Genetic testing for Hyperinsulinism

Hyperinsulinism is a heterogeneous disorder both clinically and in terms of genetic aetiology.

Congenital hyperinsulinaemic hypoglycaemia is the most frequent cause of hyperinsulinism in early infancy and it shows both recessive and dominant modes of inheritance.  Age of onset is variable and the hypoglycaemia ranges from asymptomatic through to medically unresponsive hypoglycaemia.

Hyperinsulinism due to inactivating variants in the ABCC8 and KCNJ11 genes

Pathogenic variants in KCNJ11 and ABCC8 are the commonest cause of congenital hyperinsulinism. Diffuse hyperinsulinism is most often caused by autosomal recessive inheritance with disease-causing variants being inherited from both unaffected parents although dominant inheritance has also been reported. Focal hyperinsulinism arises when an infant inherits a pathogenic paternal ABCC8 or KCNJ11 variant and there is also loss of the maternal allele within the focal lesion.  It is important to differentiate between these two types as 18F-DOPA PET-CT scanning is recommended for patients with a paternally inherited variant to locate a possible focal lesion within the pancreas as lesionectomy or partial pancreatectomy can cure focal hyperinsulinism. Loss of heterozygosity and confirmation of focal disease can be confirmed in DNA extracted from the resected tissue using microsatellite markers within the chromosome 11p15 region.  Diffuse hyperinsulinism is treated medically where possible with sub-total pancreatectomy only as a last resort since 75% of patients then develop iatrogenic diabetes.

First line urgent testing for ABCC8 and KCNJ11 is available with a result issued in 1-2 weeks, followed by a 16 gene next generation sequencing test if no disease-causing variant is identified.

Hyperinsulinism-Hyperammonaemia Syndrome due to dominant pathogenic variants in the GLUD1 gene

Hyperinsulinism-hyperammonemia syndrome is caused by pathogenic heterozygous gain-of-function variants in the GLUD1 gene.  Patients usually present outside the neonatal period and a consistent feature is the presence of hyperammonaemia with plasma ammonium levels being persistently raised.  The disease-causing variants are located in the GTP and ATP-binding domains of the enzyme which are encoded by exons 6, 7, 10, 11 and 12.  The majority of cases (~80%) are due to de novo variants, with autosomal dominant inheritance reported in the remaining 20% of families.  Treatment with diazoxide and appropriate dietary measures can prove effective.

A new test for all Hyperinsulinism genes

Next generation sequencing technology allows us to simultaneously test for pathogenic variants in all the known monogenic hyperinsulinism genes in a single test rather than analysing just one or two genes at a time.  Testing for pathogenic variants in multiple genes increases the number of patients in whom a monogenic form of hyperinsulinism is identified which can help to guide clinical management.

When should I request this test and how much does it cost?

Gene Phenotype
ABCC8 and KCNJ11 The most common cause of congenital hyperinsulinaemic hypoglycaemia (Meissner et al 1999 Hum Mutat 13:351-361, Thomas et al 1995 Science 268:426-429).
GLUD1 Hyperinsulinism-hyperammonemia (Stanley et al 1998 N Engl J Med 338:1352-1357).
HNF4A Transient diazoxide-responsive neonatal hyperinsulinaemic hypoglycaemia (Pearson et al 2007 PLoS Med 4(4):e118).
GCK Rare form of dominant hyperinsulinaemic hypoglycaemia (Glaser et al 1998 N Engl J Med 22;338(4):226-230)
HADH Autosomal recessive protein sensitive congenital hyperinsulinism (Clayton et al 2001 J Clin Invest 108:457-465).
INSR Autosomal dominant postprandial hypoglycaemia (Hojlund et al 2004 Diabetes 53:1592-1598).
SLC16A1 Autosomal dominant exercise-induced hyperinsulinism (Otonkoski et al 2007 Am J Hum Genet 81:467-474).
TRMT10A Autosomal recessive hyperinsulinaemic hypoglycaemia, microcephaly, intellectual disability, short stature, delayed puberty and seizures (Gillis et al 2014 J Med Genet 51(9):581516).
HNF1A Transient neonatal hyperinsulinaemic hypoglycaemia (Stanescu et al 2012 J Clin Endocrin Metab (97):e2026-2030).
AKT2 Autosomal dominant fasting hypoglycaemia and asymmetrical overgrowth (Hussain et al 2011 Science 334(6055):474).
CACNA1D Autosomal dominant hyperinsulinism with heart defects and severe hypotonia (Flanagan et al 2017 Pediatr Diabetes 18:320-323).
GPC3 X-linked recessive hypoglycaemia as part of Simpson-Golabi-Behmel syndrome. This syndrome is characterized by neonatal hypoglycaemia, distinctive craniofacies, congenital heart defected genitourinary defects, GI anomalies, skeletal anomalies and supernumerary nipples (Golabi et al 2011 GeneReviews® PMID: 20301398).
KDM6A X-linked dominant neonatal hypoglycaemia as part of Kabuki syndrome. This syndrome is a rare congenital disorder with a characteristic facial appearance, poor postnatal growth, short stature, variable congenital malformations (cleft palate and cardiovascular defects), learning difficulties, seizures and neonatal hypoglycaemia (Banka et al 2015 Clin Genet 87:252-258).
KMT2D Autosomal dominant neonatal hypoglycaemia as part of Kabuki syndrome. This syndrome is a rare congenital disorder with a characteristic facial appearance, poor postnatal growth, short stature, variable congenital malformations (cleft palate and cardiovascular defects), learning difficulties, seizures and neonatal hypoglycaemia (Makrythanasis et al 2013 Clin Genet 84:539-545).
PMM2 Autosomal recessive Hyperinsulinemic Hypoglycaemia and polycystic kidney disease (Rubio Cabezas et al 2017 J Am Soc Nephrol 28:2529-2539).



Research opportunities to identify novel aetiologies for congenital hyperinsulinism

The University of Exeter research team is seeking to recruit patients with congenital hyperinsulinism of unknown cause for gene discovery studies. Using Medical Research Council and Wellcome Trust/Royal Society funds, next-generation sequencing will be employed to analyse the genome of individuals with persistent hyperinsulinism where the known genetic causes have been excluded. Patients with hyperinsulinaemic hypoglycaemia that has persisted for ≥ 3 months are eligible to enrol in this study. A detailed clinical history along with samples (>5ug of DNA or fresh EDTA blood) from the affected individual, both parents and affected/unaffected siblings will be required. Further information regarding this project can be obtained by emailing Dr Sarah Flanagan (S.Flanagan@exeter.ac.uk) or follow the link to our website https://hyperinsulinismgenes.org/.

The laboratory participates in the European Molecular Genetics Quality Network (EMQN) sequencing scheme.