Faculty Collaboration Database

Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene. Am J Hum Genet 2021 Oct 07;108(10):1964-1980

Date

09/22/2021

Pubmed ID

34547244

Pubmed Central ID

PMC8546037

DOI

10.1016/j.ajhg.2021.08.011

Scopus ID

2-s2.0-85116717034 (requires institutional sign-in at Scopus site)   17 Citations

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.

Author List

Qiao L, Xu L, Yu L, Wynn J, Hernan R, Zhou X, Farkouh-Karoleski C, Krishnan US, Khlevner J, De A, Zygmunt A, Crombleholme T, Lim FY, Needelman H, Cusick RA, Mychaliska GB, Warner BW, Wagner AJ, Danko ME, Chung D, Potoka D, Kosiński P, McCulley DJ, Elfiky M, Azarow K, Fialkowski E, Schindel D, Soffer SZ, Lyon JB, Zalieckas JM, Vardarajan BN, Aspelund G, Duron VP, High FA, Sun X, Donahoe PK, Shen Y, Chung WK

Author

Amy Wagner MD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

ATP-Dependent Proteases
Animals
Case-Control Studies
Cohort Studies
Craniofacial Abnormalities
DNA Copy Number Variations
Eye Abnormalities
Female
Growth Disorders
Hernias, Diaphragmatic, Congenital
Hip Dislocation, Congenital
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mitochondrial Proteins
Mutation, Missense
Osteochondrodysplasias
Pedigree
Tooth Abnormalities