X-exome sequencing identifies a HDAC8 variant in a large pedigree with X-linked intellectual disability, truncal obesity, gynecomastia, hypogonadism and unusual face

We present a large Dutch family with 7 males affected by a novel syndrome of X-linked intellectual disability (XLID), hypogonadism, gynaecomastia, truncal obesity, short stature and recognizable craniofacial manifestations resembling but not identical to Wilson-Turner Syndrome. Eight female relatives showed a much milder expression of the phenotype. We performed X chromosome exome (X-exome) sequencing in five individuals from this family and identified a novel intronic variant in the histone deacetylase 8 gene (HDAC8), c.164+5G>A, which disturbs the normal splicing of exon 2 resulting in exon skipping and premature stop at the beginning of the histone deacetylase functional domain. HDAC8 is a member of protein family of histone deacetylases that play a major role in epigenetic gene silencing during development. HDAC8 specifically controls the patterning of the skull with the mouse HDAC8 knock-out showing craniofacial deformities of the skull. The identified variant completely segregated in this family and was absent in 96 Dutch controls and available databases. Affected female carriers showed a markedly skewed X-inactivation pattern in lymphocytes in which the mutated X-chromosome was completely inactivated. The present family provides the first evidence for involvement of HDAC8 in syndromic intellectual disability.