HDAC8

Variants (also called mutations) in the HDAC8 gene have been identified in people with Cornelia de Lange syndrome, a developmental disorder that affects many parts of the body. Researchers estimate that variants in this gene account for about 5 percent of all cases of this condition.

Most HDAC8 gene variants change single protein building blocks (amino acids) in histone deacetylase 8 or add or delete a small number of amino acids in the enzyme. All of these variants appear to reduce or eliminate the enzyme's activity, which likely alters the activity of the cohesin complex and impairs its ability to regulate genes that are critical for normal development. Although researchers do not fully understand how these changes cause Cornelia de Lange syndrome, they suspect that altered gene regulation probably underlies many of the developmental problems characteristic of the condition.

Studies suggest that variants in the HDAC8 gene cause a somewhat different pattern of signs and symptoms than those associated with variants in the NIPBL gene, which are the most common known cause of Cornelia de Lange syndrome. Affected individuals with HDAC8 gene variants often have less severe growth problems, fewer abnormalities of the arms and hands, and different characteristic facial features than those with NIPBL gene variants. They are more likely to have delayed closure of the "soft spot" on the head (the anterior fontanelle) in infancy, widely spaced eyes (hypertelorism), and dental abnormalities. Like affected individuals with NIPBL gene variants, those with HDAC8 gene variants may have significant intellectual disability.

A variant in the HDAC8 gene has also been identified in a large Dutch family with a form of X-linked intellectual disability. (X-linked refers to the fact that the HDAC8 gene is on the X chromosome, one of the two sex chromosomes.) Signs and symptoms in affected males include severe intellectual disability, short stature, obesity, breast enlargement (gynecomastia), reduced production of sex hormones (hypogonadism), an unusually small head (microcephaly), small hands, and distinctive facial features. Affected females tend to have less severe signs and symptoms, including learning disabilities and unusual facial features.

The identified variant leads to a version of histone deacetylase 8 that is missing a segment. The abnormally short protein probably alters gene regulation during development, which causes the various health problems described in this family.

The condition in this family has been described as Wilson-Turner syndrome, which is a form of X-linked intellectual disability. However, researchers speculate that it may actually be part of the same disease spectrum as Cornelia de Lange syndrome (described above).