Background/Aims: Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder classically characterized by distinctive facies, growth retardation, intellectual disability, feeding difficulties, and multiple organ system anomalies. Previously, the diagnosis of CdLS was based mainly on identifying the typical phenotype in patients. However, with the advances in clinical molecular genetic diagnostic techniques, more patients, especially patients with milder phenotypes, are being diagnosed from detecting pathogenic mutation. Methods: Pathogenic mutation in a female patient with a milder phenotype was detected using whole-exome sequencing (WES), and was further characterized using bioinformatic analysis and in vitro functional experiments, including X-chromosome inactivation analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and enzyme activity assay. Results: This patient was found to harbor a novel missense mutation (c.806T>G, p.I269R) in the coding region of the HDAC8 gene, which was predicted to be pathogenic. Compared with other CdLS patients with HDAC8 mutation, the patient lacked typical facies, including synophrys and arched eyebrows. In vitro functional experiments showed the presence of skewed X-chromosome inactivation. Furthermore, the novel mutation decreased the dissolubility and enzymatic activity of HDAC8 protein. Conclusions: The present study identified a novel missense mutation (c.806T>G, p.I269R) in the HDAC8 gene leading to CdLS, which not only provided strong evidence for diagnosis in this present patient, but also expanded the spectrum of pathogenic mutations for CdLS.
A Functional Mutation in HDAC8 Gene as Novel Diagnostic Marker for Cornelia De Lange Syndrome