title: Case report: maternal mosaicism resulting in inheritance of a novel GATA6 mutation causing pancreatic agenesis and neonatal diabetes mellitus.
abstract: BACKGROUND
  Haploinsufficiency of the GATA6 transcription factor gene was recently found to be the most common cause of pancreatic agenesis, a rare cause of neonatal diabetes mellitus. Although most cases are de novo, we describe three siblings with inherited GATA6 haploinsufficiency and the rare finding of parental mosaicism.
  
  
  METHODS
  The proband was born at term with severe intrauterine growth restriction, the first child of non-consanguineous parents. Diabetes occurred on day of life 1 with pancreatic exocrine insufficiency noted at several months of age. Pancreatic agenesis with absent gallbladder was confirmed when he underwent congenital diaphragmatic hernia and intestinal malrotation repair. A patent ductus arteriosus and pulmonary stenosis were repaired in infancy. Neurocognitive development has been normal. A second pregnancy was terminated due to tetralogy of Fallot and pulmonary hypoplasia secondary to congenital diaphragmatic hernia. The fetus also demonstrated severe pancreatic hypoplasia, gallbladder agenesis and intestinal rotation abnormalities. Despite severe hypoplasia, the pancreas demonstrated normal islet histology. Another sibling was found to have multiple cardiac abnormalities, requiring procedural intervention. Given the proband's spectrum of congenital anomalies, Sanger sequencing of the GATA6 gene was performed, revealing a novel heterozygous c.635_660del frameshift mutation (p.Pro212fs). The mutation is predicted to be pathogenic, resulting in inclusion of a premature stop codon and likely degradation of the gene transcript by nonsense-mediated decay. The abortus and the sibling with the cardiac defect were both found to have the mutation, while the father and remaining sibling were negative. The mother, who is healthy with no evidence of diabetes or cardiac disease, is mosaic for the mutation at a level of 11% in her peripheral leukocytes by next-generation sequencing.
  
  
  CONCLUSIONS
  We highlight a rare mechanism of pancreatic agenesis, this being only the second report of parental mosaicism for a GATA6 mutation and one of a handful of inherited cases. We also further define the phenotypic variability of GATA6 haploinsufficiency, even in individuals carrying the same mutation. Mutations in GATA6 should be strongly considered in cases of diabetes due to pancreatic hypoplasia or agenesis, and potentially affected family members should be tested regardless of phenotype.
authors.affiliation: Division of Pediatric Endocrinology Montreal Children's Hospital, McGill University Health Centre, 1001 Boulevard Decarie, Montreal, H4A 3J1, Quebec, Canada.
authors.forename: Daphne
authors.initials: D
authors.lastname: Yau
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Barrack Road, Exeter, EX2 5DW, UK.
authors.forename: Elisa
authors.initials: E
authors.lastname: De Franco
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Barrack Road, Exeter, EX2 5DW, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Flanagan
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Barrack Road, Exeter, EX2 5DW, UK.
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.affiliation: Department of Pathology Montreal Children's Hospital, McGill University Health Centre, 1001 Boulevard Decarie, Montreal, H4A 3J1, Quebec, Canada.
authors.forename: Miriam
authors.initials: M
authors.lastname: Blumenkrantz
authors.affiliation: Division of Pediatric Endocrinology Montreal Children's Hospital, McGill University Health Centre, 1001 Boulevard Decarie, Montreal, H4A 3J1, Quebec, Canada. john.mitchell@muhc.mcgill.ca.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mitchell
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D003920:Diabetes Mellitus / Q000235:genetics*; D005317:Fetal Growth Retardation; D016368:Frameshift Mutation; D050993:GATA6 Transcription Factor / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009030:Mosaicism; D010179:Pancreas / Q000002:abnormalities*
chemical_list: D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human
keywords: GATA6; Haploinsufficiency; Mosaicism; Neonatal diabetes mellitus; Pancreas abnormalities