Classification of Neonatal Diabetes Mellitus, 2022
| GENE NAME | MODE OF INHERITANCE* | RELATIVE INCIDENCE/FREQUENCY (PERCENT)† | PHENOTYPIC FEATURES | |
|---|---|---|---|---|
| Nonconsanguineous | Consanguineous | |||
| Most common | ||||
| KATP channel | Diabetes responds well to high-dose sulfonylurea treatment in most cases. Spectrum of neurodevelopmental dysfunction that depends on specific mutation. | |||
| KCNJ11 | Dominant | 30 | 5 | |
| ABCC8 | Dominant / Recessive | 15 | 10 | |
| 6q24 | Variable | 15 | 5 | Intrauterine growth restriction (IUGR), macroglossia, umbilical hernias are common; other features are rare. Diabetes is always transient, with median remission by age 4 months, with recurrence of diabetes around puberty or later. |
| INS | Dominant / Recessive | 10 | 10 | Progressive insulin deficiency clinically like type 1 diabetes |
|
GATA6
GATA4 | Dominant | 5 | <2.5 | Pancreatic agenesis/hypoplasia and corresponding exocrine pancreatic insufficiency; cardiac malformations; developmental delay; other features less common. |
| EIF2AK3 | Recessive | 2.5 | 25 | The most common recessive cause, especially in populations where consanguinity is more common. Wolcott-Rallison syndrome: spondyloepiphyseal dysplasia, recurrent episodic liver failure, renal failure, neurocognitive dysfunction. |
| FOXP3 | X-linked | 1.5 | 1.5 | IPEX syndrome or IPEX-like syndrome: autoimmune enteropathy, eczema, and other autoimmune manifestations (similar manifestations may be seen in other autoimmune causes, such as STAT3, LRBA, IL2RA, and others). Severe cases often require stem cell transplant. |
| GCK‡ | Recessive | 1 | 10 | Both parents will have GCK-MODY. |
| PTF1A | Recessive | <2.5 | 10 | Pancreatic agenesis; cerebellar agenesis; developmental delay. |
| Rare | ||||
| HNF1B‡, GATA4, STAT3 | Dominant | 5 | 10 | |
| GLIS3, PDX1‡, ZFP57, RFX6, NEUROG3, NKX2-2, MNX1, SLC2A2, SLC19A2, IER3IP1, CNOT1, IL2RA, LRBA, WFS1, PAX6 | Recessive | |||
| Unknown | ||||
| Fraction of cases in which no monogenic cause has yet been identified | 15 | 10 | A significant proportion of cases may represent type 1 diabetes. Several cases in this category have Down syndrome (Reference 91). | |
ABCC8, ATP-binding cassette transporter subfamily C member 8; CNOT1, CCR4-NOT transcription complex subunit 1; EIF2AK3, eukaryotic translation initiation factor 2-alpha kinase 3; FOXP3, forkhead box P3; GATA4/6, GATA-binding factor 4/6; GCK, glucokinase; GLIS3, GLI-similar zinc finger protein family member 3; HNF, hepatocyte nuclear factor; IER3IP1, immediate early response 3 interacting protein 1; IL2RA, interleukin-2 receptor alpha chain; INS, insulin; IPEX, immunodysregulation, polyendocrinopathy, enteropathy, X-linked; KATP, ATP-regulated potassium channel; KCNJ11, potassium inwardly rectifying channel subfamily J member 11; LRBA, lipopolysaccharide-responsive and beige-like anchor protein; MNX1, motor neuron and pancreas homeobox 1; MODY, maturity-onset diabetes of the young; NEUROG3, neurogenin 3; NKX2-2, NK2 homeobox 2; PAX6, paired box 6; PDX1, pancreatic and duodenal homeobox 1; PTF1A, pancreas transcription factor 1 subunit alpha; RFX6, regulatory factor X6; SLC19A2, solute carrier family 19 member 2; SLC2A2, solute carrier family 2 member 2; STAT3, signal transducer and activator of transcription 3; WFS1, wolframin endoplasmic reticulum transmembrane glycoprotein; ZFP57, zinc finger protein 57.
For the more common dominant causes of neonatal diabetes mellitus, including KATP channel genes and INS, approximately 80%–85% of cases have de novo/spontaneous mutations that were not inherited but thereafter could be passed on to future generations.
Reference 64
Heterozygous mutations in GCK, PDX1, and HNF1B may also cause MODY 2, MODY 4, and MODY 5, respectively.
SOURCE: Original table constructed by S. Greeley, M. Salguero, and R. Naylor.
From: Monogenic Forms of Diabetes
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