Submission Details

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.

HDAC8 was first reported in relation to X-linked Cornelia de Lange syndrome (CdLS) in 2012 (Deardorff et al., PMID: 22885700). HDAC8 variants expand the phenotypic spectrum of classic CdLS to include delayed closure of the anterior fontanelle, hypertelorism, hooding of eyelids, a wide nose and dental anomalies (PMIDs: 24403048, 26671848).

Nine variants (missense, nonsense, frameshift, splice) that have been reported in 9 probands in 4 publications (PMIDs: 22885700, 22889856, 25102094, 29519750) are included in this curation. 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, PMID: 22889856). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by in vitro functional assays, rescue in patient cells, and animal models.

In summary, there is definitive evidence supporting the relationship between HDAC8 and X-linked 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 Intellectual Disability and Autism Gene Curation Expert Panel on September 11, 2018 (SOP Version 5).