1 and SMARCA4, and compound heterozygous pathogenic variants in BRCA2. The role of these genes in CDH development is supported by the expression of their mouse homologs in the developing diaphragm, their high CDH-specific pathogenicity scores generated using a previously validated algorithm for genome-scale knowledge synthesis and previously published case reports.ConclusionWe conclude that ES should be ordered in cases of CDH+ when a specific diagnosis is not suspected and CNV analyses are negative. Our results also provide evidence in favour of phenotypic expansions involving CDH for genes associated with ALG12-congenital disorder of glycosylation, Rubinstein-Taybi syndrome, Fanconi anaemia, Coffin-Siris syndrome and FOXP1-related disorders.

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