ClinGen Dosage Sensitivity Curation Page

HDAC8

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
22885700 Deardorff MA et al identified four de novo missense mutations and one de novo nonsense HDAC8 mutations in 6 CdLS probands. None of the mutations was seen in 290 ethnically matched control chromosomes or in 629 individuals of the 1000 Genomes Project. All probands were diagnosed of CdLS, pre-screened and were negative for mutations in NIPBL, SMC1A and SMC3.
24403048 Kaiser FJ et al reported a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. The mutations were detected by whole-genome SNP array, and most are missense and de novo. To evaluate the effect of these mutations on protein function, they mapped mutations on crystal structure of HDAC8 and expressed each of the mutated protein in E. coli. The results showed varying loss of activity of HDAC8 protein.
26671848 Parenti I et al reported on the clinical and molecular characterization of 11 patients carrying 10 distinct variants in HDAC8. They used different approaches including Sanger sequencing, a targetd NGS panel including the five known CdLS genes, and whole exome sequencing. The variants include one exchange affecting a conserved splice donor site (c.910+1G>A), one nonsense variant p.(R166*), one frame-shift deletion p.(F207Nfs*3) and seven single amino acid substitutions, namely p.(S150P), p.(C153R), p.(N156K), p.(T280I), p.(P257L), p.(C287Y), and p.(G320R).

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Evidence for Triplosenstive Phenotype

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.