ClinGen Dosage Sensitivity Curation Page

2q37.3 terminal region (includes HDAC4)

  • Curation Status: Complete
  • id: ISCA-37394
  • Date last evaluated: 2016-06-13
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 0


Location Information

Select assembly: (NC_000002.11) ()
Evidence for haploinsufficiency 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.

Haploinsufficiency phenotype comments:

The coordinates of this region represent the minimal deleted region required for the BDMR phenotype. Deletions that extend proximally may carry a risk of congenital heart defects [PMID 15173228]. Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region. Additional studies: PMID 15173228: This study used multiplex amplifiable probe hybridization to refine the deleted region in patients with known monosomy 2q37 ("Albright hereditary osteodystrophy (AHO)-like metacarpal/metatarsal shortening brachymetaphalangism aka brachydactyly-mental retardation/BDMR syndrome"). No common breakpoints were found and they concluded that the minimum deleted region in patients with facial dysmorphism and brachymetaphalangism is approximately 3 Mb: from HDAC4 at ~240.0 Mb (hg19) to the telomere. Cases were noted to have developmental delay and facial dysmorphism (round face, flattened nasal bridge, deep-set eyes, up-slanting palpebral fissures, anteverted nares, thin upper lip) and sometimes: brachydactyly (55%), behavioral abnormalities, seizures, eczema, and/or heart defects. Considerable clinical variability was noted. PMID 16762827: This study used FISH to analyze 5 patients with cytogenetically-visisble de novo monosomy 2q37. Four patients had different terminal dels, one interstitial. They concluded that the minimum deleted region in patients with BDMR is approximately from RP11-585E12 to RP11-351E10 (~238.1-242.9 Mb, hg19). PMID 26112830: One case (case #1) of a de novo 2q37.3 deletion in a patient with developmental delay, brachydactyly type E, round face, hypoplastic midface, flat nasal bridge, and small deep-set eyes at hg19 237.7-243.0 Mb (proband tested by aCGH, parents by FISH). PMID 19365831: One case of a de novo 2q37.3 deletion in a patient with autism, mild intellectual disability, and brachymetaphalangy; no facial dysmorphism was observed (proband tested by aCGH, parents by FISH). The deletion observed is a 3.5 Mb terminal deletion with the proximal break point between 239.1-240.0 Mb. PMID 25329715: One patient (# 2) was found by aCGH to have a 2q37.3 deletion from hg19 240.9-243.2, inheritance unknown. This patient has no dysmorphisms and only mild delays, but was noted to have behavior abnormalities. Patient was reported to be negative for BDMR features.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Two duplications of this region are noted in ClinVar: hg19 ~chr2:236.2-243.1 and chr2:236.5-243.0. These duplications were from "An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities" by Kaminsky et al [PMID 21844811]. However, no further evidence exists at this time.