Clin Genet
. 2025 Sep 10.
doi: 10.1111/cge.70057. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/40931319/
LONP1 Variants Are Associated With Clinically Diverse Phenotypes
Randee E Young 1, Lu Qiao 2 3, Rebecca Hernan 1, David A Sweetser 4, Jessica L Waxler 1, Daryl A Scott 5, Tiana M Scott 5, Seema R Lalani 5, Mahshid S Azamian 5, Jill A Rosenfeld 5, Bret Bostwick 5, Lindsay C Burrage 5 6; Undiagnosed Diseases Network; Lance H Rodan 7, Bianca E Russell 8, Marina Dutra-Clarke 8, Michael Kruer 9 10, Somayeh Bakhtiarim 9 10, Hossein Darvish 11, David J Amor 12, Shamima Rahman 13, Karen Stals 14, Lisa Bradley 15, Susan Byrne 15, Leandra K Tolusso 16, Beatrix Wong 16, Laura Benedict 17, Kimberly Wallis 17, Kestutis Micke 18, Cindy Colson 19, Thomas Smol 19, Sabrina V Southwick 20, Kristen A Miller 20, Michelle L Kush 21, Odelia Chorin 22, Annick Rothschild 22, Wei Wang 23, Yufeng Shen 3 24 25, Wendy K Chung 1
Affiliations Expand
- PMID: 40931319
- DOI: 10.1111/cge.70057
Abstract
LONP1 encodes a mitochondrial protease essential for protein quality control and metabolism. Variants in LONP1 are associated with a diverse and expanding spectrum of disorders, including Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies syndrome (CODAS), congenital diaphragmatic hernia (CDH), and neurodevelopmental disorders (NDD), with some individuals exhibiting features of mitochondrial encephalopathy. We report 16 novel LONP1 variants identified in 16 individuals (11 with NDD, 5 with CDH), further expanding the clinical spectrum. Structural mapping of disease-associated missense variants revealed phenotype-specific clustering, with CODAS variants enriched in the proteolytic chamber and NDD variants more broadly distributed. CODAS is caused by biallelic variants and CDH by monoallelic variants, both of which are predicted to act through loss-of-function mechanisms. Both monoallelic and biallelic variants are associated with LONP1-related NDD, suggesting complex mechanisms such as dominant-negative effects. Our findings broaden the phenotypic and genetic spectrum of LONP1-associated disorders and highlight the essential role of LONP1 in mitochondrial function and development.
Keywords: CODAS; LONP1; congenital diaphragmatic hernia; mitochondrial encephalopathy; neurodevelopmental disorder.
© 2025 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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