Young, Randee E;
Qiao, Lu;
Hernan, Rebecca;
Sweetser, David A;
Waxler, Jessica L;
Scott, Daryl A;
Scott, Tiana M;
... Chung, Wendy K; + view all
(2025)
LONP1 Variants Are Associated With Clinically Diverse Phenotypes.
Clinical Genetics
, Article cge.70057. 10.1111/cge.70057.
(In press).
![[thumbnail of LONP1_prepub.pdf]](https://discovery.ucl.ac.uk/style/images/fileicons/text.png) |
Text
LONP1_prepub.pdf - Accepted Version Access restricted to UCL open access staff until 11 September 2026. Download (7MB) |
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.
| Type: | Article |
|---|---|
| Title: | LONP1 Variants Are Associated With Clinically Diverse Phenotypes |
| Location: | Denmark |
| DOI: | 10.1111/cge.70057 |
| Publisher version: | https://doi.org/10.1111/cge.70057 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | CODAS, congenital diaphragmatic hernia, LONP1, mitochondrial encephalopathy, neurodevelopmental disorder |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10215585 |
Archive Staff Only
 |
View Item |
