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
21 / 40
Rare Variants / Common Variants
121 / 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, Functional
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
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to DYNC1H1 (40 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 -
24 Support - Kepler LD et al. (2022) No -
25 Support - Chen Y et al. (2021) No -
26 Support - Levchenko O et al. (2022) No -
27 Support - Zhou X et al. (2022) Yes -
28 Support - More RP et al. (2023) Yes -
29 Support - Wang J et al. (2023) Yes -
30 Support - Balasar et al. (2023) No -
31 Support - Wu-Chen Wu et al. (2024) No DD, ID
32 Support - Lucie Sedlackova et al. (2024) No -
33 Support - Luigi Vetri et al. (2024) No -
34 Support - Omri Bar et al. (2024) Yes OCD, ID, epilepsy/seizures
35 Support - Marketa Wayhelova et al. (2024) No -
36 Support - Magdalena Badura-Stronka et al. (2024) No DD
37 Support - Marta Viggiano et al. (2024) Yes -
38 Recent Recommendation - Birk Möller et al. () No ASD, ADHD, epilepsy/seizures
39 Support - Raddy L Ramos et al. (2024) Yes -
40 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (121)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.10079+1G>C - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.3960+1G>A - splice_site_variant De novo - - 31139143 Long S , et al. (2019)
c.7474C>T p.Arg2492Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.13273C>T p.Gln4425Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.56C>T p.Ser19Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.584A>T p.His195Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1832G>A p.Arg611His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3278T>C p.Phe1093Ser missense_variant De novo - - 34803881 Yang H et al. (2021)
c.3351C>G p.Asn1117Lys missense_variant De novo - - 34803881 Yang H et al. (2021)
c.5884C>T p.Arg1962Cys missense_variant De novo - - 34803881 Yang H et al. (2021)
c.4079G>A p.Arg1360Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.6110G>C p.Arg2037Pro missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.6272G>A p.Arg2091Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.6340G>A p.Glu2114Lys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.6410T>C p.Leu2137Pro missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.12950C>T p.Thr4317Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.13500C>T p.Gly4500%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.12910G>T p.Glu4304Ter stop_gained De novo - Simplex 37393044 Wang J et al. (2023)
c.11084G>A p.Arg3695Gln missense_variant De novo - - 33432195 Rodin RE et al. (2021)
c.6994C>T p.Arg2332Cys missense_variant De novo - - 29286531 Tumien B , et al. (2017)
c.3347T>C p.Val1116Ala missense_variant De novo - - 32656949 Amabile S et al. (2020)
c.4234C>T p.His1412Tyr missense_variant De novo - - 32656949 Amabile S et al. (2020)
c.4532C>T p.Pro1511Leu missense_variant De novo - - 32656949 Amabile S et al. (2020)
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.12315G>A p.Trp4105Ter stop_gained De novo - Simplex 28344757 Chen R , et al. (2017)
c.17G>T p.Gly6Val missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.10973G>A p.Gly3658Glu missense_variant De novo - - 32656949 Amabile S et al. (2020)
c.6535C>T p.Arg2179Ter stop_gained Familial - Unknown 38848546 Birk Möller et al. ()
c.11608C>T p.Arg3870Ter stop_gained Unknown - Unknown 38848546 Birk Möller et al. ()
c.17G>T p.Gly6Val missense_variant Familial - Unknown 38848546 Birk Möller et al. ()
c.11595+3A>G - splice_region_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.4396-1G>C - splice_site_variant De novo - Multiplex 32094338 Husson T , et al. (2020)
c.4868G>A p.Arg1623Gln missense_variant De novo - - 38256219 Luigi Vetri et al. (2024)
c.2467G>T p.Val823Leu missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1195A>G p.Arg399Gly missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.2363A>G p.Tyr788Cys missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.1113A>T p.Lys371Asn missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.10573C>T p.Arg3525Cys missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.6698C>T p.Ala2233Val missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.7718A>G p.Asp2573Gly missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.3624G>T p.Trp1208Cys missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.3180A>C p.Leu1060Phe missense_variant De novo - Simplex 35873028 Chen Y et al. (2021)
c.925C>T p.Arg309Cys missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.623C>G p.Pro208Arg missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.791G>A p.Arg264Gln missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.925C>T p.Arg309Cys missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.12797A>T p.Asn4266Ile missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.11015C>T p.Ser3672Leu missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.4552G>A p.Glu1518Lys missense_variant De novo - - 22368300 Willemsen MH , et al. (2012)
c.10174A>G p.Met3392Val missense_variant De novo - Simplex 28325891 Lin Z , et al. (2017)
c.13088A>C p.Lys4363Thr missense_variant De novo - Simplex 30504930 Guo H , et al. (2018)
c.12560A>G p.His4187Arg missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.791G>C p.Arg264Pro missense_variant Familial - Unknown 38848546 Birk Möller et al. ()
c.1013A>G p.Asp338Gly missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.1706G>C p.Arg569Pro missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.1834G>A p.Val612Met missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.3072A>G p.Thr1024%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.4216G>A p.Glu1406Lys missense_variant Unknown - Simplex 37524782 Balasar et al. (2023)
c.3056A>G p.Tyr1019Cys missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.3185A>T p.Asp1062Val missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.3189G>A p.Met1063Ile missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.3347T>C p.Val1116Ala missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.3543G>C p.Lys1181Asn missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.3652T>C p.Trp1218Arg missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.4376T>C p.Leu1459Ser missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.4807A>G p.Arg1603Gly missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.4868G>A p.Arg1623Gln missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.5114T>C p.Val1705Ala missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.5872G>A p.Asp1958Asn missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.5884C>T p.Arg1962Cys missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.6410T>C p.Leu2137Pro missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.6870C>A p.Ser2290Arg missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.6880G>A p.Glu2294Lys missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.6989G>A p.Gly2330Glu missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.7793G>T p.Gly2598Val missense_variant De novo - Unknown 38848546 Birk Möller et al. ()
c.8080C>T p.Arg2694Cys missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.8665T>A p.Leu2889Ile missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.9041A>G p.Asn3014Ser missense_variant De novo - Unknown 38848546 Birk Möller et al. ()
c.9092C>T p.Thr3031Met missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.806G>A p.Gly269Glu missense_variant Unknown - Multiplex 37524782 Balasar et al. (2023)
c.5884C>T p.Arg1962Cys missense_variant Familial - Unknown 38848546 Birk Möller et al. ()
c.10232C>A p.Pro3411His missense_variant Unknown - Simplex 37524782 Balasar et al. (2023)
c.10016G>A p.Arg3339His missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.10352A>G p.Tyr3451Cys missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.10573C>T p.Arg3525Cys missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.11989C>T p.Arg3997Trp missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.12214G>A p.Gly4072Ser missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.13609G>A p.Glu4537Lys missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.9073G>A p.Glu3025Lys missense_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.1103G>C p.Arg368Pro missense_variant De novo - Simplex 37903666 Wu-Chen Wu et al. (2024)
c.3543G>C p.Lys1181Asn missense_variant De novo - - 38008000 Lucie Sedlackova et al. (2024)
c.12449C>T p.Pro4150Leu missense_variant De novo - Multiplex 36702863 More RP et al. (2023)
c.12315G>A p.Trp4105Ter stop_gained De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.12214G>A p.Gly4072Ser missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.10268C>T p.Ala3423Val missense_variant De novo - Simplex 37903666 Wu-Chen Wu et al. (2024)
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.11465A>C p.His3822Pro missense_variant De novo - Simplex 21076407 Vissers LE , et al. (2010)
c.9052C>T p.Pro3018Ser missense_variant De novo - Simplex 39025270 Raddy L Ramos et al. (2024)
c.10871_10874del p.Glu3624ValfsTer3 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.9209C>T p.Pro3070Leu missense_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.7501T>C p.Ser2501Pro missense_variant De novo - Simplex 38519481 Marta Viggiano et al. (2024)
c.3072A>G p.Thr1024= synonymous_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.10924_10927dup p.Pro3643ArgfsTer11 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.11691-4G>T - splice_region_variant Familial Paternal Simplex 37903666 Wu-Chen Wu et al. (2024)
c.591_593del p.Gln198del inframe_deletion Familial Maternal - 35887114 Levchenko O et al. (2022)
c.3504del p.Phe1169SerfsTer8 frameshift_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.11074C>G p.Leu3692Val missense_variant Familial Paternal Simplex 38256266 Omri Bar et al. (2024)
c.7059G>C p.Leu2353Phe missense_variant Familial Paternal - 38321498 Marketa Wayhelova et al. (2024)
c.3572_3580dup p.Arg1191_Gly1193dup inframe_insertion De novo - Simplex 35982159 Zhou X et al. (2022)
c.11858C>T p.Ala3953Val missense_variant Familial Maternal Simplex 37903666 Wu-Chen Wu et al. (2024)
c.4642_4680del p.Glu1548_Leu1560del inframe_deletion Unknown - Unknown 38848546 Birk Möller et al. ()
c.3648_3652delinsGGAGA p.Trp1218Arg missense_variant Unknown - Unknown 38848546 Birk Möller et al. ()
c.11886_11887del p.Asp3962GlufsTer14 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.7463G>A p.Arg2488His missense_variant Familial Both parents Simplex 37903666 Wu-Chen Wu et al. (2024)
c.10016G>A p.Arg3339His missense_variant De novo - Simplex 38328757 Magdalena Badura-Stronka et al. (2024)
c.10213A>C p.Met3405Leu missense_variant De novo - Multiplex (dizygotic twins) 34803881 Yang H et al. (2021)
c.4462dup p.Arg1488ProfsTer5 frameshift_variant Familial Maternal - 35183220 Álvarez-Mora MI et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 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.

1/1/2021
1
icon
1

Score remained at 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]
7/1/2020
1
icon
1

Score remained at 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]
1/1/2020
1
icon
1

Score remained at 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
3

Decreased from 3 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).

Reports Added
[The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children.2019]
10/1/2018
3
icon
3

Decreased from 3 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).

Reports Added
[Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.2018]
10/1/2017
3
icon
3

Decreased from 3 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).

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.
Original Source
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
Original Source
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.
Original Source
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