ABCC8 p.Trp143*
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[hide] Genotype and phenotype correlations in Iranian pat... BMC Res Notes. 2015 Aug 13;8:350. doi: 10.1186/s13104-015-1319-1. Senniappan S, Sadeghizadeh A, Flanagan SE, Ellard S, Hashemipour M, Hosseinzadeh M, Salehi M, Hussain K
Genotype and phenotype correlations in Iranian patients with hyperinsulinaemic hypoglycaemia.
BMC Res Notes. 2015 Aug 13;8:350. doi: 10.1186/s13104-015-1319-1., [PMID:26268944]
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BACKGROUND: Hyperinsulinaemic 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. METHODS: Retrospective clinical, biochemical and genetic information was collected on 23 patients with biochemically confirmed HH. Mutation analysis was carried out for the ATP-sensitive potassium (K(ATP)) channel genes (ABCC8 and KCNJ11), GLUD1, GCK, HADH and HNF4A. RESULTS: 78% 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. CONCLUSIONS: To 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.
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106 TableÊf;1ߒ Clinical characteristics and genetic mutations of 23 Iranian patients with hyperinsulinaemic hypoglycaemia Patient number Gender (F = female, M = male) Gestation- term Birth weight (g) Age of onset of hypoglycaemia Epilepsy Neurode- velopmen- tal delay Consanguineous parents Treatment Genotype Mutation Maternal/ paternal genotype Follow up Diazoxide responsive Octreotide responsive Pancreatectomy ABCC8 1 F Yes 3,280 2 days No No No Yes Yes Heterozygous c.2041-21G>A (splicing) None/heterozygous Died at 3 months of ago 2 F Yes 3,750 1 day Yes Yes No Yes Homozygous p.R1494W (missense) Heterozygous/heterozygous Needed insulin 3 F Yes 4,200 1 day Yes No Yes Yes Homozygous p.W143X (nonsense) Heterozygous/heterozygous Needed diazoxide 4 F Yes 5,000 1 day No No Yes Yes Homozygous p.G1376R (missense) Heterozygous/heterozygous Needed diazoxide 5 M Yes 4,200 1 day No No Yes Yes Homozygous c.2697+5G>A (intron 22, novel splicing) Heterozygous/heterozygous On diazoxide 6 M Yes 4,500 1 day No No Yes Yes Homozygous c.2697+5G>A (intron 22, novel splicing) Heterozygous/heterozygous Resolved by 4 years of ago KCNJ11 7 M Yes 4,400 1 day No No Yes Yes Compound heterozy- gous p.P34OH (missense) and pF117del (novel in-frame) Heterozygous/heterozygous Died at 4 months of ago HADH 8 M Yes 2,860 3 months Yes No Yes Yes Homozygous delA617.c (frameshift) Heterozygous/heterozygous On diazoxide 9 F Yes 3,000 1 year No No Yes Yes Homozygous delA617.c (frameshift) Heterozygous/heterozygous Stopped diazoxide/ no relapse 10 M Yes 2,900 1 day Yes Yes Yes Yes Homozygous delA617.c (frameshift) Heterozygous/heterozygous On diazoxide TableÊf;1ߒ continued Patient number Gender (F = female, M = male) Gestation- term Birth weight (g) Age of onset of hypoglycaemia Epilepsy Neurode- velopmen- tal delay Consanguineous parents Treatment Genotype Mutation Maternal/ paternal genotype Follow up Diazoxide responsive Octreotide responsive Pancreatectomy 11 F Yes 3,650 4 days No No No Yes Homozygous delA617.c (frameshift) Heterozygous/heterozygous On diazoxide 12 M Yes 3,600 3 months Yes Yes Yes Yes Homozygous delA617.c (frameshift) Heterozygous/heterozygous On diazoxide 13 M Yes 3,100 1.5 months Yes Yes No Yes Homozygous delA617.c (frameshift) Heterozygous/heterozygous On diazoxide 14 M Yes 2,900 7.5 months No No Yes Yes Homozygous delA617.c (frameshift) Heterozygous/heterozygous On diazoxide 15 F Yes 3,200 1 day Yes No No Yes Homozygous delA617.c (frameshift) Heterozygous/heterozygous On diazoxide 16 M Yes 3,600 3 months Yes Yes No Yes Homozygous delA617.c (frameshift) Heterozygous/heterozygous On diazoxide 17 M Yes 3,500 3 months Yes Yes No Yes Homozygous delA617.c (frameshift) Heterozygous/heterozygous On diazoxide 18 M Yes 3,500 3 months Yes No No Yes Homozygous delA617.c (frameshift) Heterozygous/heterozygous On diazoxide No mutation 19 M No 1,700 3 years No No Yes Yes Tapered diazoxide/ no relapse 20 M No 2,050 1 day Yes No No Yes On diazoxide 21 F Yes 2,800 9 months No No No Yes On diazoxide 22 F Yes 3,300 5 months Yes Yes Yes Yes On diazoxide F Yes 3,750 1 day No No No Yes On diazoxide In contrast to these observations, several other studies suggest a major role of KATP channel in the pathogenesis of patients with HH [19, 21, 23].
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ABCC8 p.Trp143* 26268944:106:702
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