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_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_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.
Original language | English |
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Article number | 104120 |
Number of pages | 5 |
Journal | European Journal of Medical Genetics |
Volume | 64 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Jan 2021 |
Keywords
- children
- complex 1 deficiency
- genetics
- intronic variant
- leigh
- mitchondrial disease
- mitochondrial complex
- timmdc1
- TIMMDC1
- Complex 1 deficiency
- MITOCHONDRIAL COMPLEX
- CHILDREN
- Genetics
- Mitchondrial disease
- Intronic variant
- LEIGH