Background: Haploinsufficiency of the GATA6 transcription factor gene was recently found to be the most\ncommon cause of pancreatic agenesis, a rare cause of neonatal diabetes mellitus. Although most cases are\nde novo, we describe three siblings with inherited GATA6 haploinsufficiency and the rare finding of parental\nmosaicism.\nCase Presentation: The proband was born at term with severe intrauterine growth restriction, the first\nchild of non-consanguineous parents. Diabetes occurred on day of life 1 with pancreatic exocrine insufficiency\nnoted at several months of age. Pancreatic agenesis with absent gallbladder was confirmed when he underwent\ncongenital diaphragmatic hernia and intestinal malrotation repair. A patent ductus arteriosus and pulmonary stenosis\nwere repaired in infancy. Neurocognitive development has been normal. A second pregnancy was terminated\ndue to tetralogy of Fallot and pulmonary hypoplasia secondary to congenital diaphragmatic hernia. The fetus\nalso demonstrated severe pancreatic hypoplasia, gallbladder agenesis and intestinal rotation abnormalities.\nDespite severe hypoplasia, the pancreas demonstrated normal islet histology. Another sibling was found to\nhave multiple cardiac abnormalities, requiring procedural intervention. Given the proband�s spectrum of\ncongenital anomalies, Sanger sequencing of the GATA6 gene was performed, revealing a novel heterozygous\nc.635_660del frameshift mutation (p.Pro212fs). The mutation is predicted to be pathogenic, resulting in\ninclusion of a premature stop codon and likely degradation of the gene transcript by nonsense-mediated\ndecay. The abortus and the sibling with the cardiac defect were both found to have the mutation, while\nthe father and remaining sibling were negative. The mother, who is healthy with no evidence of diabetes\nor cardiac disease, is mosaic for the mutation at a level of 11% in her peripheral leukocytes by next-generation\nsequencing.\nConclusion: We highlight a rare mechanism of pancreatic agenesis, this being only the second report of parental\nmosaicism for a GATA6 mutation and one of a handful of inherited cases. We also further define the phenotypic\nvariability of GATA6 haploinsufficiency, even in individuals carrying the same mutation. Mutations in GATA6 should be\nstrongly considered in cases of diabetes due to pancreatic hypoplasia or agenesis, and potentially affected family\nmembers should be tested regardless of phenotype.
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