Monogenic diabetes

Gene: MAFA

Green List (high evidence)

Comment on list classification: As reviewed by Kevin Colclough, there are three unrelated families reported in published literature with heterozygous variants in MAFA gene (two families with p.Ser64Phe variant and one family with p.Thr57Arg variant) and with insulinomatosis and diabetes. There is functional evidence available from experimental studies including heterozygous MAFA p.Ser64Phe mouse model in support of the disease association.

This gene can therefore be promoted to green rating in the next GMS update.

Created: 29 Apr 2026, 10:54 a.m. | Last Modified: 29 Apr 2026, 10:54 a.m.

Panel Version: 3.21

Comment on phenotypes: This gene has been associated with 'Insulinomatosis and diabetes mellitus' phenotype in OMIM (last accessed 29 April 2026).

Created: 29 Apr 2026, 10:43 a.m. | Last Modified: 29 Apr 2026, 10:43 a.m.

Panel Version: 3.20

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Insulinomatosis and diabetes mellitus, OMIM:147630; islet cell adenomatosis, MONDO:0007834

Publications

• 17682063
• 29339498
• 34644565
• 35406570

Green List (high evidence)

Two large White European families with extensive family history of insulinomatosis and diabetes underwent whole exome sequencing (PMID: 29339498). The missense variant p.Ser64Phe in the MAFA gene co-segregated with both phenotypes in both families. A total of 17 individuals with diabetes and 10 individuals with insulinomatosis were heterozygous for the variant and there was almost complete penetrance for both phenotypes (90%). Most patients diagnosed with diabetes or impaired fasting glucose were males (male-to-female ratio was 3:1), and the mean age at diagnosis was 38.4 ± 16.5 y. They were not obese (mean BMI was 25). There were no other clinical features of insulin resistance, no history of diabetic ketoacidosis, and islet autoantibodies were negative, configuring a phenotype resembling maturity-onset diabetes of the young (MODY). Diabetes was managed with diet or oral medications (i.e., metformin and/or sulphonylureas) in most cases, with current HbA1c levels ranging between 37 and 74 mmol/mol (5.5–8.9%).

A third unrelated and unpublished individual referred to the Exeter Genomics Laboratory for MODY testing (diagnosed aged 28 years, slim, not insulin treated, parent with diabetes) was found to be heterozygous for MAFA p.Ser64Phe. The family also had an extensive family history of diabetes and hyperinsulinism in ten additional family members (5 with DM, 5 with HI). Five have been tested to date and all confirmed to be heterozygous for the variant (1 DM, 4 HI).

MAFA is a strong candidate gene as it plays a pivotal role in the regulation of insulin secretion in vivo. The β-cell–enriched MAFA transcription factor is required for postnatal function of murine β-cells, acting as transactivator of insulin and several genes involved with glucose-stimulated insulin secretion.

Functional analysis demonstrated that the p.Ser64Phe mutation significantly increased the stability of MAFA, whose levels were unaffected by variable glucose concentrations in β-cell lines, but also enhanced its transactivation activity (PMID: 29339498). The lack of up-regulation of MAFA in response to hyperglycaemia is expected to impair glucose-stimulated insulin secretion, and this mechanism presumably underlies the diabetes phenotype.

A heterozygous MAFA p.Ser64Phe mouse model has also been created. Males display impaired glucose tolerance, while females are slightly hypoglycaemic with improved blood glucose clearance (PMID: 34644565).

A second MAFA missense variant has also been published in a large with insulinomatosis and diabetes (PMID: 35406570). The p.Thr57Arg is located in in MAFA’s highly conserved transactivation domain. in vitro expression studies replacing Thr57 have been performed, demonstrating a phosphorylation defect with the impairment of transactivation activity and degradation (PMID: 17682063) Mild hyperglycaemia was observed in six additional, heterozygous family members.
Sources: Expert Review

Created: 12 Mar 2026, 12:54 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Diabetes; Insulinomatosis; Hyperinsulinaemic Hypoglycaemia

Publications

• PMID: 29339498
• 34644565
• 35406570
• 17682063

Variants in this GENE are reported as part of current diagnostic practice