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Congenital diaphragmatic hernia (CDH) is a life-threatening developmental defect characterized by diaphragmatic discontinuity and pulmonary hypoplasia that often co-occurs with additional malformations. Genetic studies have established a role for de novo and inherited variants in CDH pathogenesis and recently highlighted LONP1 as a candidate risk gene (PMID:34547244).
In an exome analysis of 827 CDH proband–parent trios, damaging de novo variants in LONP1 reached a false discovery rate below 0.05, marking it among the top constrained genes enriched for CDH (PMID:34547244). Ultra-rare variant association testing in 748 independent CDH cases versus 11 220 ancestry-matched controls identified heterozygous LONP1 variants in ~3% of cases (~25/827), with significant burden compared to controls (PMID:34547244).
Segregation analysis revealed at least 3 families in which ultra-rare heterozygous LONP1 variants co-segregated with CDH, supporting an autosomal dominant inheritance model. No alternate modes or contradictory findings were reported in this cohort.
Functional studies in mice demonstrate that lung epithelium-specific deletion of Lonp1 causes neonatal lethality due to severe pulmonary hypoplasia—the key driver of mortality in human CDH—thereby providing strong in vivo support for LONP1 haploinsufficiency in diaphragmatic and lung development (PMID:34547244).
Together, de novo enrichment, case-control burden, familial segregation, and concordant murine phenotypes establish LONP1 as a strong autosomal dominant risk gene for CDH. This knowledge informs genetic diagnosis, risk assessment, and potential targeting of mitochondrial proteostasis pathways in CDH management.
Key Take-home: Screening for heterozygous LONP1 variants should be considered in CDH diagnostics to guide prognosis and family counseling.
Gene–Disease AssociationStrongApproximately 25 unrelated probands with de novo or ultra-rare LONP1 variants; segregation in 3 families; concordant murine pulmonary hypoplasia model Genetic EvidenceStrongEnrichment of damaging de novo variants in 827 trios and significant ultra-rare burden in 748 cases versus 11 220 controls ([PMID:34547244]) Functional EvidenceModerateLung epithelium-specific Lonp1 knockout mice exhibit neonatal lethality and pulmonary hypoplasia ([PMID:34547244]) |