Table 1.

Monogenic causes of congenital diabetes known to occur within the first year of life

Gene	Protein/fimction	Phenotypes/syndromes	Inheritance	Age of diabetes onset	Pancreas appearance/exocrine function	Other features	Ref
PLAGL1 HYMAI (6q24)	Over-expression of paternally expressed genes PLAGL1 (zinc finger protein or ZAC tumor suppressor) and HYMAI (non-protein coding) within the imprinted region of chromosome 6q24/unknown function	TNDM	UPD6 (40%; de novo, non-recurrent), paternal duplication (40%, may be inherited) or maternal methylation defect (20%; autosomal recessive, e.g. ZFP57)	Within days; remission within months; relapse during adolescence	Normal/normal	Very SGA; macroglossia and/or umbilical hernia often present; other features may be seen in those with HIL, especially ZFP57 mutations (see below)	[2–9]
ZFP57	Zinc finger protein 57/transcription factor with a role in maintenance of imprinted DNA methylation	TNDM	Autosomal recessive	Similar to 6q24	Normal/normal	Very SGA; HIL (9/9); macroglossia (6/9); variable developmental delay (6/9); umbilical defect (3/9); CHD (3/9); visual impairment (3/9); epilepsy (2/9)	[2–9]
KCNJ11	Inward rectifier K(+) channel (Kir6.2) subunit of ATP- sensitive potassium channel	PNDM (more often) or TNDM (less often); DEND	Spontaneous (80%) or autosomal dominant	< 6 months; rarely later	Normal/normal	Often SGA; possible developmental delay; usually responsive to sulfonylurea therapy	[10–21•]
ABCC8	Sulfonylurea receptor 1 (SURI) subunit of ATP-sensitive potassium channel	PNDM (less often) or TNDM (more often); DEND	Spontaneous (80%) or autosomal dominant	< 6 months; rarely later	Normal/normal	Often SGA; usually responsive to sulfonylurea therapy	[10–21•]
INS	Insulin/hormone	PNDM (more often), TNDM (rarely), MODY (rarely)	Spontaneous (80%), autosomal dominant or recessive (rarely)	<6 months; less often later	Normal/normal	Often SGA; rare later-onset patients with a MODY or antibody-negative phenotype	[22–26]
EIF2AK3	Eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2 AK3 )/kniase involved in regulation of translation	Wolcott-Rallison syndrome (WRS)	Autosomal recessive	Most cases within weeks (2–28 weeks); 1 case 30 months	Rare hypoplasia/ often reduced (25%)	Mild SGA or normal, rarely very SGA, Epiphyseal dysplasia (90–100%); acute liver failure (60–75%); developmental delay (60–80%); hypothyroidism (−25%); exocrine pancreatic dysfunction (−25%)	[27–30]
FOXP3	Forkhead box protein P3 (FoxP3)/transcription factor	Immunodysregulation polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome	X-linked recessive	Days-3.5 months	Normal/normal	Only males affected; severe immune dysregulation; chronic diarrhea with villus atrophy (95%); pancreatic and thyroid autoantibodies (75%); thyroiditis (20%); eczema (50%); anemia (30%); often die before 1 year	[31–32]
GCK	Glucokinase/glycolytic enzyme	PNDM; GCK-MODY	Autosomal recessive (PNDM); or autosomal dominant (GCK-MODY)	PNDM days of life MODY2 present from birth but not usually detected until later	Normal/normal	PNDM: Very SGA, 12/14 homozygous, 1/14 compound heterozygous, 1/14 heterozygous (unclear mechanism), parents have impaired fasting glucose with GCK-MODY (MODY2)	[33–37]
PDX1	Pancreas/duodenum homeobox protein 1 (PDX1 orlPFl)/ transcription factor	PNDM with pancreatic agenesis/hypoplasia PDX1-MODY (heterozygous)	Autosomal recessive; Autosomal dominant (PDX1-MODY)	3/5 cases within days; 2/5 cases 12–15 days	Absent (1/5), small (3/5) or normal (l/5)/absent (3/5) or reduced (2/5)	SGA; diarrhea; malnutrition; parents have PDX1 MODY (MODY4)	[38–41]
PTF1A	Pancreas transcription factor 1, subunit alpha (PTF1A)/ bHLH transcription factor	PNDM with cerebellar and pancreatic agenesis	Autosomal recessive	5 cases within days	Absent/absent	Very SGA; cerebellar agenesis; flexion contractures; poor subcutaneous fat; optic nerve hypoplasia; detectable C-peptide/insulin	[42–43]
NEUROD1	(NeuroDl or BETA2)/bHLH transcription factor	PNDM with cerebellar (but not pancreatic) hypoplasia MODY- like (heterozygous)	Autosomal recessive; Autosomal dominant (MODY-like)	2 cases by 2 months	Normal/normal	SGA; severe cerebellar hypoplasia; moderate to severe developmental delay; sensorineural deafness; visual impairment MODY-like	[44–45]
NEUROG3	(NeuroG3 or NGN3)/bHLH transcription factor	PNDM with severe congenital diarrhea	Autosomal recessive	2/5 cases within days; 2/5 cases by 9 yrs	Small/4/5 normal	Very SGA; severe intractable congenital diarrhea unresponsive to pancreatic enzyme replacement with absent intestinal enteroendocrine cells; hypogonadotropic hypogonadism; short stature	[46–48]
RFX6	DNA-binding protein (RFX6)/ winged-helix transcription factor	PNDM with intestinal atresia, gall bladder hypoplasia MODY- like (heterozygous)	Autosomal recessive; Autosomal dominant (MODY-like)	5 cases within days Compound heterozygote: childhood-onset RFX- MODY: 27 cases, median 32 years (IQR 24–46 years)	Small/nomial	Very SGA; intestinal atresias; gall bladder hypoplasia/aplasia; diarrhea MODY-like	[49–52•]
IER3IP1	Immediate early response 3 interacting protein 1 (IER3IP1)	PNDM with microcephaly	Autosomal recessive	2 cases: birth; 2 months	Normal/normal	Microcephaly with simplified gyral pattern; severe infantile epileptic encephalopathy	[53]
HNF1B	Hepatocyte nuclear factor 1 - beta (HNF-1 ß)/ transcription factor	TNDM/PNDM; (RCAD; MODY5)	Spontaneous or autosomal dominant	2 cases 15–17 days	Hypoplastic/ reduced	Very SGA; renal abnormalities; relapsing/remitting DM (RCAD: renal cysts, urogenital abnormalities)	[54–55]
GLIS3	Glioma-associated oncogene- similar family zinc finger 3 (GLIS3)/Kriippel-like transcription factor	Neonatal diabetes with congenital hypothyroidism (NDH)	Autosomal recessive	8 cases within days	Small, normal or cystic/normal or reduced (2/8)	SGA; congenital primary hypothyroidism; glaucoma (4/8); liver fibrosis (5/8); cystic kidney disease (4/8); osteopenia (1/8); deafness (1/8); facial dysmorphism	[56–59]
PAX6	Paired box 6/paired box and horneo domain box containing transcription factor	PNDM with severe microcephaly and eye defects	Autosomal recessive	2 brothers within days (other case: DM not reported)	Normal/not reported	Brain malformations; microcephaly; micropthalmia (eye defects in parents); panhypopituitarism	[60–61]
WFS1	Wolframin/membrane glycoprotein	Wolfram syndrome; DIDMOAD	Autosomal recessive; Autosomal dominant	Recessive: Median 6 yrs.(3 wks–14 yrs) Dominant: range 13–50 weeks	Normal/normal	Optic atrophy (earliest feature); diabetes insipidus; deafness; cataracts; hypotonia	[62–64]
SLC19A2	Thiamine transporter 1/transports thiamine across the plasma membrane	Thiamine-responsive megaloblastic anemia (TRMA) syndrome	Autosomal recessive	12 cases 2–13 months; Others: DM later	Normal/normal	Thiamine-responsive megaloblastic anemia; sensorineural deafness; occasional CHD (conduction defects); short stature	[65]
SLC2A2	GLUT2/facilitative glucose transporter	Fanconi Bickel syndrome (FBS)	Autosomal recessive	1 case 6 days Others: IGT or DM in infancy- childhood	Normal/normal	Hepatomegaly related to hepatorenal glycogen accumulation; proximal tubular nephropathy with glucosuria and hypophosphatemic rickets; glucose intolerance or diabetes; galactosemia,	[66]
LRBA	Lipopolysaccharide-responsive nd beige-like anchor protein/ vesicle trafficking	PNDM,polyautoimmunity	Autosomal recessive	In 10 cases, 6 weeks–15 months	Normal/normal	Autoimmune conditions	[67]
IL2RA	Interleukin-2 receptor subunit alpha/ membrane protein and receptor for interleukin-2	PNDM,polyautoimmunity	Autosomal recessive	In 1 case, 6 weeks	Normal/normal	Autoimmune conditions	[68]
STAT1	Signal transducer and activator of transcription 1-alpha/beta/ transcription activator	PNDM,polyautoimmunity	Autosomal dominant	In 5 cases, 11 months-5 years (one did not have diabetes, one had hyperglycemia in response to steroids)	Normal/normal	Autoimmune conditions	[69]
STAT3	Signal transducer and activator of transcription 3/transcription activator	PNDM,	Autosomal dominant	In 5 cases, 0–43 weeks (one did not have diabetes)	NormaFnormal	Autoimmune conditions; short stature	[70•]
MNX1	Motor neuron and pancreas homeobox protein 1/nuclear protein	polyautoimmunity PNDM	Autosomal recessive	In 2 cases, 1–30 weeks	NormaFnormal	Brain malformations; SGA/growth concerns; intestinal malformations; developmental delay; lung hypoplasia; short stature	[71–72]
NKX2–2	Homeobox protein Nkx-2.2/ morphogenesis of the central nervous system	PNDM	Autosomal recessive	In 3 cases, 2–7 days	NormaFnormal	Brain malformations; hearing impairment; SGA/growth concerns; eye malformations/blindness; developmental delay; short stature	[71]
GATA6	Transcription Factor GATA-6/zinc finger transcription factor	PNDM, occasionally later-onset	Autosomal dominant	In 24 cases, median 2 days (IQR 1–7 days); Others: DM later	Agenesis or hypoplasia/reduced	SGA/growth concerns; CHD; intestinal malformations; developmental delay; thyroid dysfunction; hepatobiliary defects	[73–76]
GATA4	Transcription Factor GATA-4/zinc finger transcription factor	PNDM	Autosomal dominant	In 5 cases, range 1 day-13 years	Agenesis or hypoplasia/normal or reduced	SGA/growth concerns; CHD; intestinal malformations	[77]

Adapted by permission from Springer Nature from: Greeley SAW, et al. Curr Diab Rep. 2011;11(6):519–32 [2]

TNDM transient neonatal diabetes, PNDM permanent neonatal diabetes, DEND developmental delay, epilepsy, neonatal diabetes, WS5 Wolcott-Rallison syndrome, IPEX immunodysregulation polyendocrinopathy, enteropathy, x-linked, MODY maturity-onset diabetes of the young, DIDMOAD diabetes insipidus, diabetes mellitus, optic atrophy and deafness, TRMA thiamine-responsive megaloblastic anemia syndrome, FBS Fanconi-Bickel syndrome, NDH neonatal diabetes with congenital hypothyroidism, RCAD renal cysts and diabetes, bHLH basic helix-loop-helix, SGA small for gestational age, MODY maturity-onset diabetes of the young, CEID congenital heart defect, ElIL hypomethylation of multiple imprinted loci

Updated from previously published version