Aberrant Splicing From an HDAC8 Intronic Variant c.112-15C>A Causes Familial Cornelia de Lange Syndrome in Heterozygous and Hemizygous Individuals.

The HDAC8 variant is causative for X-linked Cornelia de Lange syndrome (CdLS) and shows skewed X-inactivation in heterozygous female patients, who tend to present with milder phenotypes than hemizygous male patients. We report a slightly deep intronic HDAC8 variant, NM_018486.3:c.112-15C>A, in a family with CdLS. Patient 1 (male) had a hemizygous HDAC8 variant, showed a severe CdLS phenotype including profound developmental delay and multiple congenital abnormalities, and was deceased at 7 years old. Patient 2 (female) was a younger sister of Patient 1 and revealed mild developmental delay and consistent dysmorphic features with CdLS. Patient 2 and their mother (Patient 3) had heterozygous variants and showed a skewed X-inactivation pattern. cDNA deep sequencing of peripheral blood indicated aberrantly spliced transcripts in 0.53% of sequence reads in Patient 2, but not in Patient 3. This aberrant splicing likely results in nonsense-mediated mRNA decay with loss-of-function effects. In Patient 3, the mutated allele was strongly inactivated, and normal transcripts from the reference allele were predominant. cDNA deep sequencing was required to evaluate the pathogenicity of the intronic variants. This report suggests that leaky splicing, as well as X-inactivation, may contribute to the variation in familial phenotypic severity of HDAC8-related CdLS.