A CACNA1D mutation in a patient with persistent hyperinsulinaemic hypoglycaemia, heart defects, and severe hypotonia.

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Vairo, F 
Johnson, MB 
Caswell, R 
Laver, TW 

Congenital hyperinsulinaemic hypoglycaemia (HH) can occur in isolation or it may present as part of a wider syndrome. For approximately 40%-50% of individuals with this condition, sequence analysis of the known HH genes identifies a causative mutation. Identifying the underlying genetic aetiology in the remaining cases is important as a genetic diagnosis will inform on recurrence risk, may guide medical management and will provide valuable insights into β-cell physiology. We sequenced the exome of a child with persistent diazoxide-responsive HH, mild aortic insufficiency, severe hypotonia, and developmental delay as well as the unaffected parents. This analysis identified a de novo mutation, p.G403D, in the proband's CACNA1D gene. CACNA1D encodes the main L-type voltage-gated calcium channel in the pancreatic β-cell, a key component of the insulin secretion pathway. The p.G403D mutation had been reported previously as an activating mutation in an individual with primary hyper-aldosteronism, neuromuscular abnormalities, and transient hypoglycaemia. Sequence analysis of the CACNA1D gene in 60 further cases with HH did not identify a pathogenic mutation. Identification of an activating CACNA1D mutation in a second patient with congenital HH confirms the aetiological role of CACNA1D mutations in this disorder. A genetic diagnosis is important as treatment with a calcium channel blocker may be an option for the medical management of this patient.

CACNA1D, calcium channel, exome sequencing, hyperinsulinism, hypoglycaemia, Amino Acid Substitution, Aortic Valve Insufficiency, Calcium Channels, L-Type, DNA Mutational Analysis, Developmental Disabilities, Female, Fetal Macrosomia, Heart Defects, Congenital, Humans, Hyperinsulinism, Hypoglycemia, Infant, Newborn, Muscle Hypotonia, Mutation, Neuromuscular Diseases
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Pediatr Diabetes
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Hindawi Limited