ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000016.9) (NC_000016.10)
  • Haploinsufficiency score: Gene associated with autosomal recessive phenotype
  • Strength of Evidence (disclaimer): Gene associated with autosomal recessive phenotype

Haploinsufficiency phenotype comments:

Loss-of-function mutations in GPR56 lead to bilateral frontoparietal polymicrogyria (BFPP), an autosomal recessive disorder affecting brain development [MIM:606854]. Heterozygous GPR56 mutations are not associated with any obvious disorder and the obligate carriers are healthy. Detailed molecular and functional analysis of the wild-type GPR56 and BFPP-associated point mutants shows that individual GPR56 mutants most likely cause BFPP via different combination of multiple mechanisms. These include reduced surface receptor expression, loss of GPS proteolysis, reduced receptor shedding, inability to interact with a novel protein ligand, and differential distribution of the 7TM moiety in lipid rafts (PMID: 2134984). Although GPR56 is expressed in a wide range of tissues, the consequences of loss-of-function mutations in the GPR56 gene have only been observed in the central nervous system (PMID: 20374731). PMID: 19807741: The authors describe a patient with neuroradiological features fulfilling the diagnostic criteria for BFPP, who was heterozygous for a de novo 12Mb deletion in chromosome region 16q12.1-q21, including the GPR56 gene. Sequencing of the GPR56 gene (i.e. intact allele) did not reveal any pathogenic sequence changes. This is the first large deletion described associated with BFPP; no other similar deletion or rearrangement is known in order to make a more precise genotype-phenotype correlation.

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

Triplosensitivity phenotype comment:

No literature identified.