Relevance to Autism

De novo missense variants in the DYNC1H1 gene have previously been identified in ASD cases (De Rubeis et al., 2014; Iossifov et al., 2014). An additional de novo missense variant in this gene was identified by whole genome sequencing in an ASD proband from a simplex family as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of multiple de novo missense variants in ASD cases, a z-score > 2.0 for missense mutations, and a higher-than expected mutation rate (a false discovery rate < 15%), DYNC1H1 was determined to be an ASD candidate gene in Yuen et al., 2017. Whole exome sequencing in 116 ASD parent-proband trios as part of the University of Illinois at Chicago ACE project identified a de novo nonsense variant in DYNC1H1 in one ASD proband (Chen et al., 2017). A de novo protein-truncating variant was identified in DYNC1H1 in an ASD proband from the Autism Sequencing Consortium in Satterstrom et al., 2020; seven protein-truncating variants in this gene were observed in case samples from the Danish iPSYCH study in this same report. Furthermore, TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in Satterstrom et al., 2020 identified DYNC1H1 as a candidate gene with a false discovery rate (FDR) 0.01. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified DYNC1H1 as a gene reaching exome-wide significance (P < 2.5E-06); association of DYNC1H1 with ASD risk in this analysis was found to be driven both by de novo variants and rare inherited loss-of-function variants transmitted from unaffected parents to affected offspring. Mutations in the DYNC1H1 gene are associated with autosomal dominant mental retardation-13 (MRD13; OMIM 614563), a form of intellectual disability associated with variable neuronal migration defects resulting in cortical malformations (Vissers et al., 2010; Willemsen et al., 2012).

Molecular Function

This gene encodes a member of the cytoplasmic dynein heavy chain family. Dyneins are a group of microtubule-activated ATPases that function as molecular motors. Mutations in the DYNC1H1 gene are associated with autosomal dominant mental retardation-13 (MRD13; OMIM 614563), a form of intellectual disability associated with variable neuronal migration defects resulting in cortical malformations (Vissers et al., 2010; Willemsen et al., 2012).

External Links

References