Molecular Genetic Testing

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Congenital Hyperinsulinism (CHI, previously known as PHHI; Persistent Hyperinsulinaemic Hypoglycaemia of Infancy) is the most frequent cause of severe, persistent hypoglycaemia in early infancy. It is a genetically heterogeneous condition which shows both recessive and dominant modes of inheritance.


The “K-ATP” form of hyperinsulinism is associated with mutations of the ABCC8 or KCNJ11 genes which encode the SUR1 and Kir6.2 subunits of the ATP responsive potassium channel in the pancreatic beta cells. Diffuse HI is usually caused by autosomal recessive inheritance of ABCC8 or KCNJ11 mutations from both unaffected parents, although dominant inheritance has been reported. Focal HI arises when an infant inherits a paternal ABCC8 or KCNJ11 mutation and there is loss of the maternal gene within a focal lesion. This loss of heterozygosity can be detected using microsatellite markers within the chromosome 11p15 region (please contact the laboratory to discuss samples required for this test). It is important to differentiate these two types as surgery can cure focal but not diffuse hyperinsulinism.


Hyperinsulinism-hyperammonemia syndrome is caused by heterozygous mutations in the GLUD1 gene. The majority of cases (approx 80%) are de novo mutations, with autosomal dominant inheritance reported in the remaining 20% of families. The gain-of-function mutations are located in the GTP and ATP-binding domains of the enzyme which are encoded by exons 6, 7, 10, 11 and 12. Treatment with diazoxide and appropriate dietary measures can prove effective.


Heterozygous activating mutations in the GCK gene can also cause a dominantly inherited form of hyperinsulinism which may be treated with diazoxide.


HADH hyperinsulinism is due to loss-of-function mutations in the gene for the enzyme 3-hydroxyacyl-coenzyme A dehydrogenase (HADH) which is involved in fatty acid oxidation (OMIM 601609). Initial signs and symptoms of this disorder occur during infancy or early childhood and can include poor appetite, vomiting, diarrhea, lack of energy (lethargy), low blood sugar (hypoglycemia), muscle weakness (hypotonia), liver problems, and abnormally high levels of insulin (hyperinsulinism). This clinical syndrome shows autosomal recessive inheritance.



Known Mutation

ABCC8 exons 1-39, KCNJ11 exon 1 and *HNF4A P2 promoter exons 1d to 10 analysis by sequencing

(including dosage analysis by MLPA where appropriate) (*HNF4A sequencing in only indicated in patients diagnosed with diazoxide-responsive Hyperinsulinism within the first 2 weeks of life)

KCNJ11 exon 1 analysis by sequencing
GLUD1 exons 6,7,10,11 and 12 analysis by sequencing
GCK exons 2-10 analysis by sequencing
HADH exons 1-8 analysis by sequencing
Dosage analysis by MLPA

11p15 maternal LOH studies

(please contact the laboratory to discuss)






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