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

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

Analytical Sensitivity

For massively parallel sequencing:

Genes Tested