Characterization of ABCC8 and KCNJ11 gene mutations and phenotypes in Korean patients with congenital hyperinsulinism

ObjectiveCongenital hyperinsulinism (CHI) is characterized by persistent hypoglycemia due to the inappropriate insulin secretion. Inactivating mutations in the ABCC8 and KCNJ11 genes, which encode the sulfonylurea receptor 1 and Kir6.2 subunits of the ATP-sensitive K+ (KATP) channel in pancreatic β-cell, are the most common cause of CHI. We studied the genetic etiology and phenotypes of CHI in Korean patients.MethodsABCC8 and KCNJ11 mutational analysis was performed in 17 patients with CHI. Medical records were retrospectively reviewed to identify phenotypes.ResultsMutations (12 ABCC8 and three KCNJ11) were identified in 82% (14/17) of patients. Of these, nine ABCC8 mutations (E100X, W430X, c.1630+1G>C, D813N, Q923X, E1087_A1094delinsDKSDT, Q1134H, H1135W, and E1209Rfs) and one KCNJ11 mutation (W91X) were novel. Of the 14 patients, four had confirming recessively inherited CHI. The remaining ten patients had single heterozygous mutations. The majority (12/17) of patients were medically responsive. Of the five diazoxide-responsive patients, four had an ABCC8 mutation. The five patients unresponsive to medical management and one diazoxide-responsive patient underwent pancreatectomy and had diffuse histology. Of the operated six patients, two had recessively inherited mutations; three patients had a single heterozygous mutation (one maternally and two paternally inherited); and one patient had no identifiable KATP channel mutation.ConclusionsThis is the first study to report genotype and phenotype correlations among Korean patients with CHI. Mutations in ABCC8 and KCNJ11 are the most common causes of CHI in Korean patients. Similar to other studies, there is marked genetic heterogeneity and no clear genotype–phenotype correlation.

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Characterization of ABCC8 and KCNJ11 gene mutations and phenotypes in Korean patients with congenital hyperinsulinism

Acta Endocrinologica ◽

10.1530/eje-11-0160e ◽

2011 ◽

Vol 165 (3) ◽

pp. 485-486

Author(s):

So Eun Park ◽

Sarah E Flanagan ◽

Khalid Hussain ◽

Sian Ellard ◽

Choong Ho Shin ◽

...

Keyword(s):

Gene Mutations ◽

Congenital Hyperinsulinism ◽

Korean Patients ◽

Kcnj11 Gene

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

Case Reports in Endocrinology ◽

10.1155/2021/8826174 ◽

2021 ◽

Vol 2021 ◽

pp. 1-6

Author(s):

Somayyeh Hashemian ◽

Reza Jafarzadeh Esfehani ◽

Siroos Karimdadi ◽

Nosrat Ghaemi ◽

Peyman Eshraghi ◽

...

Keyword(s):

Mutational Analysis ◽

Genetic Diagnosis ◽

Case Series ◽

Missense Variant ◽

Congenital Hyperinsulinism ◽

Biochemical Tests ◽

Functional Studies ◽

Pathogenic Variants ◽

Abcc8 Gene ◽

Kcnj11 Gene

Background. Congenital hyperinsulinism (CHI) is a heterogeneous disease with various underlying genetic causes. Among different genes considered effective in the development of CHI, ABCC8, KCNJ11, and HADH genes are among the important genes, especially in a population with a considerable rate of consanguineous marriage. Mutational analysis of these genes guides clinicians to better treatment and prediction of prognosis for this rare disease. The present study aimed to evaluate genetic variants in ABCC8, KCNJ11, and HADH genes as causative genes for CHI in the Iranian population. Methods. The present case series took place in Mashhad, Iran, within 11 years. Every child who had a clinical phenotype and confirmatory biochemical tests of CHI enrolled in this study. Variants in ABCC8, KCNJ11, and HADH genes were analyzed by the polymerase chain reaction and sequencing in our patients. Results. Among 20 pediatric patients, 16 of them had variants in ABCC8, KCNJ11, and HADH genes. The mean age of genetic diagnosis was 18.6 days. A homozygous missense (c.2041-21G > A) mutation in the ABCC8 gene was seen in three infants. Other common variants were frameshift variants (c.3438dup) in the ABCC8 gene and a missense variant (c.287-288delinsTG) in the KCNJ11 gene. Most of the variants in our population were still categorized as variants of unknown significance and only 7 pathogenic variants were present. Conclusion. Most variants were located in the ABCC8 gene in our population. Because most of the variants in our population are not previously reported, performing further functional studies is warranted.

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Histopathology of Congenital Hyperinsulinism: Retrospective Study with Genotype Correlations

Pediatric and Developmental Pathology ◽

10.1007/s10024-002-0026-9 ◽

2003 ◽

Vol 6 (4) ◽

pp. 322-333 ◽

Cited By ~ 39

Author(s):

Mariko Suchi ◽

Courtney MacMullen ◽

Paul S. Thornton ◽

Arupa Ganguly ◽

Charles A. Stanley ◽

...

Keyword(s):

Retrospective Study ◽

Mutational Analysis ◽

Focal Lesion ◽

Compound Heterozygous ◽

Congenital Hyperinsulinism ◽

Β Cell ◽

Diagnostic Challenge ◽

Sugar Levels ◽

Inherited Mutations ◽

Nuclear Enlargement

The majority of the most severe cases of congenital hyperinsulinism (HI) are caused by defects in the β-cell adenosine triphosphate (ATP)-sensitive potassium channel and usually require pancreatectomy to control blood sugar levels. In contrast to the recent advances in understanding the pathophysiology and genetic bases of HI, the histologic classification of this condition remains controversial. A recent proposal to classify the HI pancreata into diffuse and focal forms has drawn much interest because of its relative simplicity and its good correlation with the genetic abnormalities. We undertook a retrospective study to determine whether this classification scheme could be applied to 38 pancreata resected for HI at our institution. We also obtained leukocyte genomic DNA from 29 cases and screened the exons of ABCC8 and KCNJ11 genes for the presence of mutations. Nineteen cases (50.0%) were histologically classified as diffuse HI and 14 cases (36.8%) were categorized as focal form. The mutational analysis revealed that 14 of the 16 diffuse cases analyzed had either homozygous or compound heterozygous mutations of ABCC8 or KCNJ11 and 7 of 10 focal cases had only the paternally inherited mutations, consistent with the previous observations. Two patients (5.3%) had normal pancreatic histology but had persistent hypoglycemia postoperatively, leaving the possibility of residual focal lesion. Three of 38 cases (7.9%) did not fit well into either diffuse or focal category. Two cases differed from the described pattern for the diffuse form in that the nuclear enlargement was confined to a single area of the pancreas. The other case had a focal lesion but β-cell nuclear enlargement was present in nonadjacent areas. Mutations for typical diffuse or focal HI were not identified in two of these three equivocal cases. We conclude from this study that nearly 90% of HI cases can be classified into either a diffuse or a focal form. However, a small percentage of cases represented a diagnostic challenge.

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Novel Perspectives of Super-High Dose Glybenclamide in an Infant With DEND Syndrome

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.925 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A453-A453

Author(s):

Galia Barash ◽

Haim Bassan ◽

Livne Ayelet ◽

Lilach Benyamini ◽

Eli Heyman ◽

...

Keyword(s):

Developmental Delay ◽

De Novo ◽

Glucose Monitoring ◽

Gene Mutations ◽

Missense Variant ◽

Neonatal Diabetes ◽

Heterozygous Mutation ◽

High Dose ◽

Kcnj11 Gene ◽

High Doses

Abstract Mutations in KCNJ11 gene cause a variety of persistent neonatal diabetes mellitus syndromes (PNDM), with and without developmental delay and epilepsy presentations (developmental delay, epilepsy, and neonatal diabetes - DEND Syndrome). We report a heterozygous mutation for pathogenic KCNJ11 missense variant: c.190G>A, p. (Val64Met), reported once so far, associated with severe epilepsy and neurological deterioration phenotype, responsive to a combination of super high doses of Glibenclamide (Sulfonylurea) and oral steroids. We had the patient attached to continuous glucose monitoring, performed electroencephalogramic tracings, magnetic resonance imaging and whole exome sequencing on parents and patient DNA and Sanger sequencing (SS) on candidate gene mutations. His phenotypic description and management during 18 months, demonstrates this mutation is responsive to super-high doses of SU combined with high dose 6 weeks steroids protocol. In conclusion, we have identified a de novo heterozygous missense mutation as the etiology for severe DEND syndrome in a one day old neonate, presenting with asymptomatic hyperglycemia, responsive to a novel management combination.

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Congenital hyperinsulinism due to compound heterozygous mutations in ABCC8 responsive to diazoxide therapy

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2019-0457 ◽

2020 ◽

Vol 33 (5) ◽

pp. 671-674

Author(s):

Tashunka Taylor-Miller ◽

Jayne Houghton ◽

Paul Munyard ◽

Yadlapalli Kumar ◽

Clinda Puvirajasinghe ◽

...

Keyword(s):

Insulin Secretion ◽

Compound Heterozygous ◽

Congenital Hyperinsulinism ◽

Β Cells ◽

Pancreatic Β Cells ◽

Newborn Period ◽

Case Presentation ◽

Male Baby ◽

Common Causes ◽

Compound Heterozygous Mutations

AbstractBackgroundCongenital hyperinsulinism (CHI), a condition characterized by dysregulation of insulin secretion from the pancreatic β cells, remains one of the most common causes of hyperinsulinemic, hypoketotic hypoglycemia in the newborn period. Mutations in ABCC8 and KCNJ11 constitute the majority of genetic forms of CHI.Case presentationA term macrosomic male baby, birth weight 4.81 kg, born to non-consanguineous parents, presented on day 1 of life with severe and persistent hypoglycemia. The biochemical investigations confirmed a diagnosis of CHI. Diazoxide was started and progressively increased to 15 mg/kg/day to maintain normoglycemia. Sequence analysis identified compound heterozygous mutations in ABCC8 c.4076C>T and c.4119+1G>A inherited from the unaffected father and mother, respectively. The mutations are reported pathogenic. The patient is currently 7 months old with a sustained response to diazoxide.ConclusionsBiallelic ABCC8 mutations are known to result in severe, diffuse, diazoxide-unresponsive hypoglycemia. We report a rare patient with CHI due to compound heterozygous mutations in ABCC8 responsive to diazoxide.

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