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

Last Literature 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 ClassAnalytic Sensitivity (PPA) Estimatea (%)Analytic Sensitivity (PPA) 95% Credibility Regiona (%)
SNVs99.296.9-99.4
Deletions 1-10 bp93.884.3-98.2
Deletions 11-44 bp99.987.8-100
Insertions 1-10 bp94.886.8-98.5
Insertions 11-23 bp99.962.1-100

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

GeneMIM NumberDisorderInheritance
ABCC8600509NIDDMAD
Diabetes mellitus, permanent neonatal 3, with or without neurologic featuresAD, AR
Diabetes mellitus, transient neonatal 2AD
Hyperinsulinemic hypoglycemia, familial, 1AD, AR
Hypoglycemia of infancy, leucine sensitiveAD
APPL1604299MODY, type 14AD
CEL114840MODY, type 8AD
EIF2AK3604032Wolcott-Rallison syndrome AR
FOXP3300292Immunodysregulation, polyendocrinopathy, and enteropathy, X-linkedXLR
GATA4600576Neonatal and childhood diabetesAD
GATA6601656Pancreatic agenesis and congenital heart defectsAD
GCK138079NIDDM, late onsetAD
Hyperinsulinemic hypoglycemia, familial, 3AD
MODY, type 2AD
Diabetes mellitus, permanent neonatal 1AR
HNF1A142410NIDDM 2AD
IDDM 20AD
MODY, type 3AD
HNF1B189907NIDDMAD
Renal cysts and diabetes syndromeAD
HNF4A600281NIDDMAD
Fanconi renotubular syndrome 4, with MODYAD
MODY, type 1AD
INS176730IDDM2AD
Diabetes mellitus, permanent neonatalAD, AR
HyperproinsulinemiaAD
MODY, type 10AD
KCNJ11600937Diabetes mellitus, transient neonatal, 3AD
Diabetes, permanent neonatal 2, with or without neurologic featuresAD
Hyperinsulinemic hypoglycemia, familial 2AR
MODY, type 13AD
NEUROD1601724MODY, type 6AD
NEUROG3604882Diarrhea 4, malabsorptive, congenitalAR
PDX1600733MODY, type 4AD
Pancreatic agenesis 1AR
RFX6612659Mitchell-Riley syndromeAR
SLC19A2603941Thiamine-responsive megaloblastic anemia syndromeAR
WFS1606201NIDDMAD
Wolfram-like syndrome, ADAD
Wolfram syndrome 1AR
ZFP57612192Diabetes mellitus, transient neonatal, 1AD
NIDDM, noninsulin-dependent diabetes mellitus; IDDM, insulin-dependent diabetes mellitus; XLR, X-linked recessive

References