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Expanding the phenotype of CACNA1C mutation disorders

BACKGROUND: Pathogenic variants in the L‐type Ca(2+) channel gene CACNA1C cause a multi‐system disorder that includes severe long QT syndrome (LQTS), congenital heart disease, dysmorphic facial features, syndactyly, abnormal immune function, and neuropsychiatric disorders, collectively known as Timo...

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Autores principales: Gakenheimer‐Smith, Lindsey, Meyers, Lindsay, Lundahl, Derek, Menon, Shaji C., Bunch, T. Jared, Sawyer, Briana L., Tristani‐Firouzi, Martin, Etheridge, Susan P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222832/
https://www.ncbi.nlm.nih.gov/pubmed/33797204
http://dx.doi.org/10.1002/mgg3.1673
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author Gakenheimer‐Smith, Lindsey
Meyers, Lindsay
Lundahl, Derek
Menon, Shaji C.
Bunch, T. Jared
Sawyer, Briana L.
Tristani‐Firouzi, Martin
Etheridge, Susan P.
author_facet Gakenheimer‐Smith, Lindsey
Meyers, Lindsay
Lundahl, Derek
Menon, Shaji C.
Bunch, T. Jared
Sawyer, Briana L.
Tristani‐Firouzi, Martin
Etheridge, Susan P.
author_sort Gakenheimer‐Smith, Lindsey
collection PubMed
description BACKGROUND: Pathogenic variants in the L‐type Ca(2+) channel gene CACNA1C cause a multi‐system disorder that includes severe long QT syndrome (LQTS), congenital heart disease, dysmorphic facial features, syndactyly, abnormal immune function, and neuropsychiatric disorders, collectively known as Timothy syndrome. In 2015, a variant in CACNA1C (p.R518C) was reported to cause cardiac‐only Timothy syndrome, a genetic disorder with a mixed phenotype of congenital heart disease, hypertrophic cardiomyopathy (HCM), and LQTS that lacked extra‐cardiac features. We have identified a family harboring the p.R518C pathogenic variant with a wider spectrum of clinical manifestations. METHODS: A four‐generation family harboring the p.R518C pathogenic variant was reviewed in detail. The proband and his paternal great‐uncle underwent comprehensive cardiac gene panel testing, and his remaining family members underwent cascade testing for the p.R518C pathogenic variant. RESULTS: In addition to displaying cardinal features of CACNA1C disorders including LQTS, congenital heart disease, HCM, and sudden cardiac death, family members manifested atrial fibrillation and sick sinus syndrome. CONCLUSION: Our report expands the cardiac phenotype of CACNA1C variants and reflects the variable expressivity of mutations in the L‐type Ca(2+) channel.
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spelling pubmed-82228322021-06-29 Expanding the phenotype of CACNA1C mutation disorders Gakenheimer‐Smith, Lindsey Meyers, Lindsay Lundahl, Derek Menon, Shaji C. Bunch, T. Jared Sawyer, Briana L. Tristani‐Firouzi, Martin Etheridge, Susan P. Mol Genet Genomic Med Original Articles BACKGROUND: Pathogenic variants in the L‐type Ca(2+) channel gene CACNA1C cause a multi‐system disorder that includes severe long QT syndrome (LQTS), congenital heart disease, dysmorphic facial features, syndactyly, abnormal immune function, and neuropsychiatric disorders, collectively known as Timothy syndrome. In 2015, a variant in CACNA1C (p.R518C) was reported to cause cardiac‐only Timothy syndrome, a genetic disorder with a mixed phenotype of congenital heart disease, hypertrophic cardiomyopathy (HCM), and LQTS that lacked extra‐cardiac features. We have identified a family harboring the p.R518C pathogenic variant with a wider spectrum of clinical manifestations. METHODS: A four‐generation family harboring the p.R518C pathogenic variant was reviewed in detail. The proband and his paternal great‐uncle underwent comprehensive cardiac gene panel testing, and his remaining family members underwent cascade testing for the p.R518C pathogenic variant. RESULTS: In addition to displaying cardinal features of CACNA1C disorders including LQTS, congenital heart disease, HCM, and sudden cardiac death, family members manifested atrial fibrillation and sick sinus syndrome. CONCLUSION: Our report expands the cardiac phenotype of CACNA1C variants and reflects the variable expressivity of mutations in the L‐type Ca(2+) channel. John Wiley and Sons Inc. 2021-04-01 /pmc/articles/PMC8222832/ /pubmed/33797204 http://dx.doi.org/10.1002/mgg3.1673 Text en © 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Gakenheimer‐Smith, Lindsey
Meyers, Lindsay
Lundahl, Derek
Menon, Shaji C.
Bunch, T. Jared
Sawyer, Briana L.
Tristani‐Firouzi, Martin
Etheridge, Susan P.
Expanding the phenotype of CACNA1C mutation disorders
title Expanding the phenotype of CACNA1C mutation disorders
title_full Expanding the phenotype of CACNA1C mutation disorders
title_fullStr Expanding the phenotype of CACNA1C mutation disorders
title_full_unstemmed Expanding the phenotype of CACNA1C mutation disorders
title_short Expanding the phenotype of CACNA1C mutation disorders
title_sort expanding the phenotype of cacna1c mutation disorders
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222832/
https://www.ncbi.nlm.nih.gov/pubmed/33797204
http://dx.doi.org/10.1002/mgg3.1673
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