Human Gene Module / Chromosome X / DDX3X

DDX3XDEAD (Asp-Glu-Ala-Asp) box helicase 3, X-linked

Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
2 / 9
Rare Variants / Common Variants
57 / 0
Aliases
DDX3X, CAP-Rf,  DBX,  DDX14,  DDX3,  HLP2
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
Xp11.4
Associated Disorders
EPS, ASD
Relevance to Autism

35 unique de novo variants (including 19 predicted loss-of-function alleles and 5 missense variants experimentally shown to be loss-of-function) in the DDX3X gene were identified in 38 female cases with intellectual disability, 20 of whom also presented with behavioral problems including autism spectrum disorder, hyperactivity, and aggression (Snijders Blok et al., 2015). A de novo splice-site variant in this gene was also identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014).

Molecular Function

The protein encoded by this gene is a member of the large DEAD-box protein family, that is defined by the presence of the conserved Asp-Glu-Ala-Asp (DEAD) motif, and acts as a multifunctional ATP-dependent RNA helicase. Nuclear roles for the encoded protein include transcriptional regulation, mRNP assembly, pre-mRNA splicing, and mRNA export, while in the cytoplasm, this protein is thought to be involved in translation and cellular signaling.

Reports related to DDX3X (9 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
2 Primary Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling. Snijders Blok L , et al. (2015) No ASD
3 Support Identification of Intellectual Disability Genes in Female Patients with A Skewed X Inactivation Pattern. Fieremans N , et al. (2016) No -
4 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
5 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
6 Support Lessons learned from additional research analyses of unsolved clinical exome cases. Eldomery MK , et al. (2017) No Hypotonia, microcephaly (2/3 cases), epilepsy/seiz
7 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Vissers LE , et al. (2017) No -
8 Support DDX3X mutations in two girls with a phenotype overlapping Toriello-Carey syndrome. Dikow N , et al. (2017) No Hypotonia, microcephaly
9 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) No -
Rare Variants   (57)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
sub(A->G) - splice_site_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.1126C>T p.Arg376Cys missense_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.233C>G p.Ser78Ter stop_gained De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1126C>T p.Arg376Cys missense_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.136C>T p.Arg46Ter stop_gained De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1601G>A p.Arg534His missense_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.641T>C p.Ile214Thr missense_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1520T>C p.Ile507Thr missense_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.977G>A p.Arg326His missense_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.868del p.Ser290HisfsTer31 frameshift_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1229_1230dup p.Thr411LeufsTer10 frameshift_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1105dup p.Thr369AsnfsTer14 frameshift_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.865-2A>G p.? splice_site_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1600dup p.Arg534ProfsTer13 frameshift_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.269dup p.Ser90ArgfsTer8 frameshift_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1440A>T p.Arg480Ser missense_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.873C>A p.Tyr291Ter stop_gained De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1693C>T p.Gln565Ter stop_gained De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1535_1536del p.His512ArgfsTer5 frameshift_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.766-1G>C p.? splice_site_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.599dup p.Tyr200Ter frameshift_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1321del p.Asp441IlefsTer3 frameshift_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1383dup p.Tyr462IlefsTer3 frameshift_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1384_1385dup p.His463ThrfsTer34 frameshift_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1535_1536del p.His512ArgfsTer5 frameshift_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1541T>C p.Ile514Thr missense_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.704T>C p.Leu235Pro missense_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1175T>C p.Leu392Pro missense_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1463G>A p.Arg488His missense_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1126C>T p.Arg376Cys missense_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1250A>C p.Gln417Pro missense_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.698C>T p.Ala233Val missense_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.931C>T p.Arg311Ter stop_gained De novo - - 26235985 Snijders Blok L , et al. (2015)
c.46-2A>G p.? splice_site_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1678_1680del p.Leu560del inframe_deletion De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1423C>G p.Arg475Gly missense_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.46-2A>G p.? splice_site_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1703C>T p.Pro568Leu missense_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1526A>T p.Asn509Ile missense_variant De novo - - 26235985 Snijders Blok L , et al. (2015)
c.1084C>T p.Arg362Cys missense_variant Familial Maternal Multi-generational 26235985 Snijders Blok L , et al. (2015)
c.1052G>A p.Arg351Gln missense_variant Familial Maternal Multi-generational 26235985 Snijders Blok L , et al. (2015)
c.898G>T p.Val300Phe missense_variant Familial Maternal Multiplex 26235985 Snijders Blok L , et al. (2015)
c.856G>A p.Gly286Ser missense_variant Unknown Not maternal - 27159028 Fieremans N , et al. (2016)
c.529G>T p.Gly177Ter stop_gained De novo - - 27159028 Fieremans N , et al. (2016)
c.1229_1230dup p.Thr411fs frameshift_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
c.865-2A>G p.(?) splice_site_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
c.269dup p.Ser90fs frameshift_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
c.593delT;c.641delT p.Ile198fs;p.Ile214fs frameshift_variant De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.595A>C;c.643A>C p.Lys199Gln;p.Lys215Gln missense_variant De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.1703C>T p.Pro568Leu missense_variant De novo - Simplex 28327206 Eldomery MK , et al. (2017)
c.192dupA p.Asp65ArgfsTer2 frameshift_variant De novo - Simplex 28327206 Eldomery MK , et al. (2017)
c.362G>T p.Arg121Leu missense_variant Familial Maternal - 28327206 Eldomery MK , et al. (2017)
c.233C>G p.Ser78Ter stop_gained De novo - - 28333917 Vissers LE , et al. (2017)
c.1703C>T p.Pro568Leu missense_variant De novo - - 28371085 Dikow N , et al. (2017)
c.1600C>G p.Arg534Gly missense_variant De novo - - 28371085 Dikow N , et al. (2017)
c.745G>T p.Glu249Ter stop_gained De novo - - 28554332 Bowling KM , et al. (2017)
c.619C>T p.Gln207Ter stop_gained De novo - - 28554332 Bowling KM , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

35 unique de novo variants (including 19 predicted loss-of-function alleles and 5 missense variants experimentally shown to be loss-of-function) in the DDX3X gene were identified in 38 female cases with intellectual disability, 20 of whom also presented with behavioral problems including autism spectrum disorder, hyperactivity, and aggression (Snijders Blok et al., 2015). A de novo splice-site variant in this gene was also identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A second de novo loss-of-function variant in the DDX3X gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort by whole genome sequencing as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in this gene, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), DDX3X was classified as an ASD candidate gene in Yuen et al., 2017.

2

Strong Candidate

See all Category 2 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."

04-01-2017
2S

Initial score established: 2S

Description

35 unique de novo variants (including 19 predicted loss-of-function alleles and 5 missense variants experimentally shown to be loss-of-function) in the DDX3X gene were identified in 38 female cases with intellectual disability, 20 of whom also presented with behavioral problems including autism spectrum disorder, hyperactivity, and aggression (Snijders Blok et al., 2015). A de novo splice-site variant in this gene was also identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A second de novo loss-of-function variant in the DDX3X gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort by whole genome sequencing as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in this gene, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), DDX3X was classified as an ASD candidate gene in Yuen et al., 2017.

CNVs associated with DDX3X(1 CNVs)
Xp11.4 22 Deletion-Duplication 32  /  87
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