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Deep intronic TIMMDC1 variant delays diagnosis of rapidly progressive complex I deficiency.
- Source :
-
European journal of medical genetics [Eur J Med Genet] 2021 Jan; Vol. 64 (1), pp. 104120. Date of Electronic Publication: 2020 Dec 02. - Publication Year :
- 2021
-
Abstract
- Complex I deficiency is the most common pediatric mitochondrial disease. It can cause a wide range of clinical disorders, including Leigh syndrome. TIMMDC1 encodes an assembly protein of complex I and has been recently associated with early onset mitochondrial disease in three unrelated families. In all three families the same homozygous deep intronic variant was identified leading to inclusion of a new exon resulting in a frameshift and premature stop codon (c.596 + 2146A > G, p.Gly199&#95;Thr200ins5*). Herein, we describe two brothers of Dutch descent, presenting in infancy with hypotonia and respiratory insufficiency and a rapidly progressive and fatal disease course. Laboratory findings and metabolic investigations revealed no specific abnormalities, notably no raised plasma lactate. MRI showed transient lesions in the basal ganglia of brother 1. A muscle biopsy demonstrated complex I deficiency in brother 2. Exome sequencing yielded a novel heterozygous TIMMDC1 variant: c.385C > T, p.(Arg129*). Targeted sequencing revealed the previously published deep intronic variant c.596 + 2146A > G, p.(Gly199&#95;Thr200ins5*) on the second allele which is not detected by exome sequencing. In summary, we present the fourth family with TIMMDC1-related disease, with a novel nonsense variant. This report illustrates the importance of considering mitochondrial disease even when laboratory findings are normal, and the added value of targeted sequencing of introns.<br /> (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)
- Subjects :
- Basal Ganglia diagnostic imaging
Codon, Nonsense
Delayed Diagnosis
Heterozygote
Humans
Infant
Introns
Lactic Acid blood
Male
Mitochondrial Diseases diagnosis
Mitochondrial Membrane Transport Proteins deficiency
Mitochondrial Precursor Protein Import Complex Proteins
Pedigree
Mitochondrial Diseases genetics
Mitochondrial Membrane Transport Proteins genetics
Phenotype
Subjects
Details
- Language :
- English
- ISSN :
- 1878-0849
- Volume :
- 64
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- European journal of medical genetics
- Publication Type :
- Academic Journal
- Accession number :
- 33278652
- Full Text :
- https://doi.org/10.1016/j.ejmg.2020.104120