Monogenic diabetes: An evidence-based clinical approach

Table 2 Various types of maturity-onset diabetes of the young and neonatal diabetes mellitus with the genes involved in the pathogenesis and the clinical features

	Subtype	Gene	Frequency	Gene-disease	Clinical feature	Inheritance
MODY	MODY 1	HNF4A	14%	Classical MODY	Fetal macrosomia and/or neonatal hypoglycemia, respond to low-dose SU initially, progressive β-cell failure, require insulin later, risks of complications	AD
	MODY 2	GCK	22%		Mild fasting hyperglycemia does not require treatment except during gestation determined by the GCK mutation status of the foetus	AD, rarely AR
	MODY 3	HNF1A	33%		Disproportionate glucosuria (low renal threshold), response to low-dose SU initially, progressive β-cell failure, require insulin later, risks of complications	AD, rarely AR
	MODY 4	IPF1/PDX1	< 1%		A heterozygous mutation causing MODY or T2DM or homozygous mutation causing PNDM (see below)	AD
	MODY 5	HNF1B	6%	Syndromic MODY	Renal cysts and diabetes, pancreas hypoplasia, exocrine insufficiency, β-cell defect, low magnesium, gout, altered LFT, and autism; Require insulin; Risks of complications; 40% are de novo	AD
	MODY 6	NEUROD1	1%	Classical MODY	A heterozygous mutation causing MODY or homozygous mutation causing NDM (not mentioned below)	AD
	MODY 7	KLF11	< 1%	Evidence refuted	Potentially causing T2DM in the presence of obesity rather than causing MODY	AD
	MODY 8	CEL	< 1%	Syndromic MODY	Diabetes and pancreatic exocrine dysfunction; Pancreatic cysts may be present	AD
	MODY 9	PAX4	< 1%	Evidence refuted	Potentially causing T2DM in the presence of obesity rather than causing MODY	AD
	MODY 10	INS	2%	Classical MODY	Mild defects can present as MODY whereas severe defects can present as TNDM or PNDM (as below), insulin treatment preserves β-cell mass and insulin secretion	AD
	MODY 11	BLK	< 1%	Evidence refuted	Potentially causing T2DM in the presence of obesity rather than causing MODY	AD
	MODY 12	ABCC8	4%	Classical MODY	Manifest as relapse following TNDM or as isolated MODY with no history of TNDM, respond to low-dose SU	AD
	MODY 13	KCNJ11	2%		Manifest as relapse following TNDM or as isolated MODY with no history of TNDM, respond to low-dose SU	AD
	MODY 14	APPL1	< 1%	Evidence weak	Delayed onset MODY with low penetrance and less severity; Potentially causing T2DM in the presence of obesity rather than causing MODY	AD
	RFX6-MODY	RFX6	< 1%	Classical MODY	Significantly low penetrance; Likely to respond to DPP4 inhibitors or GLP-1 receptor agonists (low GIP levels are present in these patients)	AD
NDM	TNDM 45% NDM	ZAC and HYMAI	70% TNDM	TNDM1	6q24 abnormal uniparental disomy 40%, paternal duplication 40%, maternal hypomethylation 20%, macroglossia, umbilical hernia, cardiac/renal defect, hypothyroidism	Sporadic or AD
		ABCC8	15% TNDM	TNDM2	TNDM (early infancy), remission (early childhood), and/or relapse of diabetes (in adulthood), mild developmental features may be seen, marked response to low-dose SU	Sporadic or AD
		KCNJ11	10% TNDM		TNDM (early infancy), remission (early childhood), and/or relapse of diabetes (in adulthood), mild developmental features may be seen, marked response to low-dose SU	Sporadic or AD
		INS	5% TNDM		IUGR; Doesn’t respond to SU but responds to insulin therapy	AD, rarely AR
		HNF1B			Renal cyst and pancreatic hypoplasia	AD
		SLC2A2			TNDM, PNDM (rare), or Fanconi-Bickel syndrome (Fanconi syndrome, short stature, rickets, growth retardation, hepatomegaly, and glucose/galactose intolerance)	AR
	PNDM 45% NDM	KCNJ11	50% PNDM		DEND (developmental delay, epilepsy, NDM) or iDEND syndrome (mild developmental delay, no epilepsy), severe hyperglycemia, DKA frequent, response to high-dose SU	Sporadic or AD
		INS	30% PNDM		IUGR; Doesn’t respond to SU but responds to insulin therapy	AD
		ABCC8	15% PNDM		DEND (developmental delay, epilepsy, NDM) or iDEND syndrome (mild developmental delay, no epilepsy), severe hyperglycemia, DKA frequent, response to high-dose SU	Sporadic, AD or AR
		GCK	3% PNDM		IUGR; Homozygous mutations causing PNDM requiring lifelong insulin therapy	AR
		IPF1/PDX1	2% PNDM		Pancreatic hypoplasia causing PNDM (homozygous mutation)	AR
		HNF1B			Renal cyst and pancreatic hypoplasia	AD
	Syndromic NDM; 10% NDM	EIF2AK3	Rare		PNDM with spondyloepiphyseal dysplasia, and renal anomalies (Wolcott-Rallison syndrome)	AR
		FOXP3			IPEX syndrome	XR
		GATA4/6			Permanent neonatal diabetes with pancreatic agenesis and congenital heart defects	AD
		RFX6			Neonatal diabetes, pancreatic hypoplasia, gallbladder agenesis, intestinal atresia (Mitchell-Riley syndrome)	AR
		GLIS3			Congenital hypothyroidism, glaucoma, hepatic fibrosis, polycystic kidneys, developmental delay	AR
		PTF1A			Pancreatic and cerebellar hypoplasia	AR

MODY: Maturity-onset diabetes of the young; NDM: Neonatal diabetes mellitus; TNDM: Transient neonatal diabetes mellitus; PNDM: Permanent neonatal diabetes mellitus; AD: Autosomal dominant; AR: Autosomal recessive; XR: X-linked recessive; SU: Sulfonylurea; LFT: Liver function test; T2DM: Type 2 diabetes mellitus; DPP4: Dipeptidyl peptidase-4; GLP: Glucagon-like peptide; IUGR: Intrauterine growth restriction; DEND: Developmental delay, epilepsy, neonatal diabetes mellitus; iDEND: Intermediate developmental delay, epilepsy, and neonatal diabetes syndrome; DKA: Diabetic ketoacidosis; IPEX syndrome: Immuno-dysregulation, polyendocrinopathy, enteropathy, X-linked.