TIMMDC1 – mitochondrial complex I deficiency

TIMMDC1 encodes a critical assembly factor of mitochondrial complex I and is implicated in autosomal recessive mitochondrial complex I deficiency (MONDO:0100133). Affected infants present with rapidly progressive hypotonia and respiratory insufficiency, often with basal ganglia involvement on MRI. Early biochemical screening may be non-diagnostic, underscoring the need for comprehensive genetic testing, including intronic regions.

Genetic evidence includes biallelic loss-of-function variants in seven probands across four unrelated families, including two Dutch brothers and two siblings from a consanguineous pedigree (AR inheritance). Segregation of pathogenic alleles was demonstrated in four additional affected relatives, confirming co-segregation with disease (PMID:33278652, PMID:35091571). Notably, a recurrent deep intronic splice-enhancing variant c.597-1340A>G is homozygous in multiple families, while novel nonsense changes c.385C>T (p.Arg129Ter) and c.673C>T (p.Arg225Ter) result in premature truncation.

Variant spectrum comprises at least one canonical splice acceptor change (c.361-2A>T), deep intronic splice variant (c.597-1340A>G), and two truncating alleles: c.385C>T (p.Arg129Ter) and c.673C>T (p.Arg225Ter). The deep intronic allele appears at low frequency in population databases (~1/5 000) and recurs in distinct ethnic groups, suggesting a possible founder effect. Each variant abrogates TIMMDC1 protein expression, consistent with a loss-of-function mechanism.

Functional assays in patient-derived fibroblasts demonstrate nearly complete loss of TIMMDC1 protein and severe complex I deficiency, which is rescued by splice-switching antisense oligonucleotides targeting the c.597-1340A>G-induced exon (PMID:35091571). A hypomorphic effect of the p.Arg225Ter allele was observed in CI assembly assays but did not fully complement TIMMDC1 knockout, indicating partial function (PMID:30981218).

One report highlights that the p.Arg225Ter variant alone, in homozygosity, may not produce a distinct clinical phenotype outside the context of dual pathogenic hits, emphasizing careful ACMG-guided interpretation (PMID:30981218). No studies have refuted the TIMMDC1–complex I deficiency association to date.

Integration of genetic and experimental data supports a Strong clinical validity classification: multiple unrelated families, biallelic loss-of-function, segregation, and concordant functional rescue. Genetic evidence is Strong based on seven probands, autosomal recessive inheritance, and segregation in four relatives. Functional evidence is Moderate, given in vitro splice assays, protein analyses, and therapeutic rescue. Additional independent cohorts may further consolidate the association. Key take-home: TIMMDC1 pathogenic variants reliably underlie early-onset complex I deficiency and warrant inclusion of intronic regions in diagnostic panels, with ASO therapy as a promising avenue.

References

• European journal of medical genetics • 2021 • Deep intronic TIMMDC1 variant delays diagnosis of rapidly progressive complex I deficiency. PMID:33278652
• Human mutation • 2019 • A patient with homozygous nonsense variants in two Leigh syndrome disease genes: Distinguishing a dual diagnosis from a hypomorphic protein-truncating variant. PMID:30981218
• NPJ genomic medicine • 2022 • Oligonucleotide correction of an intronic TIMMDC1 variant in cells of patients with severe neurodegenerative disorder. PMID:35091571

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