ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: () (NC_000019.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
27839873 Zech et al (2016) used whole-exome sequencing of parent-child trios to identify loss-of-function sequence mutations in KMT2B, resulting in early-onset generalized dystonia. In vitro functional studies demonstrated a reduction in mRNA levels, consistent with a haploinsufficient effect. Three of the four affected probands had de novo mutations, with one inherited. The family in which the mutation was inherited showed variable expressivity in carriers, as the father and grandfather had less severe dystonia. Other features reported in several individuals were microcephaly and mild intellectual disability.
27992417 Meyer et al (2016) describe 10 individuals with microdeletions of various sizes identified by microarray studies presenting with childhood onset dystonia. The smallest region of overlap encompassed two genes, ZBTB32 and KMT2B, and all deletions were de novo. Seven additional individuals with dystonia were found to have loss-of-function sequence mutation in KMT2B, three of which were inherited. Interestingly, those individuals with missense mutations were affected at a later age of onset than those with mutations predicted to truncate or elongate the protein. The subject with the smallest deletion of ~600 kb was originally reported in Dale et al (2012, PMID: 22515636).
  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity