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We performed whole exome sequencing in individuals from a family with autosomal dominant gastropathy resembling Ménétrier disease, a premalignant gastric disorder with epithelial hyperplasia and enhanced EGFR signalling. Ménétrier disease is believed to be an acquired disorder, but its aetiology is unknown. In affected members, we found a missense p.V742G variant in  MIB2 , a gene regulating NOTCH signalling that has not been previously linked to human diseases. The variant segregated with the disease in the pedigree, affected a highly conserved amino acid residue, and was predicted to be deleterious although it was found with a low frequency in control individuals. The purified protein carrying the p.V742G variant showed reduced ubiquitination activity in vitro and white blood cells from affected individuals exhibited significant reductions of  HES1  and  NOTCH3  expression reflecting alteration of NOTCH signalling. Because mutations of  MIB1 , the homolog of  MIB2 , have been found in patients with left ventricle non-compaction (LVNC), we investigated members of our family with Ménétrier-like disease for this cardiac abnormality. Asymptomatic left ventricular hypertrabeculation, the mildest end of the LVNC spectrum, was detected in two members carrying the  MIB2  variant. Finally, we identified an additional  MIB2  variant (p.V984L) affecting protein stability in an unrelated isolated case with LVNC. Expression of both  MIB2  variants affected NOTCH signalling, proliferation and apoptosis in primary rat cardiomyocytes.

MIB2 variants altering NOTCH signalling result in left ventricle hypertrabeculation/non-compaction and are associated with Ménétrier-like gastropathy