A CACNA1D mutation in a patient with persistent hyperinsulinaemic hypoglycaemia, heart defects, and severe hypotonia.
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.
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
S E
0000-0002-8670-6340
SE
Flanagan
Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
F
F
Vairo
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
M B
MB
Johnson
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
R
R
Caswell
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
T W
TW
Laver
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
H
H
Lango Allen
Developmental Endocrinology Research Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health and Great Ormond Street Hospital, London, UK.
K
K
Hussain
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
S
S
Ellard
D019943:Amino Acid Substitution; D001022:Aortic Valve Insufficiency / Q000209:etiology; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000209:etiology; D005260:Female; D005320:Fetal Macrosomia / Q000209:etiology; D006330:Heart Defects, Congenital / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007003:Hypoglycemia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D007231:Infant, Newborn; D009123:Muscle Hypotonia / Q000209:etiology; D009154:Mutation; D009468:Neuromuscular Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology
C472073:CACNA1D protein, human; D020746:Calcium Channels, L-Type


CACNA1D

; calcium channel; exome sequencing; hyperinsulinism; hypoglycaemia