HDAC8 – Cornelia de Lange Syndrome

Cornelia de Lange syndrome (CdLS) is a multisystem congenital disorder characterized by distinctive facial features, growth retardation, limb anomalies, and intellectual disability. Pathogenic variants in five cohesin‐related genes account for ~85% of cases, with HDAC8 mutations underlying an X-linked form, CdLS5, in ~3–5% of patients. HDAC8 encodes the SMC3 deacetylase required for cohesin recycling; loss of its function disrupts cohesin dynamics and gene regulation in development.

Genetic studies have identified 16 distinct HDAC8 variants in 27 unrelated probands, including missense, nonsense, splice, and small indel changes detected by WES and CNV analyses (PMID:26671848). De novo mutations predominate, though inherited mosaic variants and hemizygous male cases have been reported. The variant spectrum spans the catalytic domain and regulatory loops, exemplified by c.356C>G (p.Thr119Arg) in a non-classic female (PMID:34342180).

Segregation analysis in multiplex families includes two affected siblings inheriting HDAC8 variants from a mosaic mother, with marked skewing of X-inactivation in females (PMID:26671848). Skewed X-inactivation and variable expressivity in heterozygous females further support pathogenicity and X-linked dominant inheritance.

Functional assays demonstrate that HDAC8 loss-of-function mutations confer increased SMC3 acetylation, impaired cohesin release, and reduced chromatin occupancy at cohesin binding sites. Structural and enzymological studies of mutants (C153F, A188T, I243N, T311M, H334R) reveal local conformational changes that compromise catalytic activity and thermostability; many mutants can be partially rescued by small-molecule activators (PMID:22885700; PMID:25075551).

No robust conflicting evidence disputes the HDAC8–CdLS association. The breadth of genetic findings and mechanistic concordance across cellular and structural assays affirm a consistent disease mechanism.

Overall, HDAC8 mutations cause an X-linked dominant form of CdLS with variable expressivity. Diagnostic approaches should include HDAC8 sequencing and CNV analysis, with attention to mosaicism and X-inactivation. Key take-home: HDAC8 loss-of-function underlies a distinct CdLS5 subtype, enabling molecular diagnosis and highlighting potential for HDAC8 activator–based therapies.

References

• Nature • 2012 • HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle. PMID:22885700
• ACS Chemical Biology • 2014 • Compromised structure and function of HDAC8 mutants identified in Cornelia de Lange Syndrome spectrum disorders. PMID:25075551
• Clinical Genetics • 2016 • Expanding the clinical spectrum of the 'HDAC8-phenotype' - implications for molecular diagnostics, counseling and risk prediction. PMID:26671848
• Molecular Genetics & Genomic Medicine • 2021 • A novel de novo HDAC8 missense mutation causing Cornelia de Lange syndrome. PMID:34342180

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