ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000018.9) (NC_000018.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
22158542 Allen et al. 2011: Describes 14 GATA6 mutations detected in 15 cases from a group of individuals with pancreatic agenesis, including 5 different frameshift mutations resulting in a premature termination codon. Congenital heart defects were also present in 14 of the 15 affected subjects. In 12 of 15 subjects for whom parental DNA was available, the mutations were found to be de novo. None of the mutations has been reported in 1,094 population controls (from the 1000 Genomes Project database). All six missense mutations found were said to affect residues on the DNA binding surface that are conserved across vertebrate orthologs of GATA6 and in all human GATA proteins. Also, GATA6 proteins carrying four different missense mutations identified in this article did not bind to GATA6 recognition sites and were unable to activate a GATA6-responsive promoter. Per the authors, the functional studies of missense DNA-binding?domain mutations and the identification of frameshift and splicing mutations suggest that heterozygous GATA6 mutations result in loss of function and cause pancreatic agenesis through haploinsufficiency.
23223019 Franco et al. (2012) describe 9 novel GATA6 mutations detected from a group of 171 patients with neonatal diabetes mellitus (NDM) of unknown genetic etiology, including a nonsense mutation (Y323X), a frameshift, and several other missense mutations. None of the mutations were present in the dbSNP137, 1000 Genomes (March 2012 release, based on 1,197 individuals), or Exome Variants Server (June 2012 release, based on 6,503 individuals) databases. Parental DNA samples were available for eight of nine previously unreported patients. Mutations were shown to have arisen de novo in three patients and been inherited from a parent affected with diabetes and/or a history of congenital heart defect. All the patients with NDM and three of five parents with a GATA6 mutation also exhibited extrapancreatic features. Congenital heart defects were the most common, present in 21 of 24 probands (includes probands from Allen et al. 2011 as described above) and three parents (83%), and required surgical correction in 19 case subjects.
23635550 Gong et al. (2013) report two novel heterozygous frameshift mutations in two males with congenital heart defects, diabetes, and pancreatic malformations. The authors note that: "One 4-bp duplication (c. 951_954dupGCCG) was revealed for the first case, which predicted the misincorporation of 144 amino acids before the premature stop codon was introduced. For the second case, one 152-bp deletion (c.754_905del) led to the deletion of 51 amino acids and 160 amino acids were predicted to be misincorporated before the premature stop codon was introduced. Both mutations led to a complete loss of the zinc finger DNA-binding domain, which is highly conserved among different species. Furthermore, parts of the GATA-N-superfamily domain were not coded correctly. The two novel mutations were not found in the unaffected parents and the sister of case 2 [parents in case 1 not available for testing], and also not in the 96 normoglycemic controls (approx. 50% of Turkish origin)[family 2 is of Turkish origin] or in the databases of genomic variants (dbSNP135, Database of Genomic Variants, 1,000 Genomes Project, dbvar or HGMD)."

Haploinsufficiency phenotype comments:

Mutations in GATA6 have been associated with a wide spectrum of congenital heart defects, diabetes, and pancreatic hypoplasia/agenesis. Variable expressivity, including intrafamilial variability, has been noted (see, for example, PMID: 22962692).

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