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Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism
BACKGROUND: Congenital hyperinsulinism (CHI) is a clinically heterogeneous condition. Mutations in eight genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and HNF1A) are known to cause CHI. AIM: To characterise the clinical and molecular aspects of a large cohort of patients with CHI. METHODOLO...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioScientifica
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3599069/ https://www.ncbi.nlm.nih.gov/pubmed/23345197 http://dx.doi.org/10.1530/EJE-12-0673 |
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author | Kapoor, Ritika R Flanagan, Sarah E Arya, Ved Bhushan Shield, Julian P Ellard, Sian Hussain, Khalid |
author_facet | Kapoor, Ritika R Flanagan, Sarah E Arya, Ved Bhushan Shield, Julian P Ellard, Sian Hussain, Khalid |
author_sort | Kapoor, Ritika R |
collection | PubMed |
description | BACKGROUND: Congenital hyperinsulinism (CHI) is a clinically heterogeneous condition. Mutations in eight genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and HNF1A) are known to cause CHI. AIM: To characterise the clinical and molecular aspects of a large cohort of patients with CHI. METHODOLOGY: Three hundred patients were recruited and clinical information was collected before genotyping. ABCC8 and KCNJ11 genes were analysed in all patients. Mutations in GLUD1, HADH, GCK and HNF4A genes were sought in patients with diazoxide-responsive CHI with hyperammonaemia (GLUD1), raised 3-hydroxybutyrylcarnitine and/or consanguinity (HADH), positive family history (GCK) or when CHI was diagnosed within the first week of life (HNF4A). RESULTS: Mutations were identified in 136/300 patients (45.3%). Mutations in ABCC8/KCNJ11 were the commonest genetic cause identified (n=109, 36.3%). Among diazoxide-unresponsive patients (n=105), mutations in ABCC8/KCNJ11 were identified in 92 (87.6%) patients, of whom 63 patients had recessively inherited mutations while four patients had dominantly inherited mutations. A paternal mutation in the ABCC8/KCNJ11 genes was identified in 23 diazoxide-unresponsive patients, of whom six had diffuse disease. Among the diazoxide-responsive patients (n=183), mutations were identified in 41 patients (22.4%). These include mutations in ABCC8/KCNJ11 (n=15), HNF4A (n=7), GLUD1 (n=16) and HADH (n=3). CONCLUSIONS: A genetic diagnosis was made for 45.3% of patients in this large series. Mutations in the ABCC8 gene were the commonest identifiable cause. The vast majority of patients with diazoxide-responsive CHI (77.6%) had no identifiable mutations, suggesting other genetic and/or environmental mechanisms. |
format | Online Article Text |
id | pubmed-3599069 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | BioScientifica |
record_format | MEDLINE/PubMed |
spelling | pubmed-35990692013-04-01 Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism Kapoor, Ritika R Flanagan, Sarah E Arya, Ved Bhushan Shield, Julian P Ellard, Sian Hussain, Khalid Eur J Endocrinol Clinical Study BACKGROUND: Congenital hyperinsulinism (CHI) is a clinically heterogeneous condition. Mutations in eight genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and HNF1A) are known to cause CHI. AIM: To characterise the clinical and molecular aspects of a large cohort of patients with CHI. METHODOLOGY: Three hundred patients were recruited and clinical information was collected before genotyping. ABCC8 and KCNJ11 genes were analysed in all patients. Mutations in GLUD1, HADH, GCK and HNF4A genes were sought in patients with diazoxide-responsive CHI with hyperammonaemia (GLUD1), raised 3-hydroxybutyrylcarnitine and/or consanguinity (HADH), positive family history (GCK) or when CHI was diagnosed within the first week of life (HNF4A). RESULTS: Mutations were identified in 136/300 patients (45.3%). Mutations in ABCC8/KCNJ11 were the commonest genetic cause identified (n=109, 36.3%). Among diazoxide-unresponsive patients (n=105), mutations in ABCC8/KCNJ11 were identified in 92 (87.6%) patients, of whom 63 patients had recessively inherited mutations while four patients had dominantly inherited mutations. A paternal mutation in the ABCC8/KCNJ11 genes was identified in 23 diazoxide-unresponsive patients, of whom six had diffuse disease. Among the diazoxide-responsive patients (n=183), mutations were identified in 41 patients (22.4%). These include mutations in ABCC8/KCNJ11 (n=15), HNF4A (n=7), GLUD1 (n=16) and HADH (n=3). CONCLUSIONS: A genetic diagnosis was made for 45.3% of patients in this large series. Mutations in the ABCC8 gene were the commonest identifiable cause. The vast majority of patients with diazoxide-responsive CHI (77.6%) had no identifiable mutations, suggesting other genetic and/or environmental mechanisms. BioScientifica 2013-04 /pmc/articles/PMC3599069/ /pubmed/23345197 http://dx.doi.org/10.1530/EJE-12-0673 Text en © 2013 European Society of Endocrinology http://www.bioscientifica.com/journals/reuselicenceeje/ This is an Open Access article distributed under the terms of the European Journal of Endocrinology's Re-use Licence (http://www.bioscientifica.com/journals/reuselicenceeje/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Clinical Study Kapoor, Ritika R Flanagan, Sarah E Arya, Ved Bhushan Shield, Julian P Ellard, Sian Hussain, Khalid Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism |
title | Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism |
title_full | Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism |
title_fullStr | Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism |
title_full_unstemmed | Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism |
title_short | Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism |
title_sort | clinical and molecular characterisation of 300 patients with congenital hyperinsulinism |
topic | Clinical Study |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3599069/ https://www.ncbi.nlm.nih.gov/pubmed/23345197 http://dx.doi.org/10.1530/EJE-12-0673 |
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