Gene Validity Curation

IQSEC2 - complex neurodevelopmental disorder

Gene: IQSEC2 (HGNC:29059)
Classification - 06/05/2019
Disease: complex neurodevelopmental disorder (MONDO_0100038)
Mode of Inheritance: X-linked inheritance (HP:0001417)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Intellectual Disability and Autism EP
Evidence Summary: Variants in IQSEC2 were reported in humans with x-linked complex neurodevelopmental disorder (specifically intellectual disability) as early as 1988 (Suthers et al., 3177466). The affected individuals, including both males and females, typically have intellectual disability with variable seizures, autistic traits, and psychiatric problems. Males are generally more severely affected compared with females. Eight variants (nonsense and frameshift variants) were curated from one publication with a large patient cohort (30206421). To date, at least 70 variants in IQSEC2 have been reported in patients (30328660) and 47 unique variants with IQSEC2 have been classified as Pathogenic in ClinVar. In regard to experimental data, this gene-disease relationship is supported by expression studies, non-human model organisms, and cell culture models. In summary, IQSEC2 is definitively associated with x-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 6/5/19 (SOP Version 6).
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 8
16
12
Mignot C et al. 2019 Apr (PMID:30206421);
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
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
Mignot C et al. 2019 Apr (PMID:30206421);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 0.5 1.5
Hinze SJ et al. 2017 May 2 (PMID:28463240);
Cell culture model 1 0 - 2 1 1
Hinze SJ et al. 2017 May 2 (PMID:28463240);
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 2

 


 

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 2 14 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
09/26/2019
EXPERT CURATION (DATE)
Definitive
06/05/2019
EVIDENCE SUMMARY
Variants in IQSEC2 were reported in humans with x-linked complex neurodevelopmental disorder (specifically intellectual disability) as early as 1988 (Suthers et al., 3177466). The affected individuals, including both males and females, typically have intellectual disability with variable seizures, autistic traits, and psychiatric problems. Males are generally more severely affected compared with females. Eight variants (nonsense and frameshift variants) were curated from one publication with a large patient cohort (30206421). To date, at least 70 variants in IQSEC2 have been reported in patients (30328660) and 47 unique variants with IQSEC2 have been classified as Pathogenic in ClinVar. In regard to experimental data, this gene-disease relationship is supported by expression studies, non-human model organisms, and cell culture models. In summary, IQSEC2 is definitively associated with x-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 6/5/19 (SOP Version 6).