Human Gene Module / Chromosome 9 / DOLK

DOLKdolichol kinase

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
3 / 5
Rare Variants / Common Variants
5 / 0
Aliases
DOLK, UNQ2422/PRO4980,  CDG1M,  DK,  DK1,  SEC59,  TMEM15
Associated Syndromes
West syndrome, DOLK-CDG
Chromosome Band
9q34.11
Associated Disorders
ID, EPS, ASD
Relevance to Autism

A homozygous variant in the DOLK gene predicted to abolish the initiator Met residue and prevent translation (p.M1?; c.2T>C) was identified in two affected siblings born to consanguineous parents who presented with West syndrome that later developed into intellectual disability and, in one case, ASD (Helander et al., 2013).

Molecular Function

The protein encoded by this gene catalyzes the CTP-mediated phosphorylation of dolichol, and is involved in the synthesis of Dol-P-Man, which is an essential glycosyl carrier lipid for C- and O-mannosylation, N- and O-linked glycosylation of proteins, and for the biosynthesis of glycosyl phosphatidylinositol anchors in endoplasmic reticulum. Mutations in this gene are associated with dolichol kinase deficiency (DOLK-CDG) [MIM:610768], a type of congenital disorder of glycosylation.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to DOLK (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Dolichol kinase deficiency (DOLK-CDG) with a purely neurological presentation caused by a novel mutation Helander A , et al. (2013) No Epilepsy, ID, ASD
2 Support Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes Xiong J , et al. (2019) No Epilepsy, ID, ASD
3 Support - Zhou X et al. (2022) Yes -
4 Support - Cirnigliaro M et al. (2023) Yes -
5 Support - Soo-Whee Kim et al. (2024) Yes -
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1104G>A p.Ala368%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.590T>C p.Val197Ala missense_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.1195C>T p.Arg399Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.527A>G p.Tyr176Cys missense_variant Familial Both parents Simplex 31031587 Xiong J , et al. (2019)
c.2T>C p.Met1? initiator_codon_variant Familial Both parents Multiplex 23890587 Helander A , et al. (2013)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Homozygous mutations in the DOLK gene are associated with dolichol kinase deficiency (DOLK-CDG) [MIM:610768], a type of congenital disorder of glycosylation. A homozygous variant in the DOLK gene predicted to abolish the initiator Met residue and prevent translation (p.Met1?; c.2T>C) was identified in two affected siblings born to consanguineous parents who presented with West syndrome that later developed into intellectual disability and, in one case, ASD (Helander et al., 2013). Screening of 48 ASD risk genes in a cohort of 158 Chinese probands with neurological disorders identified a homozygous missense variant in the DOLK gene in a female patient with a diagnosis of DOLK-CDG who was also diagnosed with ASD and presenting with intellectual disability and epilepsy (Xiong et al., 2019).

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
S

Syndromic

See all Category S Genes

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."

10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Homozygous mutations in the DOLK gene are associated with dolichol kinase deficiency (DOLK-CDG) [MIM:610768], a type of congenital disorder of glycosylation. A homozygous variant in the DOLK gene predicted to abolish the initiator Met residue and prevent translation (p.Met1?; c.2T>C) was identified in two affected siblings born to consanguineous parents who presented with West syndrome that later developed into intellectual disability and, in one case, ASD (Helander et al., 2013). Screening of 48 ASD risk genes in a cohort of 158 Chinese probands with neurological disorders identified a homozygous missense variant in the DOLK gene in a female patient with a diagnosis of DOLK-CDG who was also diagnosed with ASD and presenting with intellectual disability and epilepsy (Xiong et al., 2019).

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.33397991386573

Ranking 24506/25841 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 0.057602442119324

Ranking 8415/18225 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
Sanders TADA Score

Score 0.93219901499906

Ranking 11912/18665 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
Larsen Cumulative Evidence Score

Score 8

Ranking 221/461 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.
Original Source
Zhang D Score

Score -0.38344094606866

Ranking 18194/20870 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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