Maturity-Onset Diabetes of the Young and Neonatal Diabetes Panel, Sequencing

Content Review: December 2020 Last Update:

Regions of low coverage and reported variants are confirmed by Sanger sequencing as necessary.

Maturity-onset diabetes of the young (MODY) typically occurs in adolescents or young adults <35 years of age. Affected individuals often have mild stable fasting hyperglycemia, weak response to pharmacologic therapy, a personal or family history of neonatal diabetes or neonatal hypoglycemia, and an autosomal dominant pattern of inheritance. Neonatal diabetes (ND) is defined by persistent hyperglycemia in infants <6 months of age. Molecular testing is recommended to guide treatment for MODY and ND.

Disease Overview

Symptoms/Associated Disorders

Maturity-Onset Diabetes of the Young :

  • Early-onset diabetes in adolescents or young adults
  • Absence of pancreatic islet autoantibodies
  • Endogenous insulin production 5 years after onset
  • Low insulin requirement
  • Lack of ketoacidosis when insulin is omitted
  • Lack of obesity or acanthosis nigricans
  • Normal triglyceride and high-density lipoprotein levels

Neonatal Diabetes:

  • Persistent hyperglycemia (>150-200 mg/dL) in infants <6 months of age
  • Mean age of diagnosis: 7 weeks
  • May present with intrauterine growth restriction, glucosuria, ketonuria, hyperketonemia, severe dehydration, and failure to thrive
  • Decreased fecal elastase and increased fat in stool in infants with pancreatic hypoplasia

Etiology

Pathogenic variants in several overlapping genes for MODY and ND

  • Pathogenic variants in GCK (30-50%),  HNF1A (30-65%),   HNF4A (5-10%),  and HNF1B (<5%)  are causative for at least 70% of MODY.
  • Pathogenic variants in GCK (4%),   INS (20%),   ABCC8 (19%),  and KCNJ11 (30%)  are causative for 73% of ND.

Epidemiology/Prevalence

  • Prevalence of MODY is estimated at 1-3%   in the U.S.
  • Prevalence of ND is rare. The incidence has been reported between 1 in 160,000 in Austria to 1 in 215,000 in Slovakia.  

Inheritance

  • Autosomal dominant (AD) for the main causative genes for MODY: GCK, HNF1A, HNF4A, and HNF1B
  • AD and autosomal recessive (AR) for main causative genes for ND
    • AD: INS, ABCC8, and KCNJ11
    • AR: GCK

Penetrance

Dependent on the causative gene

  • Pathogenic HNF1A variants are causative for 30-60% of MODY and have a 63% penetrance by age 25, 79% penetrance by 35, and 96% penetrance by age 55.
  • Pathogenic variants in KCNJ11 and ABCC8 have shown reduced penetrance for ND.

Test Description

Clinical Sensitivity

At least 70% for MODY and 73% for ND (see Etiology above)

Limitations

  • A negative result does not exclude a diagnosis of MODY or ND.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of the test result may be impacted if the patient has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of targeted genes
    • Most regulatory region and deep intronic variants
    • Noncoding transcripts
    • The following exons are not sequenced due to technical limitations of the assay:
      • CEL (NM_001807) 1, 8, 9, 11
      • ABCC8 (NM_001351295) partial exon 14 (Chr11:17449973-17450018)
    • The following may not be detected:
      • Deletions/duplications/insertions of any size by massively parallel sequencing
      • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
      • Low-level somatic variants

Analytic Sensitivity

For massively parallel sequencing:

Variant Class Analytic Sensitivity (PPA) Estimatea (%) Analytic Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

99.9

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

99.9

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

Genes Tested

Gene MIM Number Disorder Inheritance

ABCC8

600509

NIDDM

AD

Diabetes mellitus, permanent neonatal 3, with or without neurologic features

AD, AR

Diabetes mellitus, transient neonatal 2

AD

Hyperinsulinemic hypoglycemia, familial, 1

AD, AR

Hypoglycemia of infancy, leucine sensitive

AD

APPL1

604299

MODY, type 14

AD

CEL

114840

MODY, type 8

AD

EIF2AK3

604032

Wolcott-Rallison syndrome 

AR

FOXP3

300292

Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked

XLR

GATA4

600576

Neonatal and childhood diabetes

AD

GATA6

601656

Pancreatic agenesis and congenital heart defects

AD

GCK

138079

NIDDM, late onset

AD

Hyperinsulinemic hypoglycemia, familial, 3

AD

MODY, type 2

AD

Diabetes mellitus, permanent neonatal 1

AR

HNF1A

142410

NIDDM 2

AD

IDDM 20

AD

MODY, type 3

AD

HNF1B

189907

NIDDM

AD

Renal cysts and diabetes syndrome

AD

HNF4A

600281

NIDDM

AD

Fanconi renotubular syndrome 4, with MODY

AD

MODY, type 1

AD

INS

176730

IDDM2

AD

Diabetes mellitus, permanent neonatal

AD, AR

Hyperproinsulinemia

AD

MODY, type 10

AD

KCNJ11

600937

Diabetes mellitus, transient neonatal, 3

AD

Diabetes, permanent neonatal 2, with or without neurologic features

AD

Hyperinsulinemic hypoglycemia, familial 2

AR

MODY, type 13

AD

NEUROD1

601724

MODY, type 6

AD

NEUROG3

604882

Diarrhea 4, malabsorptive, congenital

AR

PDX1

600733

MODY, type 4

AD

Pancreatic agenesis 1

AR

RFX6

612659

Mitchell-Riley syndrome

AR

SLC19A2

603941

Thiamine-responsive megaloblastic anemia syndrome

AR

WFS1

606201

NIDDM

AD

Wolfram-like syndrome, AD

AD

Wolfram syndrome 1

AR

ZFP57

612192

Diabetes mellitus, transient neonatal, 1

AD

NIDDM, noninsulin-dependent diabetes mellitus; IDDM, insulin-dependent diabetes mellitus; XLR, X-linked recessive

References