Submission Details

The relationship between TTC19 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of August 21, 2019. Variants in TTC19 were first reported in humans with Leigh syndrome spectrum as early as 2011 (PMID: 21278747). More than 10 unique variants predicted to cause a loss of or reduced function of the protein have been reported in ClinVar, suggesting homozygous loss of function is the mechanism of disease for this gene. Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least eight probands with TTC19 pathogenic variants with Leigh syndrome spectrum have been reported in 6 publications (PMID: 25452764, 25887401, 25772319 ,29961508, 21278747, 24397319) to reach a max case-level evidence score of 12. This gene-disease association is further supported by evidence of TTC19 protein interaction with other genes associated with Leigh syndrome spectrum, TTC19 expression in brain, mitochondrial alterations in patient cell lines, and a TTC19 mouse model and fly model collectively exhibiting neuroimaging, biochemical, and neurocognitive phenotype that recapitulates symptoms of Leigh syndrome spectrum reaching a max experimental score of 6 pts. In summary, there is definitive evidence to support the relationship between TTC19 and autosomal recessive Leigh syndrome spectrum. More than three years have elapsed from the first proposal of the association to reach a definitive classification. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 21, 2019 (SOP Version 7).