A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis.
Document Type
Article
Publication Date
9-1-2021
Publication Title
European journal of human genetics : EJHG
Keywords
JGM
JAX Source
Eur J Hum Genet 2021 Sep; 29(9):1359-1368
Volume
29
Issue
9
First Page
1359
Last Page
1368
ISSN
1476-5438
PMID
34075211
DOI
https://doi.org/10.1038/s41431-021-00900-2
Abstract
The genetic etiology of intellectual disability remains elusive in almost half of all affected individuals. Within the Solve-RD consortium, systematic re-analysis of whole exome sequencing (WES) data from unresolved cases with (syndromic) intellectual disability (n = 1,472 probands) was performed. This re-analysis included variant calling of mitochondrial DNA (mtDNA) variants, although mtDNA is not specifically targeted in WES. We identified a functionally relevant mtDNA variant in MT-TL1 (NC_012920.1:m.3291T > C; NC_012920.1:n.62T > C), at a heteroplasmy level of 22% in whole blood, in a 23-year-old male with severe intellectual disability, epilepsy, episodic headaches with emesis, spastic tetraparesis, brain abnormalities, and feeding difficulties. Targeted validation in blood and urine supported pathogenicity, with heteroplasmy levels of 23% and 58% in index, and 4% and 17% in mother, respectively. Interestingly, not all phenotypic features observed in the index have been previously linked to this MT-TL1 variant, suggesting either broadening of the m.3291T > C-associated phenotype, or presence of a co-occurring disorder. Hence, our case highlights the importance of underappreciated mtDNA variants identifiable from WES data, especially for cases with atypical mitochondrial phenotypes and their relatives in the maternal line.
Recommended Citation
de Boer E,
Ockeloen C,
Matalonga L,
Horvath R,
Rodenburg R,
Coenen M,
Janssen M,
Henssen D,
Gilissen C,
Steyaert W,
Paramonov I,
Trimouille A,
Kleefstra T,
Verloes A,
Vissers L,
Consortium S,
Robinson P.
A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis. Eur J Hum Genet 2021 Sep; 29(9):1359-1368
Comments
Dr. Peter Robinson is a member of the Solve-RD Consortium.