Genome-wide homozygosity analysis reveals HADH mutations as a common cause of diazoxide-responsive hyperinsulinemic-hypoglycemia in consanguineous pedigrees

Flanagan, Sarah E., Patch, Ann-Marie, Locke, Jonathan M., Akcay, Teoman, Simsek, Enver, Alaei, Mohammadreza, Yekta, Zeinab, Desai, Meena, Kapoor, Ritika R., Hussain, Khalid and Ellard, Sian (2011) Genome-wide homozygosity analysis reveals HADH mutations as a common cause of diazoxide-responsive hyperinsulinemic-hypoglycemia in consanguineous pedigrees. Journal of Clinical Endocrinology and Metabolism, 96 3: E498-E502. doi:10.1210/jc.2010-1906


Author Flanagan, Sarah E.
Patch, Ann-Marie
Locke, Jonathan M.
Akcay, Teoman
Simsek, Enver
Alaei, Mohammadreza
Yekta, Zeinab
Desai, Meena
Kapoor, Ritika R.
Hussain, Khalid
Ellard, Sian
Title Genome-wide homozygosity analysis reveals HADH mutations as a common cause of diazoxide-responsive hyperinsulinemic-hypoglycemia in consanguineous pedigrees
Journal name Journal of Clinical Endocrinology and Metabolism   Check publisher's open access policy
ISSN 0021-972X
1945-7197
Publication date 2011-03
Sub-type Article (original research)
DOI 10.1210/jc.2010-1906
Volume 96
Issue 3
Start page E498
End page E502
Total pages 5
Place of publication Chevy Chase, MD, United States
Publisher The Endocrine Society
Collection year 2012
Language eng
Formatted abstract
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 forwhomconsanguinity 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.
Keyword Short Chain
Dehydrogenase Deficiency
Glutamate Dehydrogenase
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
Institute for Molecular Bioscience - Publications
 
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