title: Incomplete Timothy syndrome secondary to a mosaic mutation of the CACNA1C gene diagnosed using next-generation sequencing.
abstract: Autosomal dominant genetic diseases can occur de novo and in the form of somatic mosaicism, which can give rise to a less severe phenotype, and make diagnosis more difficult given the sensitivity limits of the methods used. We report the case of female child with a history of surgery for syndactyly of the hands and feet, who was admitted at 6 years of age to a pediatric intensive care unit following cardiac arrest. The electrocardiogram (ECG) showed a long QT interval that on occasions reached 500 ms. Despite the absence of facial dysmorphism and the presence of normal psychomotor development, a diagnosis of Timothy syndrome was made given the association of syndactyly and the ECG features. Sanger sequencing of the CACNA1C gene, followed by sequencing of the genes KCNQ1, KCNH2, KCNE1, KCNE2, were negative. The subsequent analysis of a panel of genes responsible for hereditary cardiac rhythm disorders using Haloplex technology revealed a recurrent mosaic p.Gly406Arg missense mutation of the CACNA1C gene in 18% of the cells. This mosaicism can explain the negative Sanger analysis and the less complete phenotype in this patient. Given the other cases in the literature, mosaic mutations in Timothy syndrome appear more common than previously thought. This case demonstrates the importance of using next-generation sequencing to identify mosaic mutations when the clinical picture supports a specific mutation that is not identified using conventional testing. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Centre de Génétique et Centre de Référence des Maladies Rares-Anomalies du Développement et Syndromes Malformatifs, CHU Dijon, Dijon, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Baurand
authors.affiliation: Cardiologie Pédiatrique, CHU Dijon, Dijon, France.|Cardiologie et Centre de Compétence des Troubles du Rythme Cardiaque Héréditaires, CHU Dijon, Dijon, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Falcon-Eicher
authors.affiliation: Cardiologie et Centre de Compétence des Troubles du Rythme Cardiaque Héréditaires, CHU Dijon, Dijon, France.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Laurent
authors.affiliation: Cardiologie Pédiatrique, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Villain
authors.affiliation: Cardiologie Pédiatrique, CHU Dijon, Dijon, France.|Cardiologie et Centre de Compétence des Troubles du Rythme Cardiaque Héréditaires, CHU Dijon, Dijon, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Bonnet
authors.affiliation: Centre de Génétique et Centre de Référence des Maladies Rares-Anomalies du Développement et Syndromes Malformatifs, CHU Dijon, Dijon, France.
authors.forename: Christel
authors.initials: C
authors.lastname: Thauvin-Robinet
authors.affiliation: Centre de Génétique et Centre de Référence des Maladies Rares-Anomalies du Développement et Syndromes Malformatifs, CHU Dijon, Dijon, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Jacquot
authors.affiliation: Cardiologie et Centre de Compétence des Troubles du Rythme Cardiaque Héréditaires, CHU Dijon, Dijon, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Eicher
authors.affiliation: Institut du Thorax, INSERM U1087, CHU Nantes, Nantes, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Gourraud
authors.affiliation: Service de Génétique Médicale, CHU Nantes, Nantes, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Schmitt
authors.affiliation: Service de Génétique Médicale, CHU Nantes, Nantes, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bézieau
authors.affiliation: Service de Génétique Médicale, CHU Nantes, Nantes, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Giraud
authors.affiliation: Service de Génétique Médicale, CHU Nantes, Nantes, France.
authors.forename: Solenne
authors.initials: S
authors.lastname: Dumont
authors.affiliation: EA4271, Génétique des Anomalies du Développement, Université de Bourgogne-Franche Comté, Dijon, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Kuentz
authors.affiliation: Institut du Thorax, INSERM U1087, CHU Nantes, Nantes, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Probst
authors.affiliation: Réanimation Pédiatrie, CHU Dijon, Dijon, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Burguet
authors.affiliation: Institut du Thorax, INSERM U1087, CHU Nantes, Nantes, France.|Service de Génétique Médicale, CHU Nantes, Nantes, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Kyndt
authors.affiliation: Centre de Génétique et Centre de Référence des Maladies Rares-Anomalies du Développement et Syndromes Malformatifs, CHU Dijon, Dijon, France.|Cardiologie et Centre de Compétence des Troubles du Rythme Cardiaque Héréditaires, CHU Dijon, Dijon, France.|EA4271, Génétique des Anomalies du Développement, Université de Bourgogne-Franche Comté, Dijon, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D001321:Autistic Disorder / Q000175:diagnosis* / Q000235:genetics*; D020746:Calcium Channels, L-Type / Q000235:genetics*; D002648:Child; D003062:Codon; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005260:Female; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008133:Long QT Syndrome / Q000175:diagnosis* / Q000235:genetics*; D009030:Mosaicism; D009154:Mutation; D010641:Phenotype; D013576:Syndactyly / Q000175:diagnosis* / Q000235:genetics*
chemical_list: C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type; D003062:Codon
keywords: CACNA1C; Timothy syndrome; long-QT; mosaic mutation; next-generation sequencing; syndactyly