ClinGen Dosage Sensitivity Curation Page

2q37.3 terminal region (includes HDAC4)

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
19752160 This paper studied 52 Smith-Magenis syndrome-like patients that were RAI1 negative. Array CGH was used to scan for CNVs. Two patients harbor 2q37.3 deletions of unknown inheritance: one at chr2:240,099,656-241,289,872 and the other at chr2:238,256,217-241,289,874 (hg19). Both patients have midface hypoplasia, brachydactyly type E, and abnormal behavior.
23188045 The authors studied a 3-generation family with psychomotor and behavioral abnormalities plus dysmorphism (midface hypoplasia, deep-set eyes, thin upper lip), but no brachydactyly. Array CGH analysis on available samples (2/3 affected individuals) revealed an interstitial 2q37.3 deletion including the HDAC4 and TWIST2 genes and a noncoding RNA (hg18:chr2:239,395,957-240,154,599). The authors conclude that the HDAC4 gene represents the BDMR critical region and that their findings are consistent with previously reported incomplete penetrance of the brachydactyly phenotype.
25402011 This is a report of a family with brachydactyly type E and some mild dysmorphic features, but no intellectual disability. A 2q37.3 microdeletion was detected in all affected family members that were tested via aCGH: arr[hg19] 2q37.3(239,720,311-240,211,233)x1. This interval includes part of HDAC4, TWIST2, and noncoding RNAs.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.