Human Gene Module / Chromosome 21 / DYRK1A

DYRK1ADual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A

Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
14 / 33
Rare Variants / Common Variants
103 / 0
Aliases
DYRK1A, DYRK,  DYRK1,  HP86,  MNB,  MNBH,  MRD7
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
21q22.13
Associated Disorders
DD/NDD, EP, EPS, ID, ASD
Relevance to Autism

Recurrent mutations in the DYRK1A gene have been identified in multiple individuals with ASD as described below. A total of four de novo LoF variants in the DYRK1A gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 22542183, 23160955, 25363768). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified DYRK1A as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Resequencing of the DYRK1A gene in 4716 new cases with DD/ID or ASD in van Bon et al., 2016 identified five novel truncating variants, three of which were confirmed de novo and were observed in cases with ASD and intellectual disability; no truncating variants in DYRK1A were observed in 6503 individuals from NHLBI or in 2193 unaffected SSC siblings (PMID 25707398). Furthermore, phenotypic comparison of 15 cases with DYRK1A disruptions in this report identified a syndromic disorder characterized by ASD, intellectual disability, microcephaly and other shared phenotypes. Evers et al., 2017 reported additional de novo DYRK1A variants identified in individuals from the Deciphering Developmental Disorders study presenting with intellectual disability and other features (PMID 28053047).

Molecular Function

This gene encodes a member of the Dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family. It may play a significant role in a signaling pathway regulating cell proliferation and may be involved in brain development. It is localized in the Down syndrome critical region of chromosome 21, and is considered to be a strong candidate gene for learning defects associated with Down syndrome. Defects in DYRK1A are the cause of mental retardation autosomal dominant type 7 (MRD7) [MIM:614104].

Reports related to DYRK1A (33 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Truncation of the Down syndrome candidate gene DYRK1A in two unrelated patients with microcephaly. Mller RS , et al. (2008) No Epilepsy, MR
2 Support Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly. van Bon BW , et al. (2011) No Autistic features
3 Primary Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. O'Roak BJ , et al. (2012) Yes -
4 Support De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
5 Recent Recommendation The DYRK1A gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy. Courcet JB , et al. (2012) No Epilepsy
6 Support Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. O'Roak BJ , et al. (2012) Yes -
7 Recent Recommendation DYRK1A promotes dopaminergic neuron survival in the developing brain and in a mouse model of Parkinson's disease. Barallobre MJ , et al. (2014) No -
8 Support Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. Redin C , et al. (2014) No -
9 Recent Recommendation Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
10 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
11 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) Yes Microcephaly
12 Support DYRK1A mutations in two unrelated patients. Ruaud L , et al. (2015) No Autistic features
13 Recent Recommendation Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID. van Bon BW , et al. (2015) Yes Epilepsy/seizures, microcephaly
14 Recent Recommendation Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A. Bronicki LM , et al. (2015) Yes Microcephaly
15 Recent Recommendation DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies. Ji J , et al. (2015) No ASD, epilepsy/seizures
16 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
17 Support Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities. Zhang Y , et al. (2015) No -
18 Support Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly. Rump P , et al. (2016) No Microcephaly
19 Support Case report of novel DYRK1A mutations in 2 individuals with syndromic intellectual disability and a review of the literature. Luco SM , et al. (2016) No Epilepsy/seizures
20 Recent Recommendation Phosphorylation of -Tubulin by the Down Syndrome Kinase, Minibrain/DYRK1a, Regulates Microtubule Dynamics and Dendrite Morphogenesis. Ori-McKenney KM , et al. (2016) No -
21 Support High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing. Martnez F , et al. (2016) No -
22 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
23 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies. Redin C , et al. (2016) No Autistic features
24 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Trujillano D , et al. (2016) No DD, ID, epilepsy/seizures
25 Support Structural analysis of pathogenic mutations in the DYRK1A gene in patients with developmental disorders. Evers JM , et al. (2017) No -
26 Support Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders. Reuter MS , et al. (2017) No -
27 Support Autism-associated Dyrk1a truncation mutants impair neuronal dendritic and spine growth and interfere with postnatal cortical development. Dang T , et al. (2017) Yes -
28 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) Yes -
29 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
30 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) No -
31 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders. Li J , et al. (2017) Yes -
32 Support Clinical phenotype of ASD-associated DYRK1A haploinsufficiency. Earl RK , et al. (2017) No ASD
33 Recent Recommendation Functional characterization of DYRK1A missense variants associated with a syndromic form of intellectual deficiency and autism. Widowati EW , et al. (2018) No -
Rare Variants   (103)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - Simplex 18405873 Mller RS , et al. (2008)
- - translocation De novo - Simplex 18405873 Mller RS , et al. (2008)
- - copy_number_loss De novo - - 21294719 van Bon BW , et al. (2011)
c.1098+1G>A p.? splice_site_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.1491delC p.Ala498ProfsTer94 frameshift_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.290_291delCT p.Ser97CysfsTer98 frameshift_variant De novo - - 23099646 Courcet JB , et al. (2012)
c.143_144delAT p.Ile48LysfsTer2 frameshift_variant De novo - Simplex 23160955 O'Roak BJ , et al. (2012)
c.*47+2T>G - splice_site_variant, 3_prime_UTR_variant Familial Paternal Simplex 23160955 O'Roak BJ , et al. (2012)
c.613C>T p.Arg205Ter stop_gained De novo - Simplex 25167861 Redin C , et al. (2014)
c.621_624GA p.Glu208AsnfsTer3 frameshift_variant De novo - Simplex 25167861 Redin C , et al. (2014)
c.1282C>T p.Arg428Ter stop_gained De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.473A>G p.Lys158Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1541G>A p.Gly514Glu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
del(GGTCTGTGCTGCTGC) - frameshift_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.261_263delCCCinsCC p.Pro88GlnfsTer6 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.860A>T p.Asp287Val missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.620T>C p.Leu207Pro missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1036T>C p.Ser346Pro missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.393_394dupGG p.Glu132GlyfsTer19 frameshift_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.691C>T p.Arg231Ter stop_gained De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
TTTCTCTT/TTT - splice_site_variant De novo - - 25533962 Deciphering Developmental Disorders Study (2014)
c.613C>T p.Arg205Ter stop_gained De novo - - 25641759 Ruaud L , et al. (2015)
c.932C>T p.Ser311Phe missense_variant De novo - - 25641759 Ruaud L , et al. (2015)
c.799C>T p.Gln267Ter stop_gained Unknown Not maternal - 25707398 van Bon BW , et al. (2015)
c.1240-2A>G - splice_site_variant De novo - - 25707398 van Bon BW , et al. (2015)
c.516+2T>C - splice_site_variant De novo - - 25707398 van Bon BW , et al. (2015)
c.367C>T p.Gln123Ter stop_gained De novo - - 25707398 van Bon BW , et al. (2015)
c.665-9_665-5delTTCTC - splice_site_variant De novo - - 25707398 van Bon BW , et al. (2015)
c.208-1G>A - splice_site_variant Familial Maternal - 25707398 van Bon BW , et al. (2015)
c.763C>T p.Arg255Ter stop_gained De novo - - 25920557 Bronicki LM , et al. (2015)
c.613C>T p.Arg205Ter stop_gained De novo - - 25920557 Bronicki LM , et al. (2015)
c.621_624delTGAGinsGAA p.Glu208AsnfsTer3 frameshift_variant De novo - - 25920557 Bronicki LM , et al. (2015)
c.1036T>C p.Ser346Pro missense_variant De novo - - 25920557 Bronicki LM , et al. (2015)
c.945dupG p.Gln316AlafsTer24 frameshift_variant De novo - - 25920557 Bronicki LM , et al. (2015)
- - copy_number_loss De novo - - 25920557 Bronicki LM , et al. (2015)
c.1309C>T p.Arg437Ter stop_gained Unknown - - 25920557 Bronicki LM , et al. (2015)
c.844dupA p.Ser282LysfsTer6 frameshift_variant De novo - Simplex 25920557 Bronicki LM , et al. (2015)
c.1763C>A p.Thr588Asn missense_variant De novo - Simplex 25920557 Bronicki LM , et al. (2015)
c.1232dupG p.Arg413ThrfsTer10 frameshift_variant De novo - - 25920557 Bronicki LM , et al. (2015)
c.312C>G p.Tyr104Ter stop_gained De novo - Simplex 25944381 Ji J , et al. (2015)
c.613C>T p.Arg205Ter stop_gained De novo - Simplex 25944381 Ji J , et al. (2015)
c.1399C>T p.Arg467Ter stop_gained De novo - Simplex 25944381 Ji J , et al. (2015)
c.461delA p.Lys154SerfsTer11 frameshift_variant De novo - Simplex 25944381 Ji J , et al. (2015)
c.1101_1104delAGAT p.Asp368ArgfsTer2 frameshift_variant De novo - Simplex 25944381 Ji J , et al. (2015)
c.452dupA p.Asn151LysfsTer12 frameshift_variant Unknown Not maternal Simplex 25944381 Ji J , et al. (2015)
c.563A>T p.Lys188Ile missense_variant De novo - Simplex 25944381 Ji J , et al. (2015)
c.734T>G p.Leu245Arg missense_variant De novo - Simplex 25944381 Ji J , et al. (2015)
c.883C>T p.Leu295Phe missense_variant De novo - Simplex 25944381 Ji J , et al. (2015)
- - copy_number_loss Familial Maternal Multiplex 25944381 Ji J , et al. (2015)
- - copy_number_loss De novo - Simplex 25944381 Ji J , et al. (2015)
- - copy_number_loss De novo - Simplex 25944381 Ji J , et al. (2015)
- - copy_number_loss De novo - Simplex 25944381 Ji J , et al. (2015)
c.859G>T p.Asp287Tyr missense_variant De novo - Simplex 26544041 Zhang Y , et al. (2015)
c.946C>T p.Gln316Ter stop_gained De novo - Simplex 26544041 Zhang Y , et al. (2015)
c.1433delT p.Phe478SerfsTer114 frameshift_variant Unknown Not maternal Simplex 26846091 Rump P , et al. (2016)
c.951+4_951+7delAGTA p.Val222AspfsTer22 splice_site_variant De novo - Simplex 26922654 Luco SM , et al. (2016)
c.787C>T p.Arg263Ter stop_gained De novo - Simplex 26922654 Luco SM , et al. (2016)
c.601_605delCAGAT p.Gln201fs frameshift_variant De novo - - 27620904 Martnez F , et al. (2016)
c.457G>T p.Glu153Ter stop_gained De novo - - 27824329 Wang T , et al. (2016)
c.1595C>T p.Thr532Met missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
- - translocation De novo - - 27841880 Redin C , et al. (2016)
c.1040T>G p.Leu347Arg missense_variant De novo - - 27848944 Trujillano D , et al. (2016)
delA p.Lys11AsnfsTer38 frameshift_variant De novo - - 28053047 Evers JM , et al. (2017)
c.1309C>T p.Arg437Ter stop_gained De novo - - 28053047 Evers JM , et al. (2017)
G>C p.Ala277Pro missense_variant De novo - - 28053047 Evers JM , et al. (2017)
insT p.Val306SerfsTer2 frameshift_variant De novo - - 28053047 Evers JM , et al. (2017)
delT p.Ile101ThrfsTer49 frameshift_variant De novo - - 28053047 Evers JM , et al. (2017)
c.763C>T p.Arg255Ter stop_gained De novo - - 28053047 Evers JM , et al. (2017)
G>A p.Arg467Gln missense_variant De novo - - 28053047 Evers JM , et al. (2017)
A>G p.? splice_site_variant De novo - - 28053047 Evers JM , et al. (2017)
c.787C>T p.Arg263Ter stop_gained De novo - - 28053047 Evers JM , et al. (2017)
delT p.Leu100Ter frameshift_variant De novo - - 28053047 Evers JM , et al. (2017)
- - inversion De novo - - 28053047 Evers JM , et al. (2017)
c.1309C>T p.Arg437Ter stop_gained De novo - - 28053047 Evers JM , et al. (2017)
G>T p.? splice_site_variant De novo - - 28053047 Evers JM , et al. (2017)
c.714del p.Phe238LeufsTer12 frameshift_variant De novo - Simplex 28097321 Reuter MS , et al. (2017)
c.355C>T p.His119Tyr missense_variant Unknown - - 28167836 Dang T , et al. (2017)
c.376G>T p.Asp126Tyr missense_variant Unknown - - 28167836 Dang T , et al. (2017)
c.398G>A p.Arg133Gln missense_variant Unknown - - 28167836 Dang T , et al. (2017)
c.583G>A p.Ala195Thr missense_variant Unknown - - 28167836 Dang T , et al. (2017)
c.613C>T p.Arg205Ter stop_gained Unknown - - 28167836 Dang T , et al. (2017)
c.715G>T p.Glu239Ter stop_gained Unknown - - 28167836 Dang T , et al. (2017)
c.777G>T p.Leu259Phe missense_variant Unknown - - 28167836 Dang T , et al. (2017)
c.1373G>T p.Arg458Met missense_variant Unknown - - 28167836 Dang T , et al. (2017)
c.1457G>GA p.Gly486Asp missense_variant Unknown - - 28167836 Dang T , et al. (2017)
c.183G>C p.Gln61His missense_variant Unknown - - 28167836 Dang T , et al. (2017)
c.468G>A p.Met156Ile missense_variant Unknown - - 28167836 Dang T , et al. (2017)
c.169T>C p.Ser57Pro missense_variant Unknown - - 28167836 Dang T , et al. (2017)
c.691C>T p.Arg231Ter stop_gained De novo - - 28191889 Stessman HA , et al. (2017)
c.1488_1489delCCinsC p.Ala498ProfsTer61 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.1098+1G>A p.? splice_site_variant De novo - - 28191889 Stessman HA , et al. (2017)
T>C p.? splice_site_variant Familial - Multiplex 28263302 C Yuen RK , et al. (2017)
A>G p.? splice_site_variant Familial - Simplex 28263302 C Yuen RK , et al. (2017)
G>A p.? splice_site_variant Familial - Multiplex 28263302 C Yuen RK , et al. (2017)
c.1639C>T p.Gln547Ter stop_gained De novo - - 28554332 Bowling KM , et al. (2017)
c.1313G>A p.Arg438His missense_variant De novo - - 28831199 Li J , et al. (2017)
c.1217_1220delAGAA p.Lys406ArgfsTer44 frameshift_variant De novo - - 29034068 Earl RK , et al. (2017)
c.763C>T p.Arg255Ter stop_gained De novo - - 29034068 Earl RK , et al. (2017)
c.1401delAinsGG p.Ile468AspfsTer17 frameshift_variant De novo - - 29034068 Earl RK , et al. (2017)
c.452dupA p.Asn151LysfsTer12 frameshift_variant Unknown Not maternal - 29034068 Earl RK , et al. (2017)
c.883C>T p.Leu295Phe missense_variant De novo - - 29034068 Earl RK , et al. (2017)
c.665-8_665-3delTCTTTC p.? splice_site_variant De novo - - 29034068 Earl RK , et al. (2017)
c.1248delA p.Lys416AsnfsTer35 frameshift_variant De novo - - 29034068 Earl RK , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

1S

Score Delta: Score remained at 1.1 + S

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.

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2017
1S
icon
1S

Score remained at 1S

Description

A total of four de novo LoF variants in the DYRK1A gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 22542183, 23160955, 25363768). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified DYRK1A as a gene meeting high statistical significance with a FDR ? 0.01, meaning that this gene had a ? 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Resequencing of the DYRK1A gene in 4716 new cases with DD/ID or ASD in van Bon et al., 2016 identified five novel truncating variants, three of which were confirmed de novo and were observed in cases with ASD and intellectual disability; no truncating variants in DYRK1A were observed in 6503 individuals from NHLBI or in 2193 unaffected SSC siblings (PMID 25707398). Furthermore, phenotypic comparison of 15 cases with DYRK1A disruptions in this report identified a syndromic disorder characterized by ASD, intellectual disability, microcephaly and other shared phenotypes. Evers et al., 2017 reported additional de novo DYRK1A variants identified in individuals from the Deciphering Developmental Disorders study presenting with intellectual disability and other features (PMID 28053047).

4/1/2017
1S
icon
1S

Score remained at 1S

Description

A total of four de novo LoF variants in the DYRK1A gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 22542183, 23160955, 25363768). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified DYRK1A as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). Resequencing of the DYRK1A gene in 4716 new cases with DD/ID or ASD identified five novel truncating variants, three of which were confirmed de novo and were observed in cases with ASD and intellectual disability; no truncating variants in DYRK1A were observed in 6503 individuals from NHLBI or in 2193 unaffected SSC siblings (PMID 25707398). Phenotypic comparison of 15 cases with DYRK1A disruptions in PMID 25707398 identified a syndromic disorder characterized by ASD, intellectual disability, microcephaly and other shared phenotypes. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Evers et al., 2017 reported additional de novo DYRK1A variants identified in individuals from the Deciphering Developmental Disorders study presenting with intellectual disability and other features.

Reports Added
[The contribution of de novo coding mutations to autism spectrum disorder.2014] [Autism-associated Dyrk1a truncation mutants impair neuronal dendritic and spine growth and interfere with postnatal cortical development.2017] [Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A.2015] [DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies.2015] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [De novo gene disruptions in children on the autistic spectrum.2012] [The DYRK1A gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy.2012] [DYRK1A promotes dopaminergic neuron survival in the developing brain and in a mouse model of Parkinson's disease.2014] [Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID.2015] [Case report of novel DYRK1A mutations in 2 individuals with syndromic intellectual disability and a review of the literature.2016] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Phosphorylation of -Tubulin by the Down Syndrome Kinase, Minibrain/DYRK1a, Regulates Microtubule Dynamics and Dendrite Morphogenesis.2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly.2011] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [Truncation of the Down syndrome candidate gene DYRK1A in two unrelated patients with microcephaly.2008] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.2017] [High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [Structural analysis of pathogenic mutations in the DYRK1A gene in patients with developmental disorders.2017] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [DYRK1A mutations in two unrelated patients.2015] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.2017] [Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly.2016]
1/1/2017
1S
icon
1S

Score remained at 1S

Description

A total of four de novo LoF variants in the DYRK1A gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 22542183, 23160955, 25363768). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified DYRK1A as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). Resequencing of the DYRK1A gene in 4716 new cases with DD/ID or ASD identified five novel truncating variants, three of which were confirmed de novo and were observed in cases with ASD and intellectual disability; no truncating variants in DYRK1A were observed in 6503 individuals from NHLBI or in 2193 unaffected SSC siblings (PMID 25707398). Phenotypic comparison of 15 cases with DYRK1A disruptions in PMID 25707398 identified a syndromic disorder characterized by ASD, intellectual disability, microcephaly and other shared phenotypes. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Evers et al., 2017 reported additional de novo DYRK1A variants identified in individuals from the Deciphering Developmental Disorders study presenting with intellectual disability and other features.

10/1/2016
1S
icon
1S

Score remained at 1S

Description

A total of four de novo LoF variants in the DYRK1A gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 22542183, 23160955, 25363768). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified DYRK1A as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). Resequencing of the DYRK1A gene in 4716 new cases with DD/ID or ASD identified five novel truncating variants, three of which were confirmed de novo and were observed in cases with ASD and intellectual disability; no truncating variants in DYRK1A were observed in 6503 individuals from NHLBI or in 2193 unaffected SSC siblings (PMID 25707398). Phenotypic comparison of 15 cases with DYRK1A disruptions in PMID 25707398 identified a syndromic disorder characterized by ASD, intellectual disability, microcephaly and other shared phenotypes. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

4/1/2016
1S
icon
1S

Score remained at 1S

Description

A total of four de novo LoF variants in the DYRK1A gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 22542183, 23160955, 25363768). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified DYRK1A as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). Resequencing of the DYRK1A gene in 4716 new cases with DD/ID or ASD identified five novel truncating variants, three of which were confirmed de novo and were observed in cases with ASD and intellectual disability; no truncating variants in DYRK1A were observed in 6503 individuals from NHLBI or in 2193 unaffected SSC siblings (PMID 25707398). Phenotypic comparison of 15 cases with DYRK1A disruptions in PMID 25707398 identified a syndromic disorder characterized by ASD, intellectual disability, microcephaly and other shared phenotypes. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly.2016] [The contribution of de novo coding mutations to autism spectrum disorder.2014] [Truncation of the Down syndrome candidate gene DYRK1A in two unrelated patients with microcephaly.2008] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Case report of novel DYRK1A mutations in 2 individuals with syndromic intellectual disability and a review of the literature.2016] [DYRK1A mutations in two unrelated patients.2015] [Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID.2015] [Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A.2015] [DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Phosphorylation of -Tubulin by the Down Syndrome Kinase, Minibrain/DYRK1a, Regulates Microtubule Dynamics and Dendrite Morphogenesis.2016] [Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly.2011] [The DYRK1A gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy.2012] [De novo gene disruptions in children on the autistic spectrum.2012] [DYRK1A promotes dopaminergic neuron survival in the developing brain and in a mouse model of Parkinson's disease.2014]
1/1/2016
1S
icon
1S

Score remained at 1S

Description

A total of four de novo LoF variants in the DYRK1A gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 22542183, 23160955, 25363768). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified DYRK1A as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). Resequencing of the DYRK1A gene in 4716 new cases with DD/ID or ASD identified five novel truncating variants, three of which were confirmed de novo and were observed in cases with ASD and intellectual disability; no truncating variants in DYRK1A were observed in 6503 individuals from NHLBI or in 2193 unaffected SSC siblings (PMID 25707398). Phenotypic comparison of 15 cases with DYRK1A disruptions in PMID 25707398 identified a syndromic disorder characterized by ASD, intellectual disability, microcephaly and other shared phenotypes. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [The contribution of de novo coding mutations to autism spectrum disorder.2014] [Truncation of the Down syndrome candidate gene DYRK1A in two unrelated patients with microcephaly.2008] [Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.2014] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [The DYRK1A gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy.2012] [Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID.2015] [Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A.2015] [DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies.2015] [DYRK1A mutations in two unrelated patients.2015] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly.2016] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Case report of novel DYRK1A mutations in 2 individuals with syndromic intellectual disability and a review of the literature.2016] [Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly.2011] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [De novo gene disruptions in children on the autistic spectrum.2012] [DYRK1A promotes dopaminergic neuron survival in the developing brain and in a mouse model of Parkinson's disease.2014]
4/1/2015
1S
icon
1S

Score remained at 1S

Description

A total of four de novo LoF variants in the DYRK1A gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 22542183, 23160955, 25363768). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified DYRK1A as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). Resequencing of the DYRK1A gene in 4716 new cases with DD/ID or ASD identified five novel truncating variants, three of which were confirmed de novo and were observed in cases with ASD and intellectual disability; no truncating variants in DYRK1A were observed in 6503 individuals from NHLBI or in 2193 unaffected SSC siblings (PMID 25707398). Phenotypic comparison of 15 cases with DYRK1A disruptions in PMID 25707398 identified a syndromic disorder characterized by ASD, intellectual disability, microcephaly and other shared phenotypes.

1/1/2015
1
icon
1S

Score remained at 1S

Description

A total of four de novo LoF variants in the DYRK1A gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 22542183, 23160955, 25363768). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified DYRK1A as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). Resequencing of the DYRK1A gene in 4716 new cases with DD/ID or ASD identified five novel truncating variants, three of which were confirmed de novo and were observed in cases with ASD and intellectual disability; no truncating variants in DYRK1A were observed in 6503 individuals from NHLBI or in 2193 unaffected SSC siblings (PMID 25707398). Phenotypic comparison of 15 cases with DYRK1A disruptions in PMID 25707398 identified a syndromic disorder characterized by ASD, intellectual disability, microcephaly and other shared phenotypes.

10/1/2014
2
icon
1

Decreased from 2 to 1

Description

A total of four de novo LoF variants in the DYRK1A gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 22495309, 22542183, 23160955, 25363768). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified DYRK1A as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

7/1/2014
No data
icon
2

Increased from No data to 2

Description

Likely gene-disruptive de novo variants in the DYRK1A gene in autistic probands from simplex families have been identified in three separate reports. In the first report, 1 of ~200 de novo protein-altering variants was found in the DYRK1A gene (PMID 22495309). In the second report, 1 of 343 likely gene-disrupting (frameshift) variants was found in the DYRK1A gene (PMID 22542183). In the third report, MLPA screening of 44 candidate genes in 2446 ASD probands identified additional DYRK1A variation (PMID 23160955). No controls; many missense changes in controls in EGV.

4/1/2014
No data
icon
2

Increased from No data to 2

Description

Likely gene-disruptive de novo variants in the DYRK1A gene in autistic probands from simplex families have been identified in three separate reports. In the first report, 1 of ~200 de novo protein-altering variants was found in the DYRK1A gene (PMID 22495309). In the second report, 1 of 343 likely gene-disrupting (frameshift) variants was found in the DYRK1A gene (PMID 22542183). In the third report, MLPA screening of 44 candidate genes in 2446 ASD probands identified additional DYRK1A variation (PMID 23160955). No controls; many missense changes in controls in EGV.

Krishnan Probability Score

Score 0.57879561121083

Ranking 602/25841 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.
ExAC Score

Score 0.99958454172665

Ranking 895/18225 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
Iossifov Probability Score

Score 0.99

Ranking 26/239 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
Sanders TADA Score

Score 1.9918805103288E-6

Ranking 6/18665 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).
Larsen Cumulative Evidence Score

Score 77

Ranking 16/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.13355028307668

Ranking 5486/20870 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.
CNVs associated with DYRK1A(1 CNVs)
21q22.13 5 Deletion-Duplication 9  /  7
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ABLIM1 actin binding LIM protein 1 Human Protein Modification 3983 O14639
C10ORF71 Uncharacterized protein C10orf71 Human Protein Binding 118461 Q711Q0-3
CAPN1 Calpain-1 catalytic subunit Human Protein Binding 823 P07384
DCHS1 dachsous 1 (Drosophila) Human Protein Binding 8642 Q96JQ0
FAM53C family with sequence similarity 53, member C Human Protein Binding 51307 Q9NYF3
GLCCI1 glucocorticoid induced transcript 1 Human Protein Binding 113263 Q86VQ1
GluN2A Glutamate receptor ionotropic, NMDA 2A Rat Protein Modification 24409 Q00959
HISTIH2B3 histone cluster 1, H3a Human Protein Modification 8350 P68431
histone H3 Histone H3.1 Human Protein Modification 8350 P68431
IFI44 Interferon-induced protein 44 Human DNA Binding 10561 Q8TCB0
IL1a interleukin 1, alpha Human DNA Binding 3552 P01583
IL6 interleukin 6 (interferon, beta 2) Human DNA Binding 3569 B4DVM1
IL8 interleukin 8 Human DNA Binding 3576 P10145
LRCH3 leucine-rich repeats and calponin homology (CH) domain containing 3 Human Protein Binding 84859 Q96II8
LZTS3 leucine zipper, putative tumor suppressor family member 3 Human Protein Binding 9762 O60299
NFATC1 nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 Human Protein Modification 4772 B5B2M8
RCAN1 regulator of calcineurin 1 Human Protein Modification 1827 P53805
RFPL2 Ret finger protein-like 2 Human Protein Binding 10739 O75678-2
RNF169 ring finger protein 169 Human Protein Binding 254225 Q8NCN4
SNAP91 synaptosomal-associated protein 91 Rat Protein Modification 65178 Q05140
Synj synaptojanin Fruit Fly Protein Binding 37517 Q5U0V7
Synj1 synaptojanin 1 Rat Protein Modification 85238 Q62910
TNFa Tumor necrosis factor, membrane form Human DNA Binding 7124 P01375
TNFAIP6 Tumor necrosis factor-inducible gene 6 protein Human DNA Binding 7130 P98066
TRMT61B tRNA methyltransferase 61 homolog B (S. cerevisiae) Human Protein Binding 55006 Q9BVS5
TROAP trophinin associated protein Human Protein Binding 10024 Q12815
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