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


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.


CONCLUSIONS
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.
Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter, EX2 5DW, United Kingdom.
Sarah E
SE
Flanagan
Ann-Marie
AM
Patch
Jonathan M
JM
Locke
Teoman
T
Akcay
Enver
E
Simsek
Mohammadreza
M
Alaei
Zeinab
Z
Yekta
Meena
M
Desai
Ritika R
RR
Kapoor
Khalid
K
Hussain
Sian
S
Ellard
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000235:genetics*; D015331:Cohort Studies; D003241:Consanguinity; D003981:Diazoxide; D004232:Diuretics; D005260:Female; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics*; D007003:Hypoglycemia / Q000235:genetics*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation / Q000502:physiology*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
D004232:Diuretics; D015094:3-Hydroxyacyl CoA Dehydrogenases; D003981:Diazoxide
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