Inflammatory bowel disease
Gene: PMM2
“A specific pattern of variation in PMM2 as a novel association of early-onset IBD with distinctive gastric pathology.”
Cohort of patients affected by hyperinsulinaemic hypoglycaemia and ARPKD with a specific underlying variant in the PMM2 promoter. Three of these patients additionally developed IBD in childhood and manifest a distinctive pattern of gastric antral disease involvement.
The authors describe the development of IBD in three patients with PMM2-HIPKD, with onset of IBD at 0, 6 and 10 years of age. IBD was of variable severity at onset. The organ level pattern of disease manifestations in PMM2-HIPKD-IBD may reflect a loss of cis-acting regulatory control by hepatocyte nuclear factor 4 alpha (HNF4A).
All three patients have the same genotype, two pathogenic variants (ClinVar): A promoter variant, c.-167G>T, in trans with c.422G>A; p.(Arg141His). The promoter region is not covered in gnomAD. c.422G>A is in gnomAD v2 891 hets, v3 557 hets.
Functional studies: Protein expression of PMM2 and HNF4A assessed by immunohistochemistry for two patients. Patient 1 there appeared to be reduced protein expression compared to the control, especially in the gastric antrum and colon, but for patient 2, the expression profile closely matched the control.
Observation of intestinal inflammation and gastric antral foveolar hyperplasia in three patients with identical pathogenic genetic variants in the PMM2 locus, from independent kindreds, extends the previously reported spectrum of PMM2-related HI/ARPKD disease. It identifies PMM2 as a potential novel Mendelian association of early-onset IBD. Estimate low penetrance of IBD of 10% based on 30 patients in the literature.
Sources: LiteratureCreated: 2 Mar 2023, 3:41 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Inflammatory bowel disease, hyperinsulinism, polycystic kidney disease
Publications
Gene: pmm2 has been classified as Red List (Low Evidence).
Phenotypes for gene: PMM2 were changed from Inflammatory bowel disease, hyperinsulinism, polycystic kidney disease to Congenital disorder of glycosylation, type Ia, MIM# 212065; Inflammatory bowel disease, hyperinsulinism, polycystic kidney disease
Gene: pmm2 has been classified as Red List (Low Evidence).
gene: PMM2 was added gene: PMM2 was added to Inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: PMM2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PMM2 were set to 36773065 Phenotypes for gene: PMM2 were set to Inflammatory bowel disease, hyperinsulinism, polycystic kidney disease Penetrance for gene: PMM2 were set to Incomplete Review for gene: PMM2 was set to RED