Genes implicated in intellectual disability associated with mitochondrial dysfunction

Mitochondrial dysfunction correlates strongly with neurodevelopmental disorders, in which the underlying cause can arise from insults to either mitochondrial DNA (mtDNA) or nuclear-encoded mitochondrial genes. The spectrum of phenotype consequences vary between single-organ or multisystem manifestations, with the most effect on those tissues with high-energy demand. The next generation sequencing (NGS) era has yielded a significant number of genes associated with mitochondrial diseases, estimated to be more than 250 hitherto. Through the research into the elucidation of genetic causes underlying hereditary intellectual disability (ID) in two separate cohorts of 136 and 404 families –largely with two or more affected individuals– we identified potentially disease-causing variants in 78 families (73 genes) and 219 families (184 genes) respectively. Of these, a combined total of approximately 20 genes have been identified to harbor a likely causal variant in regard to mitochondrial dysfunction, among which there are a number of recently reported ID candidate genes, including HEMK1, PGAM5, SLC25A23, and TMEM135. Moreover, for two of the known genes, namely L2HGDH and SURF1, allelic mutations have been noticed in more than one single family. In sum, by the use of NGS in 540 predominantly Iranian families, potentially ID-causative variants in 257 genes –297 families– have been detected in our study, from which ~20 are mitochondrial-related genes giving rise to ID in almost 22 families that indicate a proportion of 7.7%. These findings highlight the important contribution of mitochondrial derangements towards cognitive impairment.

Keywords:

intellectual disability , mitochondrial dysfunction , next generation sequencing