Association between de novo variants of nuclear-encoded mitochondrial-related genes and undiagnosed developmental disorder and autism

Abstract

Background: Evidence suggests that mitochondrial abnormalities increase the risk of two neurodevelopmental disorders: undiagnosed developmental disorder (UDD) and autism spectrum disorder (ASD). However, which nuclear-encoded mitochondrial-related genes (NEMGs) were associated with UDD-ASD is unclear.

Aim: To explore the association between de novo variants (DNVs) of NEMGs and UDD-ASD.

Design: Comprehensive analysis based on DNVs of NEMGs identified in patients (31 058 UDD probands and 10 318 ASD probands) and 4262 controls.

Methods: By curating NEMGs and cataloging publicly published DNVs in NEMGs, we compared the frequency of DNVs in cases and controls. We also applied a TADA-denovo model to highlight disease-associated NEMGs and characterized them based on gene intolerance, functional networks and expression patterns.

Results: Compared with levels in 4262 controls, an excess of protein-truncating variants and deleterious missense variants in 1421 cataloged NEMGs from 41 376 patients (31 058 UDD and 10 318 ASD probands) was observed. Overall, 3.23% of de novo deleterious missense variants and 3.20% of de novo protein-truncating variants contributed to 1.1% and 0.39% of UDD-ASD cases, respectively. We prioritized 130 disease-associated NEMGs and showed distinct expression patterns in the developing human brain. Disease-associated NEMGs expression was enriched in both excitatory and inhibitory neuronal lineages from the developing human cortex.

Conclusions: Rare genetic alterations of disease-associated NEMGs may play a role in UDD-ASD development and lay the groundwork for a better understanding of the biology of UDD-ASD.