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

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.