Human Gene Module / Chromosome X / DDX3X

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

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
15 / 47
Rare Variants / Common Variants
267 / 0
Aliases
DDX3X, CAP-Rf,  DBX,  DDX14,  DDX3,  HLP2
Associated Syndromes
-
Chromosome Band
Xp11.4
Associated Disorders
DD/NDD, ADHD, ID, EP, 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.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBase
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to DDX3X (47 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 Epilepsy/seizures, microcephaly
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 -
10 Support High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies Hamdan FF , et al. (2017) No DD/ID
11 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
12 Support A hypomorphic inherited pathogenic variant in DDX3X causes male intellectual disability with additional neurodevelopmental and neurodegenerative features Kellaris G , et al. (2018) No -
13 Support Phenotypic expansion in DDX3X - a common cause of intellectual disability in females Wang X , et al. (2018) No -
14 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
15 Support Three de novo DDX3X variants associated with distinctive brain developmental abnormalities and brain tumor in intellectually disabled females Scala M , et al. (2019) No Autistic features (hand stereotypies)
16 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) No Autistic features, stereotypies
17 Support Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing Bruel AL , et al. (2019) No -
18 Support Expansion of phenotype of DDX3X syndrome: six new cases Beal B , et al. (2019) No -
19 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
20 Recent Recommendation Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development Lennox AL et al. (2020) No ASD, ADHD
21 Support Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability Chevarin M et al. (2020) No Marfanoid habitus
22 Support - Hildebrand MS et al. (2020) No ASD, DD, ID
23 Support A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders Suzuki T et al. (2020) No -
24 Support A de novo DDX3X Variant Is Associated With Syndromic Intellectual Disability: Case Report and Literature Review Chen Y et al. (2020) No DD, ID, epilepsy/seizures, stereotypy
25 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
26 Support - Ohashi K et al. (2021) Yes -
27 Support - Brunet T et al. (2021) No ASD, ID
28 Support - Tang L et al. (2021) No ASD, DD
29 Support - Boitnott A et al. (2021) No -
30 Support - Valentino F et al. (2021) Yes DD
31 Support - Pode-Shakked B et al. (2021) No -
32 Support - Mahjani B et al. (2021) Yes -
33 Support - Bruno LP et al. (2021) Yes -
34 Support - Álvarez-Mora MI et al. (2022) No -
35 Support - Stefaniak U et al. (2022) Yes -
36 Support - Leite AJDC et al. (2022) No -
37 Support - Dai Y et al. (2022) No ASD, epilepsy/seizures
38 Support - Shen H et al. (2022) No -
39 Support - Hu C et al. (2022) Yes -
40 Support - Hoye ML et al. (2022) No -
41 Support - Levchenko O et al. (2022) No -
42 Support - Zhou X et al. (2022) Yes -
43 Recent Recommendation - Kundishora AJ et al. (2023) No ASD, DD
44 Support - Chaves LD et al. (2023) No DD
45 Support - Miyake N et al. (2023) Yes -
46 Support - Spataro N et al. (2023) No -
47 Support - Hu C et al. (2023) Yes -
Rare Variants   (267)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - stop_gained De novo NA - 30349862 Wang X , et al. (2018)
- - inframe_deletion De novo NA - 30349862 Wang X , et al. (2018)
- - inframe_deletion De novo NA - 30936465 Scala M , et al. (2019)
- - frameshift_variant De novo NA - 30349862 Wang X , et al. (2018)
- - frameshift_variant De novo NA - 31274575 Beal B , et al. (2019)
- - splice_region_variant De novo NA - 30349862 Wang X , et al. (2018)
- - splice_site_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.600T>A p.Tyr200Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.889C>T p.Pro297Ser stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.1498-2A>G - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.1770-1G>A - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.-82G>A - splice_site_variant De novo NA - 30349862 Wang X , et al. (2018)
c.-82G>C - splice_site_variant Unknown - - 32135084 Lennox AL et al. (2020)
- - frameshift_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.1712T>A p.Leu571Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
- - splice_site_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.103+15T>C - intron_variant Familial Maternal - 37007974 Hu C et al. (2023)
c.1386C>G p.Tyr462Ter stop_gained Unknown - - 30349862 Wang X , et al. (2018)
c.284+1G>A - splice_site_variant De novo NA - 30349862 Wang X , et al. (2018)
c.-82G>A - splice_site_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1615+14T>C - intron_variant Familial Maternal - 37007974 Hu C et al. (2023)
c.1029C>A p.Tyr343Ter stop_gained De novo NA - 35982159 Zhou X et al. (2022)
c.874C>T p.Arg292Ter stop_gained De novo NA - 30349862 Wang X , et al. (2018)
c.71C>A p.Ser24Ter stop_gained De novo NA - 32135084 Lennox AL et al. (2020)
c.79C>T p.Gln27Ter stop_gained De novo NA - 32135084 Lennox AL et al. (2020)
c.46-2A>G - splice_site_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1171-2A>G - splice_site_variant Unknown - - 36943625 Chaves LD et al. (2023)
- - frameshift_variant De novo NA Simplex 28327206 Eldomery MK , et al. (2017)
c.173C>A p.Ser58Ter stop_gained De novo NA - 32135084 Lennox AL et al. (2020)
c.233C>G p.Ser78Ter stop_gained De novo NA - 32135084 Lennox AL et al. (2020)
c.151+1G>T - splice_site_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.284+1G>A - splice_site_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.895G>A p.Val299Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.898G>T p.Val300Phe missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.971C>A p.Pro324Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.976C>T p.Arg326Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.26C>G p.Ala9Gly missense_variant De novo NA - 30349862 Wang X , et al. (2018)
c.599dup p.Tyr200Ter stop_gained De novo NA - 32135084 Lennox AL et al. (2020)
c.619C>T p.Gln207Ter stop_gained De novo NA - 32135084 Lennox AL et al. (2020)
c.731C>G p.Ser244Ter stop_gained De novo NA - 32135084 Lennox AL et al. (2020)
c.745G>T p.Glu249Ter stop_gained De novo NA - 32135084 Lennox AL et al. (2020)
c.874C>T p.Arg292Ter stop_gained De novo NA - 32135084 Lennox AL et al. (2020)
c.1595C>T p.Thr532Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1703C>T p.Pro568Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.88G>C p.Gly30Arg missense_variant De novo NA - 30349862 Wang X , et al. (2018)
c.1372G>T p.Glu458Ter stop_gained De novo NA - 32135084 Lennox AL et al. (2020)
c.1710G>A p.Trp570Ter stop_gained De novo NA - 32135084 Lennox AL et al. (2020)
c.1728T>G p.Tyr576Ter stop_gained De novo NA - 32135084 Lennox AL et al. (2020)
c.1804C>T p.Arg602Ter stop_gained De novo NA - 32135084 Lennox AL et al. (2020)
c.1807C>T p.Arg603Ter stop_gained De novo NA - 32135084 Lennox AL et al. (2020)
c.233C>G p.Ser78Ter stop_gained De novo NA - 28333917 Vissers LE , et al. (2017)
c.136C>T p.Arg46Ter stop_gained De novo NA Simplex 35392274 Dai Y et al. (2022)
c.865-1G>A - splice_site_variant De novo NA Simplex 35392274 Dai Y et al. (2022)
c.703C>T p.Leu235%3D missense_variant De novo NA - 33004838 Wang T et al. (2020)
c.641T>C p.Ile214Thr missense_variant De novo NA - 35982159 Zhou X et al. (2022)
c.46-2A>G - splice_site_variant De novo NA Simplex 30564305 Guo H , et al. (2018)
c.-73_-72insTATA - frameshift_variant De novo NA - 30349862 Wang X , et al. (2018)
c.1641insT p.Arg548Ter stop_gained De novo NA - 32135084 Lennox AL et al. (2020)
c.619C>T p.Gln207Ter stop_gained De novo NA - 28554332 Bowling KM , et al. (2017)
c.745G>T p.Glu249Ter stop_gained De novo NA - 28554332 Bowling KM , et al. (2017)
c.865-2A>G - splice_site_variant De novo NA - 27479843 Lelieveld SH et al. (2016)
c.894C>A p.Cys298Ter stop_gained De novo NA Simplex 35392274 Dai Y et al. (2022)
c.1171-2A>C - splice_site_variant De novo NA Simplex 35392274 Dai Y et al. (2022)
c.1126C>T p.Arg376Cys missense_variant De novo NA - 33004838 Wang T et al. (2020)
c.1666T>G p.Leu556Val missense_variant De novo NA - 33004838 Wang T et al. (2020)
c.865-1G>C - splice_site_variant De novo NA Simplex 33993884 Tang L et al. (2021)
c.758C>T p.Ala253Val missense_variant De novo NA - 30349862 Wang X , et al. (2018)
c.887G>C p.Arg296Pro missense_variant De novo NA - 30349862 Wang X , et al. (2018)
c.949T>C p.Cys317Arg missense_variant De novo NA - 30349862 Wang X , et al. (2018)
c.569T>G p.Ile190Ser missense_variant Unknown - - 32135084 Lennox AL et al. (2020)
c.577G>T p.Gly193Ter stop_gained De novo NA - 27159028 Fieremans N , et al. (2016)
c.-78del - frameshift_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.1628C>G p.Ser543Ter stop_gained De novo NA Simplex 35392274 Dai Y et al. (2022)
c.1766A>G p.Lys589Arg splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.544-8_544-6del - splice_region_variant De novo NA - 35982159 Zhou X et al. (2022)
c.922C>T p.Gln308Ter stop_gained De novo NA Simplex 33993884 Tang L et al. (2021)
c.1498-2A>G - splice_site_variant De novo NA Simplex 33993884 Tang L et al. (2021)
c.1021T>C p.Cys341Arg missense_variant De novo NA - 30349862 Wang X , et al. (2018)
c.1244T>A p.Ile415Asn missense_variant De novo NA - 30349862 Wang X , et al. (2018)
c.1304T>C p.Leu435Pro missense_variant De novo NA - 30349862 Wang X , et al. (2018)
c.1438A>G p.Arg480Gly missense_variant De novo NA - 30349862 Wang X , et al. (2018)
c.1595C>T p.Thr532Met missense_variant De novo NA - 30349862 Wang X , et al. (2018)
c.1600C>T p.Arg534Cys missense_variant De novo NA - 30349862 Wang X , et al. (2018)
c.1805G>A p.Arg602Gln missense_variant De novo NA - 30349862 Wang X , et al. (2018)
c.119C>G p.Pro40Arg missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.281G>A p.Gly94Glu missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.113A>G p.Tyr38Cys missense_variant De novo NA - 36943625 Chaves LD et al. (2023)
c.1177G>A p.Ala393Thr missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.-83A>G - splice_site_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.70T>G p.Ser24Ala missense_variant Familial Maternal - 35741772 Hu C et al. (2022)
c.1710G>A p.Trp570Ter stop_gained De novo NA Simplex 33993884 Tang L et al. (2021)
c.1600C>G p.Arg534Gly missense_variant De novo NA - 28371085 Dikow N , et al. (2017)
c.1703C>T p.Pro568Leu missense_variant De novo NA - 28371085 Dikow N , et al. (2017)
c.1511G>A p.Gly504Glu missense_variant De novo NA - 30936465 Scala M , et al. (2019)
c.1502C>A p.Ala501Glu missense_variant De novo NA - 33590427 Ohashi K et al. (2021)
c.544T>G p.Phe182Val missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.592A>C p.Thr198Pro missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.610A>C p.Thr204Pro missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.616G>A p.Val206Met missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.672C>T p.Ala224%3D missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.698C>T p.Ala233Val missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.704T>A p.Leu235Gln missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.764A>G p.Lys255Arg missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.857C>A p.Ala286Asp missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.878C>T p.Ser293Phe missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.887G>C p.Arg296Pro missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.968C>T p.Thr323Ile missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.977G>A p.Arg326His missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.46-2A>G - splice_site_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.262_264del p.Arg88del inframe_deletion De novo NA - 30349862 Wang X , et al. (2018)
c.1616-2A>G - splice_site_variant De novo NA Simplex 32530565 Suzuki T et al. (2020)
c.1088G>A p.Arg363Lys missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1126C>T p.Arg376Cys missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1175T>C p.Leu392Pro missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1243A>T p.Ile415Phe missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1250A>C p.Gln417Pro missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1292T>G p.Leu431Arg missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1438A>G p.Arg480Gly missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1439G>C p.Arg480Thr missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1462C>T p.Arg488Cys missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1463G>A p.Arg488His missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1481T>G p.Ile494Ser missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1490C>T p.Ala497Val missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1493C>T p.Thr498Ile missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1513C>G p.Leu505Val missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1541T>C p.Ile514Thr missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1582C>T p.Arg528Cys missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1595C>T p.Thr532Met missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1676T>A p.Leu559His missense_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.70T>A p.Ser24Thr splice_site_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.75T>G p.Asp25Glu splice_site_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.584T>G p.Ile195Ser missense_variant De novo NA - 35390071 Leite AJDC et al. (2022)
c.136C>T p.Arg46Ter stop_gained De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.233C>G p.Ser78Ter stop_gained De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.976C>T p.Arg326Cys missense_variant De novo NA - 34356170 Valentino F et al. (2021)
c.873C>A p.Tyr291Ter stop_gained De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.931C>T p.Arg311Ter stop_gained De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.329G>A p.Arg110His missense_variant Familial Maternal - 35392274 Dai Y et al. (2022)
c.605G>C p.Arg202Pro missense_variant De novo NA Simplex 35392274 Dai Y et al. (2022)
c.611C>T p.Thr204Ile missense_variant De novo NA Simplex 35392274 Dai Y et al. (2022)
c.635C>T p.Pro212Leu missense_variant De novo NA Simplex 35392274 Dai Y et al. (2022)
c.1846_1848del p.Ser616del inframe_deletion De novo NA - 35982159 Zhou X et al. (2022)
c.869dup p.Tyr291IlefsTer4 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.551A>G p.Asp184Gly splice_site_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1171-2A>G - splice_site_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.1693C>T p.Gln565Ter stop_gained De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.1051C>T p.Arg351Trp missense_variant De novo NA Simplex 35392274 Dai Y et al. (2022)
c.1084C>G p.Arg362Gly missense_variant De novo NA Simplex 35392274 Dai Y et al. (2022)
c.1463G>A p.Arg488His missense_variant De novo NA Simplex 35392274 Dai Y et al. (2022)
c.1595C>T p.Thr532Met missense_variant De novo NA Simplex 35392274 Dai Y et al. (2022)
c.1679T>G p.Leu560Arg missense_variant De novo NA Simplex 35392274 Dai Y et al. (2022)
c.1703C>T p.Pro568Leu missense_variant De novo NA Simplex 35392274 Dai Y et al. (2022)
c.3G>A p.Met1? initiator_codon_variant De novo NA Simplex 35392274 Dai Y et al. (2022)
c.724dup p.Ile242AsnfsTer53 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1868dup p.Gly624ArgfsTer6 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.875G>T p.Arg292Leu missense_variant De novo NA Simplex 33993884 Tang L et al. (2021)
c.976C>T p.Arg326Cys missense_variant De novo NA Simplex 33993884 Tang L et al. (2021)
c.107G>A p.Gly36Glu missense_variant Familial Maternal - 30349862 Wang X , et al. (2018)
c.1834dup p.Ser612LysfsTer19 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1091T>C p.Ile364Thr missense_variant De novo NA Simplex 35982159 Zhou X et al. (2022)
c.3G>C p.Met1? initiator_codon_variant De novo NA Simplex 33993884 Tang L et al. (2021)
c.679+3_679+4inv - splice_region_variant De novo NA Simplex 33993884 Tang L et al. (2021)
c.226dup p.Ser76LysfsTer2 splice_site_variant De novo NA - 31274575 Beal B , et al. (2019)
c.977G>A p.Arg326His missense_variant De novo NA Unknown 33619735 Brunet T et al. (2021)
c.1138_1140del p.Met380del inframe_deletion De novo NA - 32135084 Lennox AL et al. (2020)
c.1206_1208del p.Phe402del inframe_deletion De novo NA - 32135084 Lennox AL et al. (2020)
c.1244_1246del p.Ile415del inframe_deletion De novo NA - 32135084 Lennox AL et al. (2020)
c.1491_1493del p.Thr498del inframe_deletion De novo NA - 32135084 Lennox AL et al. (2020)
c.693_695del p.Ala233del inframe_deletion De novo NA Simplex 35392274 Dai Y et al. (2022)
c.853G>A p.Glu285Lys missense_variant Unknown Not maternal - 33993884 Tang L et al. (2021)
c.1745dup p.Ser583Ter frameshift_variant De novo NA Simplex 32714884 Chen Y et al. (2020)
c.1513C>G p.Leu505Val missense_variant De novo NA Multiplex 35982159 Zhou X et al. (2022)
c.1148C>G p.Ala383Gly missense_variant De novo NA Unknown 33619735 Brunet T et al. (2021)
c.1502C>A p.Ala501Glu missense_variant De novo NA Simplex 36973392 Miyake N et al. (2023)
c.80dup p.Ser28GlufsTer23 frameshift_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.192dup p.Asp65ArgfsTer2 frameshift_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.977G>A p.Arg326His missense_variant De novo NA Simplex 29346770 Takata A , et al. (2018)
c.581A>T p.Asn194Ile missense_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.641T>C p.Ile214Thr missense_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.698C>T p.Ala233Val missense_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.704T>C p.Leu235Pro missense_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.977G>A p.Arg326His missense_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.236_241dup p.Arg79_Gly80dup inframe_insertion De novo NA - 30349862 Wang X , et al. (2018)
c.1052G>A p.Arg351Gln missense_variant Familial Maternal - 32135084 Lennox AL et al. (2020)
c.1105A>G p.Thr369Ala missense_variant Familial Maternal - 32135084 Lennox AL et al. (2020)
c.1399G>T p.Ala467Ser missense_variant Familial Maternal - 32135084 Lennox AL et al. (2020)
c.147del p.Gly51ValfsTer170 frameshift_variant Familial - - 31231135 Bruel AL , et al. (2019)
c.833dup p.Leu278PhefsTer17 frameshift_variant Familial - - 31231135 Bruel AL , et al. (2019)
c.1144A>C p.Ser382Arg missense_variant De novo NA Simplex 32135084 Lennox AL et al. (2020)
c.1245C>G p.Ile415Met missense_variant De novo NA Simplex 32135084 Lennox AL et al. (2020)
c.45+12G>A - intron_variant Unknown Not maternal Simplex 35326346 Stefaniak U et al. (2022)
c.113A>G p.Tyr38Cys missense_variant De novo NA Simplex 35887114 Levchenko O et al. (2022)
c.1126C>T p.Arg376Cys missense_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.1175T>C p.Leu392Pro missense_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.1250A>C p.Gln417Pro missense_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.1423C>G p.Arg475Gly missense_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.1440A>T p.Arg480Ser missense_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.1463G>A p.Arg488His missense_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.1520T>C p.Ile507Thr missense_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.1541T>C p.Ile514Thr missense_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.1601G>A p.Arg534His missense_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.1703C>T p.Pro568Leu missense_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.1678_1680del p.Leu560del inframe_deletion De novo NA Simplex 35392274 Dai Y et al. (2022)
NM_001193416.1:c.1804C>T p.Arg602Ter stop_gained De novo NA - 30349862 Wang X , et al. (2018)
c.147del p.Gly51ValfsTer170 frameshift_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.623del p.Lys208SerfsTer13 frameshift_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.691dup p.Thr231AsnfsTer64 frameshift_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.868del p.Ser290HisfsTer31 frameshift_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1321del p.Asp441IlefsTer3 frameshift_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1383dup p.Tyr462IlefsTer3 frameshift_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1462del p.Arg488AlafsTer8 frameshift_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.685_687del p.Gly229del inframe_deletion Unknown - Simplex 31130284 Monies D , et al. (2019)
c.1601G>A p.Arg534His missense_variant De novo NA Simplex 29100083 Hamdan FF , et al. (2017)
c.599dup p.Tyr200Ter frameshift_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.1138_1140del p.Met380del inframe_deletion De novo NA Simplex 33993884 Tang L et al. (2021)
c.1206_1208del p.Phe402del inframe_deletion De novo NA Simplex 33993884 Tang L et al. (2021)
- - frameshift_variant De novo NA Multiplex (monozygotic twins) 30349862 Wang X , et al. (2018)
c.241_242insCTT p.Lys81delinsThrTer stop_gained De novo NA - 32135084 Lennox AL et al. (2020)
c.1105dup p.Thr369AsnfsTer14 frameshift_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1256del p.Val419GlufsTer17 frameshift_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1099dup p.Gln367ProfsTer16 frameshift_variant De novo NA - 36980980 Spataro N et al. (2023)
c.362G>T p.Arg121Leu missense_variant Familial Maternal - 28327206 Eldomery MK , et al. (2017)
c.269dup p.Ser90ArgfsTer8 frameshift_variant De novo NA - 27479843 Lelieveld SH et al. (2016)
c.758C>T p.Ala253Val missense_variant De novo NA Simplex 28327206 Eldomery MK , et al. (2017)
c.426_437del p.Ser143_Leu146del frameshift_variant De novo NA - 31274575 Beal B , et al. (2019)
c.734_736del p.Asp245del inframe_deletion De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.371del p.Asn124ThrfsTer97 frameshift_variant De novo NA Simplex 35392274 Dai Y et al. (2022)
c.1579del p.His527IlefsTer9 frameshift_variant De novo NA Simplex 35392274 Dai Y et al. (2022)
c.251G>T p.Gly84Val missense_variant Familial Maternal Simplex 34948243 Bruno LP et al. (2021)
c.1535_1536del p.His512ArgfsTer5 frameshift_variant Unknown - - 32135084 Lennox AL et al. (2020)
c.1776dup p.Ser593Ter frameshift_variant De novo NA Multiplex 31398340 Ruzzo EK , et al. (2019)
c.1633insT p.Phe545PhefsTer2 frameshift_variant De novo NA Simplex 35392274 Dai Y et al. (2022)
c.126_129del p.His42GlnfsTer178 frameshift_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.830_831del p.Glu277ValfsTer17 frameshift_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.831_832dup p.Leu278CysfsTer44 frameshift_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.856G>A p.Ala286Thr missense_variant Unknown Not maternal - 27159028 Fieremans N , et al. (2016)
c.1628C>T p.Ser543Leu missense_variant De novo NA Simplex 34580403 Pode-Shakked B et al. (2021)
c.1276_1279del p.Asp426AsnfsTer9 frameshift_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.1534_1535del p.His512CysfsTer5 frameshift_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.160dup p.Asp54GlyfsTer2 frameshift_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.1199_1200delinsC p.Tyr400SerfsTer6 frameshift_variant De novo NA - 35982159 Zhou X et al. (2022)
c.1395_1399del p.Tyr466MetfsTer13 frameshift_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.641del p.Ile214ThrfsTer7 frameshift_variant De novo NA Simplex 28263302 C Yuen RK et al. (2017)
c.620_626dup p.His209GlnfsTer88 frameshift_variant De novo NA Simplex 35392274 Dai Y et al. (2022)
c.749_756del p.Ala250GlyfsTer42 frameshift_variant De novo NA Simplex 35392274 Dai Y et al. (2022)
c.655dup p.Asp219GlyfsTer76 frameshift_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.1321del p.Asp441IlefsTer3 frameshift_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.1383dup p.Tyr462IlefsTer3 frameshift_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.723_724del p.Gln241HisfsTer53 frameshift_variant De novo NA Simplex 33993884 Tang L et al. (2021)
c.641_643delinsCC p.Ile214ThrfsTer7 frameshift_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.749_750insGCCTC p.Leu251ProfsTer3 frameshift_variant De novo NA - 32135084 Lennox AL et al. (2020)
c.147del p.Gly51ValfsTer170 frameshift_variant De novo NA Simplex 32277047 Chevarin M et al. (2020)
c.236G>A p.Arg79Lys missense_variant Familial Maternal Multiplex 29490693 Kellaris G , et al. (2018)
c.1415A>G p.His472Arg missense_variant De novo NA Simplex 35183220 Álvarez-Mora MI et al. (2022)
c.1229_1230dup p.Thr411LeufsTer10 frameshift_variant De novo NA - 27479843 Lelieveld SH et al. (2016)
c.1474del p.Ser492AlafsTer4 frameshift_variant De novo NA Simplex 32345733 Hildebrand MS et al. (2020)
c.439_440dup p.Gln148AsnfsTer74 frameshift_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.590_591del p.Leu197HisfsTer97 frameshift_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.1535_1536del p.His512ArgfsTer5 frameshift_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.1371_1382delinsCTC p.Glu458_Leu461delinsSer inframe_indel De novo NA - 32135084 Lennox AL et al. (2020)
c.1384_1385dup p.His463ThrfsTer34 frameshift_variant De novo NA Simplex 32135084 Lennox AL et al. (2020)
c.1229_1230dup p.Thr411LeufsTer10 frameshift_variant De novo NA - 26235985 Snijders Blok L , et al. (2015)
c.491_494delinsTCTC p.Asp164_Asp165delinsValSer inframe_indel De novo NA - 30936465 Scala M , et al. (2019)
c.898G>T p.Val300Phe missense_variant Familial Maternal Multiplex 26235985 Snijders Blok L , et al. (2015)
c.595A>C;c.643A>C p.Lys199Gln;p.Lys215Gln missense_variant De novo NA Simplex 28263302 C Yuen RK et al. (2017)
c.107G>A p.Gly36Glu missense_variant Familial Maternal Extended multiplex 26235985 Snijders Blok L , et al. (2015)
c.1084C>T p.Arg362Cys missense_variant Familial Maternal Extended multiplex 26235985 Snijders Blok L , et al. (2015)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

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.

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."

4/1/2021
1
icon
1

Score remained at 1

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.

Reports Added
[Prospective and detailed behavioral phenotyping in DDX3X syndrome2021]
1/1/2021
1
icon
1

Score remained at 1

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.

Reports Added
[Comprehensive Genetic Analysis of Non-syndromic Autism Spectrum Disorder in Clinical Settings2021] [De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
10/1/2020
1
icon
1

Score remained at 1

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.

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
7/1/2020
1
icon
1

Score remained at 1

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.

Reports Added
[A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders2020] [A de novo DDX3X Variant Is Associated With Syndromic Intellectual Disability: Case Report and Literature Review2020]
4/1/2020
1
icon
1

Score remained at 1

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.

Reports Added
[Pathogenic DDX3X Mutations Impair RNA Metabolism and Neurogenesis during Fetal Cortical Development2020] [Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability2020]
10/1/2019
2S
icon
1

Decreased from 2S to 1

New Scoring Scheme
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.

Reports Added
[New Scoring Scheme]
7/1/2019
2S
icon
2S

Decreased from 2S to 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.

Reports Added
[Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019] [Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing.2019] [Expansion of phenotype of DDX3X syndrome: six new cases.2019] [Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
4/1/2019
2S
icon
2S

Decreased from 2S to 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.

Reports Added
[Three de novo DDX3X variants associated with distinctive brain developmental abnormalities and brain tumor in intellectually disabled females.2019]
1/1/2019
2S
icon
2S

Decreased from 2S to 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.

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
10/1/2018
2S
icon
2S

Decreased from 2S to 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.

Reports Added
[Phenotypic expansion in DDX3X - a common cause of intellectual disability in females.2018]
10/1/2017
2S
icon
2S

Decreased from 2S to 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.

Reports Added
[High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies.2017]
4/1/2017
3S
icon
2S

Decreased from 3S to 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.

Reports Added
[Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Identification of Intellectual Disability Genes in Female Patients with A Skewed X Inactivation Pattern.2016] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017] [Lessons learned from additional research analyses of unsolved clinical exome cases.2017] [A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology.2017] [DDX3X mutations in two girls with a phenotype overlapping Toriello-Carey syndrome.2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
7/1/2016
3S
icon
3S

Decreased from 3S to 3S

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).

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016]
4/1/2016
3S
icon
3S

Decreased from 3S to 3S

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).

Reports Added
[Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Identification of Intellectual Disability Genes in Female Patients with A Skewed X Inactivation Pattern.2016]
7/1/2015
icon
3S

Increased from to 3S

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).

Krishnan Probability Score

Score 0.5862682256489

Ranking 514/25841 scored genes


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

Score 0.99893006535012

Ranking 1082/18225 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 0.47427199943605

Ranking 396/18665 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 0.29074388690476

Ranking 2871/20870 scored genes


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