Klara Rozenkova1, Jana Malikova1, Azizun Nessa1, Lenka Dusatkova1, Lise Bjørkhaug1, Barbora Obermannova1, Petra Dusatkova1, Jitka Kytnarova1, Ingvild Aukrust1, Laeya A Najmi1, Blanka Rypackova1, Zdenek Sumnik1, Jan Lebl1, Pål R Njølstad1, Khalid Hussain1, Stepanka Pruhova1. 1. Department of Paediatrics, Second Faculty of Medicine (K.R., J.M., L.D., B.O., P.D., Z.S., J.L., S.P.), Charles University in Prague and University Hospital in Motol, Prague 150 06, Czech Republic; Genetics and Epigenetics in Health and Disease, Genetics and Genomic Medicine Programme (A.N., K.H.), Institute of Child Health, University College London, London WC1N 1EH, United Kingdom; KG Jebsen Center for Diabetes Research, Department of Clinical Science (L.B., I.A., L.A.N., P.R.N.), University of Bergen, Bergen N-5021, Norway; Department of Biomedicine (L.B.), University of Bergen, Bergen N-5021, Norway; Department of Paediatrics, First Faculty of Medicine (J.K.), Charles University in Prague and the General University Hospital in Prague, Prague 121 08, Czech Republic; Center for Medical Genetics and Molecular Medicine (I.A., L.A.N.), Haukeland University Hospital, Bergen N-5021, Norway; Center for Research of Diabetes, Metabolism and Nutrition and Second Department of Internal Medicine FNKV, Third Faculty of Medicine (B.R.), Charles University in Prague, Prague 100 00, Czech Republic; Department of Pediatrics (P.R.N.), Haukeland University Hospital, Bergen, N-5020 Norway; and Department of Paediatric Endocrinology (K.H.), Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom.
Abstract
CONTEXT: Congenital hyperinsulinism of infancy (CHI) represents a group of heterogeneous disorders characterized by oversecretion of insulin from pancreatic β-cells causing severe hypoglycemia. OBJECTIVE: We studied the distribution of genetic causes of CHI in a Czech population. METHODS: Countrywide collection of patients with CHI included 40 subjects (12 females, median age of diagnosis, 1 wk [interquartile range, 1-612 wk]). We sequenced the ABCC8, KCNJ11, GLUD1, GCK, HADH, UCP2, SLC16A1, HNF4A, and HNF1A genes and investigated structural changes in the ABCC8 gene. We functionally tested novel variants in the ABCC8 gene by Rb(86+) efflux assay and novel variants in the HNF1A gene by transcriptional activation and DNA-binding tests. RESULTS: We found causal mutations in 20 subjects (50%): 19 carried a heterozygous mutation while one patient was homozygous for mutation in the ABCC8 gene. Specifically, we detected 11 mutations (seven novel) in ABCC8, one novel mutation in KCNJ11, five mutations (two novel) in HNF1A, two novel mutations in HNF4A, and one in GCK. We showed a decrease of activation by diazoxide in mutant KATP channels with novel ABCC8 variants by 41-91% (median, 82%) compared with wild-type (WT) channels and reduced transcriptional activity of mutant HNF1A proteins (2.9% for p.Asn62Lysfs93* and 22% for p.Leu254Gln) accompanied by no DNA-binding ability compared with WT HNF1A. CONCLUSION: We detected a higher proportion of heterozygous mutations causing CHI compared with other cohorts probably due to lack of consanguinity and inclusion of milder CHI forms. Interestingly, HNF1A gene mutations represented the second most frequent genetic cause of CHI in the Czech Republic. Based on our results we present a genetic testing strategy specific for similar populations.
CONTEXT: Congenital hyperinsulinism of infancy (CHI) represents a group of heterogeneous disorders characterized by oversecretion of insulin from pancreatic β-cells causing severe hypoglycemia. OBJECTIVE: We studied the distribution of genetic causes of CHI in a Czech population. METHODS: Countrywide collection of patients with CHI included 40 subjects (12 females, median age of diagnosis, 1 wk [interquartile range, 1-612 wk]). We sequenced the ABCC8, KCNJ11, GLUD1, GCK, HADH, UCP2, SLC16A1, HNF4A, and HNF1A genes and investigated structural changes in the ABCC8 gene. We functionally tested novel variants in the ABCC8 gene by Rb(86+) efflux assay and novel variants in the HNF1A gene by transcriptional activation and DNA-binding tests. RESULTS: We found causal mutations in 20 subjects (50%): 19 carried a heterozygous mutation while one patient was homozygous for mutation in the ABCC8 gene. Specifically, we detected 11 mutations (seven novel) in ABCC8, one novel mutation in KCNJ11, five mutations (two novel) in HNF1A, two novel mutations in HNF4A, and one in GCK. We showed a decrease of activation by diazoxide in mutant KATP channels with novel ABCC8 variants by 41-91% (median, 82%) compared with wild-type (WT) channels and reduced transcriptional activity of mutant HNF1A proteins (2.9% for p.Asn62Lysfs93* and 22% for p.Leu254Gln) accompanied by no DNA-binding ability compared with WT HNF1A. CONCLUSION: We detected a higher proportion of heterozygous mutations causing CHI compared with other cohorts probably due to lack of consanguinity and inclusion of milder CHI forms. Interestingly, HNF1A gene mutations represented the second most frequent genetic cause of CHI in the Czech Republic. Based on our results we present a genetic testing strategy specific for similar populations.
Authors: Daphne Yau; Thomas W Laver; Antonia Dastamani; Senthil Senniappan; Jayne A L Houghton; Guftar Shaikh; Tim Cheetham; Talat Mushtaq; Ritika R Kapoor; Tabitha Randell; Sian Ellard; Pratik Shah; Indraneel Banerjee; Sarah E Flanagan Journal: PLoS One Date: 2020-02-06 Impact factor: 3.240
Authors: Maria Gϋemes; Sofia Asim Rahman; Ritika R Kapoor; Sarah Flanagan; Jayne A L Houghton; Shivani Misra; Nick Oliver; Mehul Tulsidas Dattani; Pratik Shah Journal: Rev Endocr Metab Disord Date: 2020-12 Impact factor: 6.514