ClinGen Dosage Sensitivity Curation Page

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

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for Triplosenstive Phenotype

Evidence for triplosensitivity 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.

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.