Limb disordersGene: HDAC4
Variants previously reported in OMIM in association with BRACHYDACTYLY-MENTAL RETARDATION SYNDROME are now reclassified as VUS following reports of Villavicencio-Lorini et al. (2013)(PMID:23188045) and Wheeler et al. (2014)(PMID:24715439).
Williams et al (2010)(PMID: 20691407) refined the BDMR critical region to a single gene, HDAC4. 2 unrelated cases of patients with no CNV covering HDAC4, but with SNVs in HDAC4 (c.2399_2400insC leading to p.Gly801TrpfsX77 and c.490+56_121del65 probably altering splicing of exons 5–6 ) and BDMR features including Brachydactyly type E in both patients.
Villavicencio-Lorini et al. 2013 (PMID: 23188045) report a family with a deletion covering the HDAC4, FLJ43879, and TWIST2 genes and presenting with very mild developmental delay and dysmorphic facial features but no brachydactyly. The conclusion was that HDAC4 haploinsufficiency is not fully penetrant for brachydactyly type E.
Ogura et al. (2014)(PMID: 25329715) heterozygous 3.2-Mb deletion that included the HDAC4 gene and did have brachydactyly type E.
Wheeler et al. (2014)(PMID: 24715439) reported a mother and 2 sons with a heterozygous 887-kb deletion including the entire coding region of the HDAC4 gene, 2 noncoding RNA sequences (MGC16025 and LOC150935), and 4 microRNAs. None of the individuals had intellectual disability, but the mother and the older son had type E brachydactyly.
Jean-Marçais et al (2015)(PMID: 25402011) - family with deletion covering HDAC4 and TWIST2. Patients presented with BDE and short stature without intellectual disability.
In conclusion, haploinsufficiency of HDAC4 appears to be associated with Brachydactyly type E but not always intellectual disability.
Created: 9 Dec 2018, 10:17 p.m.
Comment when marking as ready: Associated with phenotype in G2P. Numerous reports of haploinsufficiency suggest involvement of HDAC4 in skeletal dysplasia..
Created: 12 Jul 2016, 8:23 a.m.
Created: 17 Jun 2016, 8:04 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Albright hereditary osteodystrophy type 3, Albright hereditary osteodystrophy-like syndrome, Brachydactyly-intellectual disability, Del(2)(q37) 600430
Variants in this GENE are reported as part of current diagnostic practice
Ana Beleza: Tier 2
Expert Review Green was added to HDAC4. Panel: Limb disorders UKGTN was added to HDAC4. Panel: Limb disorders Radboud University Medical Center, Nijmegen was added to HDAC4. Panel: Limb disorders Expert list was added to HDAC4. Panel: Limb disorders Emory Genetics Laboratory was added to HDAC4. Panel: Limb disorders Model of inheritance for gene HDAC4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene HDAC4 was set to ['20691407', '15521982', '19365831']
London South East RGC GSTT was added to HDAC4. Panel: Limb disorders
HDAC4 was added to Limb disorders panel. Sources: Viapath
HDAC4 was created by Ellen McDonagh