Gene Validity Classification Summary

Gene/Disease Pair:

HDAC8 : Cornelia de Lange syndrome

HGNC:13315 | MONDO_0016033
Mode of Inheritance: X-linked inheritance (HP:0001417)
Expert Panel: Autism and Intellectual Disability EP
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
10
10
Deardorff MA et al. 2012 Sep 13 (PMID:22885700); Feng L et al. 2014 Sep (PMID:25102094); Saikusa T et al. 2018 May (PMID:29519750);
Proband with predicted or proven null variant 1.5 0-2 10 1.5 1.5
Harakalova M et al. 2012 Aug (PMID:22889856);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
0.5
0.5
Deardorff MA et al. 2012 Sep 13 (PMID:22885700);
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 Evidence of segregation in one or more families   Sequencing Method 0-3 3
3
3  
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total 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 Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
0.5
Deardorff MA et al. 2012 Sep 13 (PMID:22885700);
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
Haberland M et al. 2009 Jul 15 (PMID:19605684);
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
Rescue in patient cells 1 0 - 2 1
Deardorff MA et al. 2012 Sep 13 (PMID:22885700);
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
EXPERT CURATION (DATE)
Definitive
09/11/2018
EVIDENCE SUMMARY
The HDAC8 gene has been associated with X-linked Cornelia de Lange syndrome (CdLS) using the ClinGen Clinical Validity Framework as of 08/13/2018. This association was made using case-level and experimental data. At least 9 variants (missense, nonsense, frameshift, splice) have been reported in humans. HDAC8 was first associated with this disease in humans in 2012 (Deardorff et al.) and expands the phenotypic spectrum of classic CdLS to include delayed closure of the anterior fontanelle, hypertelorism, hooding of eyelids, a wide nose and dental anomalies (Kaiser et al. 2014, Parenti et al. 2016). Summary of Case Level Data: 12 points. Association is seen in at least 9 probands in 4 publications (22885700, 25102094, 22889856, 29519750). Variants in this gene usually occur de novo but segregation with disease was observed in 11 members of a Dutch family (Harakalova et al 2012). This gene-disease association is supported by in vitro functional assays, rescue in patient cells, and animal models. In summary, HDAC8 is definitively associated with Cornelia de Lange 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 Autism and Intellectual Disability Working Group on 9/11/2018.