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. Author manuscript; available in PMC: 2019 Jun 13.
Published in final edited form as: Curr Diab Rep. 2018 Jun 13;18(7):46. doi: 10.1007/s11892-018-1016-2

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) [29]
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) [29]
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 [1021•]
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 [1021•]
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 [2226]
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%) [2730]
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 [3132]
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) [3337]
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) [3841]
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 [4243]
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 [4445]
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 [4648]
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 [4952•]
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) [5455]
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 [5659]
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 [6061]
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 [6264]
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 [7172]
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 [7376]
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