ClinGen Dosage Sensitivity Curation Page

7q36.3 ZRS (SHH cis-regulatory) duplication region (within LMBR1 intron 5)

  • Curation Status: Complete
  • id: ISCA-37467
  • Date last evaluated: 2018-02-14
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 0
  • ClinGen Triplosensitivity Score: 3


Location Information

Select assembly: (NC_000007.13) ()
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity
Evidence for gain of function phenotype
PubMed ID Description
18178630 Klopocki et al (2008) reported 15 affected individuals in a German family with variable triphalangeal thumb and polysyndactyly (TPT-PS) and a ~589 kb duplication encompassing the intronic SHH cis-regulatory element, ZRS, detected by array CGH (Bac and oligo) and qPCR.
18417549 Sun et al (2008) reported six Han Chinese families with TPT-PS and/or Syndactyly, type IV (SD4) and non-recurrent intragenic LMBR1 duplications encompassing the ZRS. The duplications were initially mapped using linkage and haplotype analysis, followed by minimum region refinement by qPCR (32.7 kb commonly duplicated region, familial duplications ranged from 131 to 398 kb).
19291772 Wu et al (2009) reported eight affected individuals in a family with SD4 with tibial hypoplasia and an intragenic (97 kb) LMBR1 duplication encompassing the ZRS, detected by qPCR and array.

Triplosensitivity phenotype comment:

During development normal SHH expression in the zone of polarizing activity (ZPA) of the limb bud is regulated by a long-range enhancer, called the ZPA regulatory sequence (ZRS). The ZRS resides within intron 5 of the LMBR1 gene, ~1 Mb upstream of the SHH gene. Duplications and other mutations involving this region lead to autosomal dominant limb malformation phenotypes including TPT-PS, SD4, and PPD. Genomic coordinates for this region were determined by comparison of the 773 bp ZRS sequence published by Lettice and Hill (2005)(PMID 15917205) to human genome reference assembly (GRCh37/hg19). Note the exact minimal and maximal duplicated region sufficient to cause limb malformation phenotypes is unknown. Reported duplication sizes range from 97 kb to 589 kb and encompass the ZRS within intron 5 of LMBR1. Additional relevant literature is summarized below: Additional duplications: PMID 2792209: Wang et al (2016) reported 16 affected individuals of a Chinese family with PPD or TPTS and an intragenic (exact size unknown) LMBR1 duplication (or multiplication, copy number uncertain) that was characterized by qPCR. PMID 28035386: Liu et al (2017) reported a proband with 288 kb paternally inherited duplication encompassing the ZRS, with breakpoints in the 3? region of the gene LMBR1 and encompassing the gene NOM1 (chr7:156,484,201-156,772,643, hg19). The proband, father and additional untested family members were affected by TPT-PS. The proband also had a de novo 22q11.21 2.6 Mb deletion known to be causative of DiGeorge syndrome, which was associated with additional clinical findings. Given the specificity of TPT-PS and additional affected family members (including carrier father), the 7q36.3 duplication was attributed as a cause of TPT-PS in this family. Other mutations: In addition to duplications, heterozygous gain-of-function-type point mutations and an insertion within the ZRS have been described in association with limb malformation phenotypes, including preaxial polydactyly, type II (PPD2)[MIM #174500] and Werner mesomelic syndrome [MIM #188770]. See PMID 19847792 for a 2010 review of ZRS-associated syndromes and suggestion for clinical subclassification by molecular alteration.