Genome-Wide Homozygosity Analysis Reveals HADH Mutations as a Common Cause of Diazoxide-Responsive Hyperinsulinemic-Hypoglycemia in Consanguineous Pedigrees
| العنوان: | Genome-Wide Homozygosity Analysis Reveals HADH Mutations as a Common Cause of Diazoxide-Responsive Hyperinsulinemic-Hypoglycemia in Consanguineous Pedigrees |
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| المؤلفون: | M Desai, Sarah E. Flanagan, Zeinab Yekta, Khalid Hussain, Mohammad Reza Alaei, Ritika R. Kapoor, Enver Simsek, Jonathan M. Locke, Sian Ellard, Teoman Akcay, Ann-Marie Patch |
| المصدر: | The Journal of Clinical Endocrinology and Metabolism |
| بيانات النشر: | Endocrine Society, 2011. |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Male, Proband, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, 030209 endocrinology & metabolism, Genome-wide association study, Single-nucleotide polymorphism, Consanguinity, Hypoglycemia, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, Biochemistry, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Hyperinsulinism, Internal medicine, medicine, Humans, Diuretics, Hyperinsulinemic hypoglycemia, 030304 developmental biology, Genetic testing, Genetics, 0303 health sciences, Mutation, medicine.diagnostic_test, Diazoxide, Homozygote, Biochemistry (medical), Infant, Newborn, 3-Hydroxyacyl CoA Dehydrogenases, Infant, JCEM Online: Brief Reports, medicine.disease, Pedigree, Haplotypes, Female, Genome-Wide Association Study, Microsatellite Repeats |
| الوصف: | HADH mutations are common in consanguineous pedigrees with diazoxide-responsive hyperinsulinaemichypoglycemia; therefore, genetic testing is recommended, even in the absence of abnormal fatty acid oxidation. Context and Objective: Recessive mutations in the hydroxyacyl-CoA dehydrogenase (HADH) gene encoding the enzyme 3-hydroxyacyl-CoA dehydrogenase are a rare cause of diazoxide-responsive hyperinsulinemic hypoglycemia (HH) with just five probands reported to date. HADH deficiency in the first three identified patients was associated with detectable urinary 3-hydroxyglutarate and raised plasma 3-hydroxybutyryl-carnitine levels, but two recent cases did not have abnormal urine organic acids or acylcarnitines. Research Design and Methods: We studied 115 patients with diazoxide-responsive HH in whom the common genetic causes of HH had been excluded. No patients were reported to have abnormal acylcarnitines or urinary organic acids. Homozygosity mapping was undertaken in probands from 13 consanguineous pedigrees to search for regions harboring mutations that are identical by descent. Results: HADH sequencing was performed after genome-wide single nucleotide polymorphism analysis revealed a large shared region of homozygosity spanning the HADH locus in six unrelated probands. Homozygous mutations were identified in three of these patients and in a further two probands from consanguineous families. HADH analysis in the remainder of the cohort identified mutations in a further six probands for whom consanguinity was not reported, but who originated from countries with high rates of consanguinity. Six different HADH mutations were identified in 11/115 (10%) patients tested. Conclusion: HADH mutations are a relatively common cause of diazoxide-responsive HH with a frequency similar to that of GLUD1 and HNF4A mutations. We recommend that HADH sequence analysis is considered in all patients with diazoxide-responsive HH when recessive inheritance is suspected. |
| اللغة: | English |
| تدمد: | 1945-7197 0021-972X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c3b07e198da171288ae1a1633b4c1f8bTest http://europepmc.org/articles/PMC3100671Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c3b07e198da171288ae1a1633b4c1f8b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19457197 0021972X |
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