A MT-TL1 variant identified by whole exome sequencing in an individual with intellectual disability, epilepsy, and spastic tetraparesis

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.

The RD‐Connect Genome‐Phenome Analysis Platform: Accelerating diagnosis, research, and gene discovery for rare diseases

“…To this end, 19,000 genome‐phenome datasets are in the process of being collected, processed, and analyzed in the RD‐Connect GPAP. Programmatic reanalysis of the first ~4,000 families resulted in rapid resolution of 120 families (de Boer et al, 2021; Matalonga et al, 2021; Schüle et al, 2021; te Paske et al, 2021; Topf et al, 2021). These numbers, which have increased substantially since publication, were achieved through the identification of causative variants that had either been missed by the original variant filtering strategies undertaken by submitting centers, or were dismissed as being unimportant at the time due to a lack of supporting evidence, but for which further information has come to light linking the gene to the phenotype of the case in the intervening period.…”

2021 at European Journal of Human Genetics: the year in review

“…Yves Sznajer (UCLouvain), Eaaswarkhanth Muthukrishnan (Abu Dhabi) and Zerin Hyder (Manchester) felt the special issue on SOLVE-RD was of special interest [14,15]. The SOLVE-RD project involves a very large cohort of rare disease patients, being well powered to identify novel genetic variants and characterise phenotypes.…”