Haploinsufficiency of HDAC4 Causes Brachydactyly Mental Retardation Syndrome, with Brachydactyly Type E, Developmental Delays, and Behavioral Problems

Abstract

Brachydactyly mental retardation syndrome (BDMR) is associated with a deletion involving chromosome 2q37. BDMR presents with a range of features, including intellectual disabilities, developmental delays, behavioral abnormalities, sleep disturbance, craniofacial and skeletal abnormalities (including brachydactyly type E), and autism spectrum disorder. To date, only large deletions of 2q37 have been reported, making delineation of a critical region and subsequent identification of candidate genes difficult. We present clinical and molecular analysis of six individuals with overlapping deletions involving 2q37.3 that refine the critical region, reducing the candidate genes from >20 to a single gene, histone deacetylase 4 (HDAC4). Driven by the distinct hand and foot anomalies and similar cognitive features, we identified other cases with clinical findings consistent with BDMR but without a 2q37 deletion, and sequencing of HDAC4 identified de novo mutations, including one intragenic deletion probably disrupting normal splicing and one intragenic insertion that results in a frameshift and premature stop codon. HDAC4 is a histone deacetylase that regulates genes important in bone, muscle, neurological, and cardiac development. Reportedly, Hdac4(-/-) mice have severe bone malformations resulting from premature ossification of developing bones. Data presented here show that deletion or mutation of HDAC4 results in reduced expression of RAI1, which causes Smith-Magenis syndrome when haploinsufficient, providing a link to the overlapping findings in these disorders. Considering the known molecular function of HDAC4 and the mouse knockout phenotype, taken together with deletion or mutation of HDAC4 in multiple subjects with BDMR, we conclude that haploinsufficiency of HDAC4 results in brachydactyly mental retardation syndrome.

The 2q37-deletion syndrome: an update of the clinical spectrum including overweight, brachydactyly and behavioural features in 14 new patients

“…A precise mapping of the deleted regions is not often available, as most published cases have been characterized by conventional cytogenetics, subtelomeric fluorescence in situ hybridization (FISH) or microsatellite markers, and array-based comparative genomic hybridization (array-CGH) has only been used in a few studies. [1][2][3][4][5][6][7][8][9][10] At least 197 genes are located in the 2q37 region (230.7-243.2 Mb; Hg19; NCBI map viewer http://www.ncbi.nlm.nih.gov/mapview/). Of these, 11 have been reported as being potentially related to the 2q37-deletion phenotype so far, 5,[10][11][12][13][14][15][16][17] but the phenotypic implications of most of them remain unknown.…”

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

“…9 Recently, HDAC4 haploinsufficiency has been identified as the critical genetic mechanism responsible for developmental delay, behavioural abnormalities, and BDE in BDMR patients with 2q37 deletion. 5 This was supported by the detection of intragenic de novo HDAC4 mutations in two patients with core findings of BDMR syndrome.…”

“…To evaluate further diagnostic criteria for the 2q37 deletion syndrome, we compared the clinical findings of our patients and a representative cohort of other published patients carrying HDAC4 mutations or overlapping interstitial or terminal 2q37 deletions ( Figure 3, Table 1). 3,5,[15][16][17][18][19][20][21][22][23][24] The female to male ratio was 21/6. Regarding the body measurements, 4/18 of the patients were microcephalic, 8/24 revealed a short stature and 7/20 an overweight.…”

“…Accordingly, a regulatory connexion between HDAC4 and RAI1 the major gene for the phenotypic features of SMS has been proven. 5 Interestingly, with regard to the memory deficits claimed by the index patients mother, HDACs seem to be related to memory functions of the brain as shown in an Alzheimeŕs disease mouse model. 18 With regard to the BDMR-associated facial dysmorphism we compared the facial characteristics of our patients and the other patients reported in the literature with the features previously described in GeneReviews (see features marked with an asterisk in Table 1).…”

No evidence for GNAS copy number variants in patients with features of Albright's hereditary osteodystrophy and abnormal platelet Gs activity

“…In addition, an AHO-like phenotype is also described in patients with HDAC4 happloinsufficiency due to gene mutations or 2q37 microdeletions. 17,18 In the last decade, hundreds of submicroscopic copy number variants (CNVs) and inversions have been described in the human genome. [19][20][21][22][23] This type of variants can contain millions of bases of DNA, encompassing entire genes and their regulatory regions.…”