Human Gene Module / Chromosome 14 / DYNC1H1

DYNC1H1dynein cytoplasmic 1 heavy chain 1

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
15 / 23
Rare Variants / Common Variants
36 / 0
EAGLE Score
13.45
Strong Learn More
Aliases
DYNC1H1, CMT2O,  DHC1,  DHC1a,  DNCH1,  DNCL,  DNECL,  DYHC,  Dnchc1,  HL-3,  SMALED1,  p22
Associated Syndromes
-
Chromosome Band
14q32.31
Associated Disorders
ID, ASD, EPS
Genetic Category
Rare Single Gene Mutation, Syndromic
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). Two de novo missense variants in DYNC1H1 that had previously been identified in ASD probands in De Rubeis et al., 2014 and Krumm et al., 2015 were determined to be postzygotic mosaic mutations in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 21/84,448 expected; hypergeometric P-value of 8.8E-03).

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
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBase
Reports related to DYNC1H1 (23 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support A de novo paradigm for mental retardation Vissers LE , et al. (2010) No -
2 Support Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects Willemsen MH , et al. (2012) No -
3 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
4 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
5 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
6 Recent Recommendation Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
7 Support Whole-exome sequencing identifies a novel de novo mutation in DYNC1H1 in epileptic encephalopathies Lin Z , et al. (2017) No West syndrome
8 Support Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism Chen R , et al. (2017) Yes -
9 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) No -
10 Recent Recommendation Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
11 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
12 Support Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice Tumien B , et al. (2017) Yes -
13 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
14 Support The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children Long S , et al. (2019) Yes -
15 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
16 Support Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use Husson T , et al. (2020) Yes -
17 Support DYNC1H1-related disorders: A description of four new unrelated patients and a comprehensive review of previously reported variants Amabile S et al. (2020) No ASD, ID, epilepsy/seizures
18 Support - Rodin RE et al. (2021) Yes -
19 Support - Pode-Shakked B et al. (2021) No -
20 Support - Mahjani B et al. (2021) Yes -
21 Support - Yang H et al. (2021) No -
22 Support - Álvarez-Mora MI et al. (2022) No -
23 Support - Woodbury-Smith M et al. (2022) Yes -
Rare Variants   (36)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.3960+1G>A - splice_site_variant De novo NA - 31139143 Long S , et al. (2019)
c.3278T>C p.Phe1093Ser missense_variant De novo NA - 34803881 Yang H et al. (2021)
c.3351C>G p.Asn1117Lys missense_variant De novo NA - 34803881 Yang H et al. (2021)
c.5884C>T p.Arg1962Cys missense_variant De novo NA - 34803881 Yang H et al. (2021)
c.4741A>C p.Lys1581Gln missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.5096A>G p.Asn1699Ser missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.9418C>T p.Arg3140Trp missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.9521G>A p.Arg3174His missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.11084G>A p.Arg3695Gln missense_variant De novo NA - 33432195 Rodin RE et al. (2021)
c.6994C>T p.Arg2332Cys missense_variant De novo NA - 29286531 Tumien B , et al. (2017)
c.3347T>C p.Val1116Ala missense_variant De novo NA - 32656949 Amabile S et al. (2020)
c.4234C>T p.His1412Tyr missense_variant De novo NA - 32656949 Amabile S et al. (2020)
c.4532C>T p.Pro1511Leu missense_variant De novo NA - 32656949 Amabile S et al. (2020)
c.2363A>G p.Tyr788Cys missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.12315G>A p.Trp4105Ter stop_gained De novo NA Simplex 28344757 Chen R , et al. (2017)
c.10973G>A p.Gly3658Glu missense_variant De novo NA - 32656949 Amabile S et al. (2020)
c.4396-1G>C - splice_site_variant De novo NA Multiplex 32094338 Husson T , et al. (2020)
c.2467G>T p.Val823Leu missense_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
c.10573C>T p.Arg3525Cys missense_variant De novo NA - 28554332 Bowling KM , et al. (2017)
c.6698C>T p.Ala2233Val missense_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
c.7718A>G p.Asp2573Gly missense_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
c.925C>T p.Arg309Cys missense_variant De novo NA Simplex 25961944 Krumm N , et al. (2015)
c.12797A>T p.Asn4266Ile missense_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
c.4552G>A p.Glu1518Lys missense_variant De novo NA - 22368300 Willemsen MH , et al. (2012)
c.10174A>G p.Met3392Val missense_variant De novo NA Simplex 28325891 Lin Z , et al. (2017)
c.13088A>C p.Lys4363Thr missense_variant De novo NA Simplex 30504930 Guo H , et al. (2018)
c.9073G>A p.Glu3025Lys missense_variant De novo NA Simplex 28263302 C Yuen RK et al. (2017)
c.6258T>C p.Tyr2086%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.9192C>T p.Val3064%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.12315G>A p.Trp4105Ter stop_gained De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.12214G>A p.Gly4072Ser missense_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.11465A>C p.His3822Pro missense_variant De novo NA Simplex 21076407 Vissers LE , et al. (2010)
c.9209C>T p.Pro3070Leu missense_variant De novo NA Simplex 34580403 Pode-Shakked B et al. (2021)
c.3072A>G p.Thr1024= synonymous_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.4462dup p.Arg1488ProfsTer5 frameshift_variant Familial Maternal - 35183220 Álvarez-Mora MI et al. (2022)
c.10213A>C p.Met3405Leu missense_variant De novo NA Multiplex (dizygotic twins) 34803881 Yang H et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

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). 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).

Score Delta: Decreased from 3 to 1

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

10/1/2021
3
icon
1

Decreased from 3 to 1

Description

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). 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).

7/1/2021
3
icon
1

Decreased from 3 to 1

Description

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). 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).

4/1/2021
3
icon
1

Decreased from 3 to 1

Description

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). 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).

1/1/2021
3
icon
1

Decreased from 3 to 1

Description

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). 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).

Reports Added
[The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing2021]
10/1/2020
3
icon
1

Decreased from 3 to 1

Description

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). 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).

7/1/2020
3
icon
1

Decreased from 3 to 1

Description

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). 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).

Reports Added
[DYNC1H1-related disorders: A description of four new unrelated patients and a comprehensive review of previously reported variants2020]
4/1/2020
3
icon
1

Decreased from 3 to 1

Description

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). 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).

1/1/2020
3
icon
1

Decreased from 3 to 1

Description

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). 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).

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020] [Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use.2020]
10/1/2019
3
icon
1

Decreased from 3 to 1

New Scoring Scheme
Description

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). 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).

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
1

Decreased from 3 to 1

Description

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). 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).

Reports Added
[The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children.2019]
4/1/2019
3
icon
1

Decreased from 3 to 1

Description

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). 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).

1/1/2019
3
icon
1

Decreased from 3 to 1

Description

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). 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).

10/1/2018
3
icon
1

Decreased from 3 to 1

Description

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). 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).

Reports Added
[Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.2018]
7/1/2018
4.4 + acc2
icon
3

Decreased from 4.4 + acc2 to 3

Description

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). 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).

4/1/2018
3
icon
4.4 + acc2

Increased from 3 to 4.4 + acc2

Description

3

Reports Added
[Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice.2017]
10/1/2017
3
icon
1

Decreased from 3 to 1

Description

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). 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).

Reports Added
[Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.2017]
4/1/2017
icon
3

Increased from to 3

Description

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). 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).

Krishnan Probability Score

Score 0.49505790574011

Ranking 3234/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
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ExAC Score

Score 1

Ranking 12/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
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Iossifov Probability Score

Score 0.909

Ranking 126/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.57467998807286

Ranking 631/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.17111697182878

Ranking 4778/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
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