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Conditions

Monogenic diabetes

Monogenic diabetes is a genetic condition caused by a pathogenic variant in the DNA sequence of a single gene.

Overview

The clinical features of monogenic diabetes (MD) vary depending on the gene affected. The condition can broadly be separated into neonatal diabetes (diabetes diagnosed at under six months of age) and young onset diabetes (which typically presents outside of the neonatal period but below the age of 25). Young onset MD may occur as an isolated, non-syndromic form of diabetes known as maturity onset diabetes of the young (MODY) or as part of a monogenic syndrome with additional extra-pancreatic clinical features.

Clinical features

Neonatal diabetes

  • Diagnosed at under six months of age.
  • May be permanent or transient (diabetes remits in early infancy and may relapse in late childhood or early adulthood).
  • May, in rare cases, be associated with other features, depending on the gene affected and/or the specific pathogenic variant within the gene. Other features include learning difficulties, liver failure, pancreatic agenesis and congenital cardiac anomalies.
  • The most common genetic causes are inherited in an autosomal dominant manner, though other forms may be recessive. Pathogenic variants that cause disease inherited in a dominant pattern commonly arise spontaneously (de novo) in the child, which means that there may be no family history.

Young onset MD (MODY)

  • Typically diagnosed in patients under 25 years of age.
  • Inherited in an autosomal dominant pattern.
  • Non-insulin dependent (not insulin treated and not detectable via a C-peptide test outside of the usual honeymoon period).
  • Negative islet autoantibodies (GAD, IA2 and ZnT8).

Young onset MD (syndromic diabetes)

  • Typically diagnosed at under 25 years of age.
  • Inheritance may be dominant, recessive or mitochondrial, and parents are often unaffected.
  • May require insulin treatment but with negative islet-autoantibodies.
  • Presence of additional non-diabetic clinical features suggestive of a monogenic syndrome is often noted. Clinical features include renal cysts or dysplasia, lipodystrophy, deafness, optic atrophy and cardiac anomalies.

Genetics

Over 60 different genes have been identified that can cause MD. All are characterised by different clinical features, modes of inheritance and effects on beta cell function. The most prevalent subtypes of MD in the UK are shown in table 1 below.

  • Genomic testing is required to identify the causative gene. Doing so will highlight the key features, treatment requirements and risk to family members and future offspring.
  • Testing is typically undertaken using massively parallel sequencing (next generation sequencing), which can analyse all of the known genes in a single test.
  • The specific panel of genes analysed depends on whether a diagnosis of neonatal or young onset MD or MODY is suspected. The relevant panels will analyse syndromic diabetes genes even if there is no clinical suspicion of a syndrome in the patient.
  • A genetic diagnosis is made in 80% of patients with neonatal diabetes, and in 20%–25% of patients with young onset diabetes.
  • Rapid sequencing of the GCK gene only is also available for patients with the distinctive GCK phenotype. A genetic diagnosis is made in 70% of GCK gene tests.
  • Testing is centrally funded for NHS England patients who meet the eligibility criteria. GPs will not be invoiced for testing.

Table 1: The most prevalent monogenic diabetes subtypes and their features

Gene affected Age of onset Key features Management considerations
KCNJ11 Under six months Can lead to transient or permanent neonatal diabetes. Learning difficulties may be a feature, depending on the variant. Best treated with high doses of sulphonylureas.
ABCC8 Under six months Can lead to transient or permanent neonatal diabetes. Learning difficulties may be a feature, depending on the variant. Best treated with high doses of sulphonylureas.
Imprinting anomalies at the 6q24 region on chromosome 6 Under six months Causes transient neonatal diabetes that remits after about three months and may relapse as MODY in late childhood or early adulthood. The neonatal diabetes is treated with insulin, and relapsing diabetes can be managed with oral agents.
Glucokinase (GCK) hyperglycaemia Raised glucose present from birth Mild, stable hyperglycaemia, raised fasting glucose typically 5.5mmol/L–8mmol/L, HbA1c 40mmol/mol–60mmol/mol.

No increased chance of diabetes-related complications.

The patient should not be classified as having diabetes.

 Generally requires no treatment or follow up. The exception is in pregnancy. When the fetus has not inherited the maternal GCK variant, maternal high glucose can lead to large for gestational age. When the fetus has inherited the gene variant, a normal birthweight is expected. So, it is not necessary to treat all mothers with insulin. Non-invasive prenatal testing can help to determine the fetal genotype and guide pregnancy management (see resources list below).
HNF1A MODY Adolescence or young adulthood Most common cause of MD in the UK.

Low renal threshold for glucose.

Raised probability of coronary heart disease, which can be fatal.

 Sulphonylurea sensitive (best treated on low doses). Consider statin therapy by age 40 regardless of lipid profile.
HNF4A MODY Adolescence or young adulthood Macrosomia and transient neonatal hypoglycaemia seen in fetuses inheriting the variant. Specialist advice required during pregnancy, even if the affected parent is the father. Neonatal hypoglycaemia may require treatment with diazoxide or chlorthiazide.

Sulphonylurea sensitive (best treated on low doses).
HNF1B MODY Variable (0–65 years) Renal developmental anomalies (frequently cysts, but can include single or dysplastic kidney). Varies from normal renal function to requiring dialysis or transplant.

May have genital tract anomalies (bicornuate uterus, uterus didelphys or undescended testes). Biochemical features include hypomagnesaemia, hyperuricaemia, low faecal elastase and abnormal LFTs. Neurodevelopmental problems such as autism can occur in patients with a deletion of the HNF1B gene.

Variable phenotype often seen within the same family.

 Requires insulin treatment and patients may have pancreatic insufficiency, requiring pancrelipase (sold under the brand name Creon).

Assessment of renal function and renal ultrasound is recommended for patients with isolated diabetes.
m.3243A>G

(Mitochondrial gene variant causing maternally inherited diabetes and deafness (MIDD))

 Variable, but typically 20–50 years Causes bilateral sensorineural deafness (typically presents before the diabetes), which results in difficulty with high-pitched sounds and usually requires hearing aids and possibly a cochlear implant. Other features include myopathy, renal disease and gastrointestinal problems.

Maternally inherited. Males will not pass on the variant to their offspring.

Phenotype variable within families, from mildly affected to mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), and includes both insulin-dependent and non-insulin dependent diabetes.

Patients may have diabetes and no other clinical features or family history, with a genetic diagnosis made unexpectedly.

 Usually requires insulin within two years.

Audiological assessment is recommended for patients with isolated diabetes.

Guidelines for management of diabetes in mitochondrial conditions are available (see resources list below). Metformin should be avoided as there is an increased chance of lactic acidosis.

For information about testing for monogenic diabetes, see Presentation: Child with incidental hyperglycaemia.

Inheritance and genomic counselling

  • Monogenic diabetes is typically inherited in an autosomal dominant pattern. However, MIDD is maternally inherited, and some forms of neonatal diabetes and syndromic diabetes are autosomal recessive.
  • If a parent has inherited MD in an autosomal dominant manner, each child is at 50% chance of inheriting the affected variant and developing MD. The probability is 25% for autosomal recessive MD.
  • Referral to clinical genetics is recommended for families with a genetic diagnosis, especially for complex conditions such as mitochondrial diabetes.

Management

Appropriate management of MD varies depending on the gene affected, from:

  • no treatment (GCK MODY); to
  • low doses of sulphonylureas (HNF1A and HNF4A MODY); to
  • high doses of sulphonylureas (KCNJ11 and ABCC8 neonatal diabetes); to
  • insulin (HNF1B MODY and MIDD).

Further guidance, including when and how to transfer from insulin to sulphonylureas, is available via the specialist diabetes team at Royal Devon and Exeter NHS Foundation Trust. Specialist advice for the management of affected pregnancies should be sought via the same team.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 23/03/2023
  • Next review due: 23/03/2025
  • Authors: Professor Maggie Shepherd
  • Reviewers: Dr Asma Hamad, Dr Mary O’Driscoll