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Incomplete Timothy syndrome secondary to a mosaic mutation of the CACNA1C gene diagnosed using next-generation sequencing.
Am J Med Genet A. 2017 Feb; 173(2):531-536.AJ

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+Show Affiliations

Centre de Génétique et Centre de Référence des Maladies Rares-Anomalies du Développement et Syndromes Malformatifs, CHU Dijon, Dijon, France.Cardiologie Pédiatrique, CHU Dijon, Dijon, France. Cardiologie et Centre de Compétence des Troubles du Rythme Cardiaque Héréditaires, CHU Dijon, Dijon, France.Cardiologie et Centre de Compétence des Troubles du Rythme Cardiaque Héréditaires, CHU Dijon, Dijon, France.Cardiologie Pédiatrique, Hôpital Necker-Enfants Malades, Paris, France.Cardiologie Pédiatrique, CHU Dijon, Dijon, France. Cardiologie et Centre de Compétence des Troubles du Rythme Cardiaque Héréditaires, CHU Dijon, Dijon, France.Centre de Génétique et Centre de Référence des Maladies Rares-Anomalies du Développement et Syndromes Malformatifs, CHU Dijon, Dijon, France.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.Institut du Thorax, INSERM U1087, CHU Nantes, Nantes, France.Service de Génétique Médicale, CHU Nantes, Nantes, France.Service de Génétique Médicale, CHU Nantes, Nantes, France.Service de Génétique Médicale, CHU Nantes, Nantes, France.Service de Génétique Médicale, CHU Nantes, Nantes, France.EA4271, Génétique des Anomalies du Développement, Université de Bourgogne-Franche Comté, Dijon, France.Institut du Thorax, INSERM U1087, CHU Nantes, Nantes, France.Réanimation Pédiatrie, CHU Dijon, Dijon, France.Institut du Thorax, INSERM U1087, CHU Nantes, Nantes, France. Service de Génétique Médicale, CHU Nantes, Nantes, France.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.

Pub Type(s)

Case Reports
Journal Article
Review

Language

eng

PubMed ID

27868338

Citation

Baurand, Amandine, et al. "Incomplete Timothy Syndrome Secondary to a Mosaic Mutation of the CACNA1C Gene Diagnosed Using Next-generation Sequencing." American Journal of Medical Genetics. Part A, vol. 173, no. 2, 2017, pp. 531-536.
Baurand A, Falcon-Eicher S, Laurent G, et al. Incomplete Timothy syndrome secondary to a mosaic mutation of the CACNA1C gene diagnosed using next-generation sequencing. Am J Med Genet A. 2017;173(2):531-536.
Baurand, A., Falcon-Eicher, S., Laurent, G., Villain, E., Bonnet, C., Thauvin-Robinet, C., Jacquot, C., Eicher, J. C., Gourraud, J. B., Schmitt, S., Bézieau, S., Giraud, M., Dumont, S., Kuentz, P., Probst, V., Burguet, A., Kyndt, F., & Faivre, L. (2017). Incomplete Timothy syndrome secondary to a mosaic mutation of the CACNA1C gene diagnosed using next-generation sequencing. American Journal of Medical Genetics. Part A, 173(2), 531-536. https://doi.org/10.1002/ajmg.a.38045
Baurand A, et al. Incomplete Timothy Syndrome Secondary to a Mosaic Mutation of the CACNA1C Gene Diagnosed Using Next-generation Sequencing. Am J Med Genet A. 2017;173(2):531-536. PubMed PMID: 27868338.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Incomplete Timothy syndrome secondary to a mosaic mutation of the CACNA1C gene diagnosed using next-generation sequencing. AU - Baurand,Amandine, AU - Falcon-Eicher,Sylvie, AU - Laurent,Gabriel, AU - Villain,Elisabeth, AU - Bonnet,Caroline, AU - Thauvin-Robinet,Christel, AU - Jacquot,Caroline, AU - Eicher,Jean-Christophe, AU - Gourraud,Jean-Baptiste, AU - Schmitt,Sébastien, AU - Bézieau,Stéphane, AU - Giraud,Mathilde, AU - Dumont,Solenne, AU - Kuentz,Paul, AU - Probst,Vincent, AU - Burguet,Antoine, AU - Kyndt,Florence, AU - Faivre,Laurence, Y1 - 2016/11/21/ PY - 2016/02/17/received PY - 2016/10/14/accepted PY - 2016/11/22/pubmed PY - 2017/10/25/medline PY - 2016/11/22/entrez KW - CACNA1C KW - Timothy syndrome KW - long-QT KW - mosaic mutation KW - next-generation sequencing KW - syndactyly SP - 531 EP - 536 JF - American journal of medical genetics. Part A JO - Am J Med Genet A VL - 173 IS - 2 N2 - 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. SN - 1552-4833 UR - https://www.unboundmedicine.com/medline/citation/27868338/Incomplete_Timothy_syndrome_secondary_to_a_mosaic_mutation_of_the_CACNA1C_gene_diagnosed_using_next_generation_sequencing_ L2 - https://doi.org/10.1002/ajmg.a.38045 DB - PRIME DP - Unbound Medicine ER -