Clinical presentation and genetic characterisation of mitochondrial disease in Kuwait

Abstract

Mitochondrial disorders are a group of clinically heterogenous conditions affecting multiple systems with a prevalence that is estimated to affect 1 in 4,300 individuals. Mitochondrial function is under the control of both the mitochondrial and nuclear genomes which encode >1200 mitochondrial proteins. Manifold biochemical pathways and possible gene targets contribute to the highly variable genotype-phenotype correlations observed in mitochondrial patients, posing distinct challenges in reaching a genetic diagnosis. Whole Exome Sequencing (WES) is a gene agnostic approach that has been hugely powerful in diagnosing mitochondrial disease patients and broadening the genotypic spectrum of disease. Mitochondrial genetic disease is largely understudied in Kuwait where levels of consanguinity reach 50% in the community. Studying the genetics and aetiology of mitochondrial disorders in Kuwait presents huge potential in identifying novel Mendelian causes of disease. I custom-designed mitochondrial disease criteria to evaluate and recruit patients suspected of mitochondrial disease in Kuwait. WES led to the diagnosis of 14 out of 22 recruited families: 8 families harboured variants in known mitochondrial disease genes (SLC19A3, PDHX, SURF1, MPC1, TTC19, NDUFA13, NDUFB9 and RRM2B), 2 harboured variants in a novel mitochondrial disease gene (LETM1), and 4 were diagnosed with phenocopies of mitochondrial disease (RNASEH2C, TREX1, VPS13B and ATP8A2). Functional validation of novel variant pathogenicity was performed in patient fibroblasts from 4 families. Functional validation was also carried out on additional mitochondrial patients from Newcastle and external collaborators (COX15, TTC19, NDUFAF3 and NDUFC2). Complexome profiling helped characterise the effect of NDUFC2 variants (a novel candidate gene) on Complex I assembly while a controlled lentiviral rescue experiment partially recovered protein expression and validated variant pathogenicity. My work highlights the potential of employing WES to identify novel causes of disease in understudied consanguineous populations and emphasises the importance of establishing functional pipelines alongside the genetic studies in the Kuwait Medical Genetics Centre