Gene Validity Curation

DDX3X - X-linked syndromic intellectual disability

Gene: DDX3X (HGNC:2745)
Classification - 05/05/2020
Disease: X-linked syndromic intellectual disability (MONDO_0020119)
Mode of Inheritance: X-linked inheritance (HP:0001417)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Intellectual Disability and Autism EP
Evidence Summary: DDX3X was first associated with X-linked syndromic intellectual disability as early as 2015 (Snijders Blok et al., PMID: 26235985). More than 100 unique variants have been reported in the literature (PMID: 32135084). Approximately half of the variants observed in humans are missense, although nonsense, frameshift, splice site, and in-frame indel variants have also been reported. Eight variants were included in this curation to reach a classification of definitive, however more evidence is available in the literature (PMID: 26235985, 30349862, 30936465, 30734472). Variants in this gene segregated with disease in 3 family members. More research is needed to determine whether disease is caused by haploinsufficiency or a dominant negative mechanism. This gene-disease association is supported by animal models, expression studies, and in vitro functional assays (PMID: 27179789, 27656019, 32135084). In summary, DDX3X is definitively associated with X-linked syndromic intellectual disability.
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12 6
12
12
Snijders Blok L et al. 2015 Aug 6 (PMID:26235985); Wang X et al. 2018 Oct (PMID:30349862); Scala M et al. 2019 Aug (PMID:30936465); Nicola P et al. 2019 Apr (PMID:30734472);
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 2
0.2
0.2
Snijders Blok L et al. 2015 Aug 6 (PMID:26235985);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Lennox AL et al. 2020 Feb 28. (PMID:32135084);
Functional Alteration Patient cells 1 0 - 2 2
0.5
Non-patient cells 0.5 0 - 1 1 0.5
Chen HH et al. 2016 Sep 21 (PMID:27656019);
Models Non-human model organism 2 0 - 4 4 2 1.5 2
Chen CY et al. 2016 July 15 (PMID:27179789); Lennox AL et al. 2020 Feb 28. (PMID:32135084);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2 1 0.5
Chen HH et al. 2016 Sep 21 (PMID:27656019);
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 3

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 3 15 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
05/05/2020
EXPERT CURATION (DATE)
Definitive
05/05/2020
EVIDENCE SUMMARY
DDX3X was first associated with X-linked syndromic intellectual disability as early as 2015 (Snijders Blok et al., PMID: 26235985). More than 100 unique variants have been reported in the literature (PMID: 32135084). Approximately half of the variants observed in humans are missense, although nonsense, frameshift, splice site, and in-frame indel variants have also been reported. Eight variants were included in this curation to reach a classification of definitive, however more evidence is available in the literature (PMID: 26235985, 30349862, 30936465, 30734472). Variants in this gene segregated with disease in 3 family members. More research is needed to determine whether disease is caused by haploinsufficiency or a dominant negative mechanism. This gene-disease association is supported by animal models, expression studies, and in vitro functional assays (PMID: 27179789, 27656019, 32135084). In summary, DDX3X is definitively associated with X-linked syndromic intellectual disability.