Dissecting the multifaceted contribution of the mitochondrial genome to autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) is a clinically heterogeneous class of neurodevelopmental conditions with a strong, albeit complex, genetic basis. The genetic architecture of ASD includes different genetic models, from monogenic transmission at one end, to polygenic risk given by thousands of common variants with small effects at the other end. The mitochondrial DNA (mtDNA) was also proposed as a genetic modifier for ASD, mostly focusing on maternal mtDNA, since the paternal mitogenome is not transmitted to offspring. We extensively studied the potential contribution of mtDNA in ASD pathogenesis and risk through deep next generation sequencing and quantitative PCR in a cohort of 98 families. While the maternally-inherited mtDNA did not seem to predispose to ASD, neither for haplogroups nor for the presence of pathogenic mutations, an unexpected influence of paternal mtDNA, apparently centered on haplogroup U, came from the Italian families extrapolated from the test cohort (n = 74) when compared to the control population. However, this result was not replicated in an independent Italian cohort of 127 families and it is likely due to the elevated paternal age at time of conception. In addition, ASD probands showed a reduced mtDNA content when compared to their unaffected siblings. Multivariable regression analyses indicated that variants with 15%–5% heteroplasmy in probands are associated to a greater severity of ASD based on ADOS-2 criteria, whereas paternal super-haplogroups H and JT were associated with milder phenotypes. In conclusion, our results suggest that the mtDNA impacts on ASD, significantly modifying the phenotypic expression in the Italian population. The unexpected finding of protection induced by paternal mitogenome in term of severity may derive from a role of mtDNA in influencing the accumulation of nuclear de novo mutations or epigenetic alterations in fathers’ germinal cells, affecting the neurodevelopment in the offspring. This result remains preliminary and needs further confirmation in independent cohorts of larger size. If confirmed, it potentially opens a different perspective on how paternal non-inherited mtDNA may predispose or modulate other complex diseases.

A systematic review of non-coding RNA genes with differential expression profiles associated with autism spectrum disorders

“…tRNA genes are encoded for by both nuclear and mitochondrial genomes. The mitochondrial genome has been proposed as a genetic modifier for ASD [ 170 ] and theories related to mitochondrial dysfunction in ASD have been hypothesised [ 171 ]. The mitochondrial genome encodes 22 transfer RNA genes and harbours the majority of pathogenic variants that result in broad and disparate disorders [ 172 ].…”

Whole genome analysis of rare deleterious variants adds further evidence to BRSK2 and other risk genes in Autism Spectrum Disorder

“…We analysed WES and WGS data from all 435 individuals of our cohort, focussing on rare variants affecting coding exons and canonical splice sites as these provide the most direct links between gene function and disease pathogenesis. We did not use WGS data to investigate mitochondrial DNA, as deep sequencing of the entire mitogenome and quantification of mtDNA cellular content of this cohort has been previously described 14 .…”

Genomic analysis of 116 autism families strengthens known risk genes and highlights promising candidates

“…We analysed WES and WGS data from all 435 individuals of our cohort, focussing on rare variants affecting coding exons and canonical splice sites as these provide the most direct links between gene function and disease pathogenesis. We did not use WGS data to investigate mitochondrial DNA, as deep sequencing of the entire mitogenome and quantification of mtDNA cellular content of this cohort has been previously described 15 .…”