ArticleAmerican journal of human genetics2021
Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene.
Article in American journal of human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 45 citations in OpenAlex.
- How Epigenetics Bridges Genes and Environment: A Multiomics Evidence Chain in Congenital Diaphragmatic Hernia.Birth defects research · 2026Review
- Cell fate specification during respiratory development requires ARID1A-containing canonical BAF complex activity.Nature communications · 2026Article
- Mechanical compression causes lung hypoplasia in congenital diaphragmatic hernia with GATA4 genetic variants.American journal of physiology. Lung cellular and molecular physiology · 2026Article
- LONP1 Variants Are Associated With Clinically Diverse Phenotypes.Clinical genetics · 2026Article
- Modeling patient variants ofbioRxiv : the preprint server for biology · 2026Article
- Role of LONP1 in human diseases: molecular mechanisms and therapeutic potential.Cellular & molecular biology letters · 2026Review
- WNT4 deficiency impacts heart, diaphragm, and palate development: Insights from human genetics, machine learning, and mouse models.Developmental biology · 2026Article
- Beyond the genome: clinical challenges in diagnosingFrontiers in cell and developmental biology · 2026Article
- Genetic Diagnosis and Clinical Features of Fetuses With Congenital Diaphragmatic Hernia.Prenatal diagnosis · 2025Article
- Modulation of Lonp1 Activity by Small Compounds.Biomolecules · 2025Review
- De novo variants in RYBP are associated with a severe neurodevelopmental disorder and congenital anomalies.Genetics in medicine : official journal of the American College of Medical Genetics · 2025Article
- RNA binding proteins (RBPs) on genetic stability and diseases.Global medical genetics · 2025Review
- Mitochondrial Lon Peptidase 1 Controls Diaphragm and Lung Development in a Context-Dependent Manner.Journal of respiratory biology and translational medicine · 2025Article
- Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants.American journal of human genetics · 2024Article
- Context-dependent roles of mitochondrial LONP1 in orchestrating the balance between airway progenitor versus progeny cells.Cell stem cell · 2024Article
- Statistical methods for assessing the effects of de novo variants on birth defects.Human genomics · 2024Review
- The etiology of congenital diaphragmatic hernia: the retinoid hypothesis 20 years later.Pediatric research · 2024Review
- TREX tetramer disruption alters RNA processing necessary for corticogenesis in THOC6 Intellectual Disability Syndrome.Nature communications · 2024Article
- Rescuing lung development through embryonic inhibition of histone acetylation.Science translational medicine · 2024Article
- Role of genetics and the environment in the etiology of congenital diaphragmatic hernia.World journal of pediatric surgery · 2024Review
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Authors and funding
38 authors at 19 institutions in 3 countries.
Funding
Abstract
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-associated 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 candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals 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 affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 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, most likely because of the observed severe reduction of lung growth, a known contributor to 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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