Phenotypic variant of Brachydactyly-mental retardation syndrome in a family with an inherited interstitial 2q37.3 microdeletion including HDAC4

Abstract

Deletions of the chromosomal region 2q37 cause brachydactyly-mental retardation syndrome (BDMR), also known as Albright hereditary osteodystrophy-like syndrome. Recently, histone deacetylase 4 (HDAC4) haploinsufficiency has been postulated to be the critical genetic mechanism responsible for the main clinical characteristics of the BDMR syndrome like developmental delay and behavioural abnormalities in combination with brachydactyly type E (BDE). We report here on the first three generation familial case of BDMR syndrome with inheritance of an interstitial microdeletion of chromosome 2q37.3. The deletion was detected by array comparative genomic hybridization and comprises the HDAC4 gene and two other genes. The patients of this pedigree show a variable severity of psychomotor and behavioural abnormalities in combination with a specific facial dysmorphism but without BDE. Given that only about half of the patients with 2q37 deletions have BDE; we compared our patients with other patients carrying 2q37.3 deletions or HDAC4 mutations known from the literature to discuss the diagnostic relevance of the facial dysmorphism pattern in 2q37.3 deletion cases involving the HDAC4 gene. We conclude that HDAC4 haploinsufficiency is responsible for psychomotor and behavioural abnormalities in combination with the BDMR syndrome-specific facial dysmorphism pattern and that these clinical features have a central diagnostic relevance.

The Class IIa histone deacetylase HDAC4 and neuronal function: Nuclear nuisance and cytoplasmic stalwart?

“…Analysis of HDAC4 expression showed it was reduced to 67% in mother and 23% in her son, compared to normal controls level of HDAC4, therefore the amount of HDAC4 correlated with the severity of the phenotype (Morris et al, 2012). Further evidence that HDAC4 is causative in BDMR arose from a three generation familial case in which three family members were found to carry a 800 kb microdeletion of 2q37.2 which included HDAC4, FLJ43879 and TWIST2, which was inherited in an autosomal dominant manner, and associated with intellectual disability, memory deficits, reduced spatial orientation and developmental delays, with variable severity (Villavicencio-Lorini et al, 2013). However, haploinsufficiency of HDAC4 does not always result in intellectual disability.…”

Reorganization of inter‐ chromosomal interactions in the 2q37‐deletion syndrome

“…The patients' sole behavioral peculiarity is a “very friendly” disposition in all affected members and III‐1 recently developed self‐injuring behavior (skin picking). Genotype–phenotype comparisons and phenotype—2q37‐breakpoint correlations showed that clinical features are variable in ˜50% of patients (Aldred et al , ; Casas et al , ; Falk & Casas, ; Villavicencio‐Lorini et al , ). B, CHand (B) and feet (C) photographs of the affected individual II‐1 with obvious BDE of fingers and toes. DqPCR was used to reduce the critical deletion region on chromosome 2q37; genomic positions refer to human genome assembly hg19. Amplification values were normalized to the non‐affected proband I‐2.…”

Long-Term Memory inDrosophilaIs Influenced by Histone Deacetylase HDAC4 Interacting with SUMO-Conjugating Enzyme Ubc9

“…To that end, we recently demonstrated that in Drosophila, RNA interference (RNAi)-mediated knockdown of HDAC4 in the adult brain impairs long-term memory (LTM) in the courtship suppression assay, a model of associative memory (Fitzsimons et al 2013). Similarly in humans, loss of one copy of HDAC4 correlates with brachydactyly mental retardation syndrome (BDMR), the neurological symptoms of which include intellectual disability and autism (Williams et al 2010;Morris et al 2012;Villavicencio-Lorini et al 2013), and in mice, conditional knockout of HDAC4 in the brain results in impairments in hippocampal-dependent associative LTM . Despite this growing evidence of a critical role, the mechanism(s) through which HDAC4 positively influences LTM is unknown.…”