HDAC4 – 2q37 Microdeletion Syndrome

Histone deacetylase 4 (HDAC4) haploinsufficiency underlies brachydactyly-mental retardation syndrome, also known as 2q37 microdeletion syndrome, an autosomal dominant neurodevelopmental disorder characterized by intellectual disability, developmental delay, behavioral abnormalities, and skeletal anomalies including brachydactyly type E. The association between HDAC4 and this syndrome has been supported by multiple lines of genetic and functional evidence over the past decade, establishing a definitive causal role.

Large-scale clinical and molecular analyses of six individuals with overlapping 2q37.3 deletions refined the critical region to HDAC4, and sequencing identified intragenic splice-disrupting deletions and frameshift insertions in probands without large chromosomal deletions (PMID:20691407). Subsequent studies reported seven unrelated de novo missense variants clustering at a conserved 14-3-3 binding motif in HDAC4, implicating impaired nucleocytoplasmic shuttling in pathogenesis (PMID:33537682).

Familial segregation analyses further corroborate autosomal dominant inheritance: a three-generation pedigree with an interstitial 2q37.3 deletion encompassing HDAC4 showed variable expressivity of psychomotor delay and behavioral abnormalities (PMID:23188045); a parent–child pair demonstrated dosage-dependent severity correlating with 67% versus 23% HDAC4 expression (PMID:22753018); and a four-member family with a missense variant c.2204G>A (p.Arg735Gln) exhibited fully co-segregating phenotypes across affected relatives (PMID:37020696).

Functional studies reveal that Hdac4 knockout mice phenocopy key skeletal malformations due to premature ossification, mirroring human brachydactyly type E, and demonstrate downstream dysregulation of RAI1 expression (PMID:20691407). Dosage experiments in patients support a gene–dose effect on phenotype severity, confirming haploinsufficiency as the pathogenic mechanism (PMID:22753018).

Some individuals with HDAC4 deletions lack cognitive impairment, indicating incomplete penetrance and variable expressivity in intellectual outcomes (PMID:24715439). Despite this variability, the cumulative evidence firmly establishes HDAC4 haploinsufficiency as the definitive cause of 2q37 microdeletion syndrome.

Key Take-home: HDAC4 testing is clinically useful for diagnosis of 2q37 microdeletion syndrome and stratification of recurrence risk in families.

References

• American Journal of Human Genetics • 2010 • Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems. PMID:20691407
• HGG Advances • 2021 • Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome. PMID:33537682
• European Journal of Human Genetics • 2013 • Phenotypic variant of Brachydactyly-mental retardation syndrome in a family with an inherited interstitial 2q37.3 microdeletion including HDAC4. PMID:23188045
• American Journal of Medical Genetics Part A • 2012 • Dose dependent expression of HDAC4 causes variable expressivity in a novel inherited case of brachydactyly mental retardation syndrome. PMID:22753018
• Clinical Pediatric Endocrinology • 2023 • A family with brachydactyly mental retardation syndrome with a missense variant in HDAC4. PMID:37020696
• American Journal of Medical Genetics Part A • 2014 • Haploinsufficiency of HDAC4 does not cause intellectual disability in all affected individuals. PMID:24715439

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