Genotype and phenotype correlations in Iranian patients with hyperinsulinaemic hypoglycaemia

Abstract

BackgroundHyperinsulinaemic hypoglycaemia (HH) is a group of clinically and genetically heterogeneous disorders characterized by unregulated insulin secretion. Abnormalities in nine different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A, UCP2 and HNF1A) have been reported in HH, the most common being ABCC8 and KCNJ11. We describe the genetic aetiology and phenotype of Iranian patients with HH.MethodsRetrospective clinical, biochemical and genetic information was collected on 23 patients with biochemically confirmed HH. Mutation analysis was carried out for the ATP-sensitive potassium (KATP) channel genes (ABCC8 and KCNJ11), GLUD1, GCK, HADH and HNF4A.Results78 % of the patients were identified to have a genetic cause for HH. 48 % of patients had mutation in HADH, whilst ABCC8/KCNJ11 mutations were identified in 30 % of patients. Among the diazoxide-responsive patients (18/23), mutations were identified in 72 %. These include two novel homozygous ABCC8 mutations. Of the five patients with diazoxide-unresponsive HH, three had homozygous ABCC8 mutation, one had heterozygous ABCC8 mutation inherited from an unaffected father and one had homozygous KCNJ11 mutation. 52 % of children in our cohort were born to consanguineous parents. Patients with ABCC8/KCNJ11 mutations were noted to be significantly heavier than those with HADH mutation (p = 0.002). Our results revealed neurodevelopmental deficits in 30 % and epilepsy in 52 % of all patients.ConclusionsTo the best of our knowledge, this is the first study of its kind in Iran. We found disease-causing mutations in 78 % of HH patients. The predominance of HADH mutation might be due to a high incidence of consanguineous marriage in this population. Further research involving a larger cohort of HH patients is required in Iranian population.

Genotyping of ABCC8, KCNJ11, and HADH in Iranian Infants with Congenital Hyperinsulinism

“…Most of their patients had variants in the HADH gene and the ABCC8 gene was the next gene with frequent variants. e only similar variants between this study and the present one are the splicing variants in the ABCC8 gene (c.2041-21G > A) [16]. ey reported that their female heterozygous patient had died at the age of 3 months.…”

“…In our studied population, only one compound heterozygous variant was found. Compound heterozygous status has been reported in other studies while Senniappan et al have previously reported the same heterozygous variants in the Iranian population [16,19]. eir patient was a female child who died at 3 months of age [16].…”

“…Compound heterozygous status has been reported in other studies while Senniappan et al have previously reported the same heterozygous variants in the Iranian population [ 16 , 19 ]. Their patient was a female child who died at 3 months of age [ 16 ]. Similar to the Senniappan et al's study, Mohnike et al also demonstrated a case of paternally heterozygous child with c.2041-21G > A variant in the ABCC8 gene and focal CHI [ 20 ].…”

“…Alaei et al [ 14 ] reported that one of their patients had this variant in homozygous form while our patient had this variant in compound heterozygous form. Another study from Iran evaluated 23 patients with hyperinsulinemic hypoglycemia [ 16 ]. The authors demonstrated that after screening for ABCC8, HADH, HNF4A, KCNJ11 , GLUD1 , and GCK , only 4 patients did not show any variant in these genes.…”

Genome-edited zebrafish model of ABCC8 loss-of-function disease

“…Complete knockout of channel activity was confirmed in isolated membrane patches of β-cells from homozygous mutant fish (see below), which we thus term SUR1 -/-. Infants with CHI often have macrosomia 28,29 , but, as with mouse knockouts 18,30,31 there was no significant difference in growth between SUR1 mutants and wild type (Fig. 1B).…”