Gene Validity Curation

ARID1B - Coffin-Siris syndrome

Gene: ARID1B (HGNC:18040)
Classification - 12/04/2019
Disease: Coffin-Siris syndrome (MONDO_0015452)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Intellectual Disability and Autism EP
Evidence Summary: ARID1B was reported in relation to autosomal dominant Coffin-Siris syndrome by three different groups around the same time in 2012 (Tsurusaki, et al., PMID: 22426308; Santen, et al., PMID: 22426309; Hoyer, et al., PMID: 22405089). Coffin-Siris syndrome is characterized by intellectual disability associated with coarse facial features, hypertrichosis, sparse scalp hair, and hypoplastic or absent fifth fingernails or toenails. More than 170 unique pathogenic or likely pathogenic variants in ARID1B have been reported in ClinVar, with the majority of them de novo truncating variants (van der Sluijs, et al., PMID: 30349098). Evidence supporting this gene-disease relationship includes case-level data and experimental data. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is haploinsufficiency (Hoyer, et al., PMID: 22405089). The gene-disease association is also supported by animal and cell culture models. Noteworthy, Coffin-Siris syndrome can be caused by variants in additional genes, including ARID1A, SMARCB1, SMARCA4, SMARCE1, ARID2, DPF2, SMARCC2, SOX11, and SOX4 (see OMIM). In summary, ARID1B is definitively associated with autosomal dominant Coffin-Siris syndrome. 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 12/02/19 (SOP Version 7).
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
Wieczorek D et al. 2013 Dec 20 (PMID:23906836); Pranckėnienė L et al. 2019 Oct 19 (PMID:31628733);
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
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
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 2 2.5
Jung EM et al. 2017 Dec (PMID:29184203);
Cell culture model 1 0 - 2 1 0.5
Vasileiou G et al. 2015 Sep 3 (PMID:26340334);
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) 2.5

 


 

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 2.5 14.5 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
12/04/2019
EXPERT CURATION (DATE)
Definitive
12/04/2019
EVIDENCE SUMMARY
ARID1B was reported in relation to autosomal dominant Coffin-Siris syndrome by three different groups around the same time in 2012 (Tsurusaki, et al., PMID: 22426308; Santen, et al., PMID: 22426309; Hoyer, et al., PMID: 22405089). Coffin-Siris syndrome is characterized by intellectual disability associated with coarse facial features, hypertrichosis, sparse scalp hair, and hypoplastic or absent fifth fingernails or toenails. More than 170 unique pathogenic or likely pathogenic variants in ARID1B have been reported in ClinVar, with the majority of them de novo truncating variants (van der Sluijs, et al., PMID: 30349098). Evidence supporting this gene-disease relationship includes case-level data and experimental data. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is haploinsufficiency (Hoyer, et al., PMID: 22405089). The gene-disease association is also supported by animal and cell culture models. Noteworthy, Coffin-Siris syndrome can be caused by variants in additional genes, including ARID1A, SMARCB1, SMARCA4, SMARCE1, ARID2, DPF2, SMARCC2, SOX11, and SOX4 (see OMIM). In summary, ARID1B is definitively associated with autosomal dominant Coffin-Siris syndrome. 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 12/02/19 (SOP Version 7).