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
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Synaptic, transcriptional and chromatin genes disrupted in autism.
Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
Validation of targeted next-generation sequencing panels in a cohort of Polish patients with epilepsy: assessing variable performance across clinical endophenotypes and uncovering novel genetic varian
The homozygous mutant Dync1h1 mouse model with a missense mutation found in humans (P3018S) shows embryonic lethality, while the heterozygote mutant is viable. The heterozygote mutants show decreased brain size and enlarged ventricles, and developmental motor phenotypes, like decreased negative geotaxis, hindlimb clasping, and slipping on the balance beam test.
References
Type
Title
Author, Year
Primary
Patient-specific mutation of Dync1h1 in mice causes brain and behavioral deficits
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Homozygous knockin mice carry two alleles with a P3016S missense mutation (c9052C>T point mutation) in the Dync1h1 gene.
Allele Type: ASD mutation
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line: Not applicable
Mutant ES Cell Line: Model Source: The Gene Modification Facility within the Cancer Center at Albert Einstein College of Medicine
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Heterozygous knockin mice carry one allele with a P3016S missense mutation (c9052C>T point mutation) in the Dync1h1 gene.
Allele Type: ASD mutation
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line: Not applicable
Mutant ES Cell Line: Model Source: The Gene Modification Facility within the Cancer Center at Albert Einstein College of Medicine
Description: Hindlimb clasping appears in heterozygous males but not females at 3-4 months of age, and both males and females show the phenotype when tested at 6 months of age and older.
Description: When the brains of wildtype and heterozygous mice were weighed and examined at 8 weeks of age, the cerebrum of heterozygous male and female mice weighed significantly less than wildtype littermates; whereas the cerebellum weighed the same.
Description: Disrupted neuronal lamination in the dorsal and lateral neocortex was seen in all heterozygous male and female mice, characterized by smearing of the border between layers I and II and a general increase in cells present in layer I compared to wildtype mice.
Exp Paradigm: hematoxylin and eosin, Nissl, propidium iodide
Description: EchoMRI shows that heterozygous mice have less fat and more lean muscle relative to total body weight when compared to wildtype littermates.
Description: Metabolic testing shows a significant increase in energy expenditure (EE) and RER (O2 and CO2 volume) in heterozygous mice relative to wildtype indicating that heterozygous mice expend more energy over a 5-day period that covers both the light cycles when mice are more inactive, and dark cycles when mice are most active.
Description: At postnatal day 21 (P21), show a reduction in the body weight of heterozygous pups in both sexes relative to wildtype littermates. While still apparent at 6 months of age, the difference in body weight is not significantly different by 11 months of age.
Description: Of 124 pups born from heterozygous matings, 68 (54.8%) were heterozygous and 56 (45.2%) were wildtype. No homozygous pups were obtained from any matings. The observed wildtype, heterozygote and homozygote frequencies were significantly different from the expected wildtype, heterozygote and homozygote ratio of 31:62:31 or the expected wild-type and heterozygote ratio of 41:82 assuming the homozygotes are missing.
Genotypic ratio of progeny from heterozygous parents
