GeneticsTier 2Medical Sciences concept

Maturity-onset diabetes of the young (MODY) - gene subtypes and phenotypes

Core concept

Gene	Subtype	Phenotype
HNF1A	MODY 3	Most common MODY; progressive beta-cell failure; sensitive to sulfonylureas; low renal glucose threshold (glycosuria at lower BSL)
GCK	MODY 2	Mild, stable, non-progressive fasting hyperglycaemia from birth - often needs no treatment
HNF4A	MODY 1	Similar to HNF1A, sulfonylurea-sensitive; associated with macrosomia and neonatal hypoglycaemia
HNF1B	MODY 5	Diabetes + renal cysts/dysplasia, genital tract abnormalities

Key detail

Autosomal dominant, single-gene beta-cell defect - distinct from T1DM (autoimmune) and T2DM (polygenic + insulin resistance)
Suspect MODY: diagnosed <25y, non-obese, islet autoantibody-negative, strong 3-generation family history, preserved C-peptide
GCK-MODY is a glucose-sensor defect (raised set-point, not progressive) - the subtype that stands apart from the rest

Clinical relevance

Correct genetic diagnosis changes management: GCK-MODY -> stop unnecessary treatment; HNF1A/HNF4A-MODY -> switch from insulin to low-dose sulfonylurea
HNF1B-MODY - screen for renal and genital tract anomalies, not glycaemic control alone
A young "type 1" diabetic who is antibody-negative with a strong family history should prompt genetic testing before committing to lifelong insulin

Correlations

Diabetes mellitus type 1 and type 2 (contrast)
Antibody testing for autoimmune endocrine disease
Hereditary renal cystic disease

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