Somatic mosaicism contributes to phenotypic variation in Timothy syndrome

Timothy syndrome type 1 (TS‐1) is a rare disorder that affects multiple organ systems and has a high incidence of sudden death due to profound QT prolongation and resultant ventricular arrhythmias. All previously described cases of TS‐1 are the result of a missense mutation in exon 8A (p.G406R), an...

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Bibliographic Details
Published in:American journal of medical genetics. Part A 2011-10, Vol.155 (10), p.2578-2583
Main Authors: Etheridge, Susan P., Bowles, Neil E., Arrington, Cammon B., Pilcher, Thomas, Rope, Alan, Wilde, Arthur A.M., Alders, Marielle, Saarel, Elizabeth V., Tavernier, Rene, Timothy, Katherine W., Tristani‐Firouzi, Martin
Format: Article
Language:English
Subjects:
Adolescent
Alternative splicing
Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy
Arrhythmia
arrhythmias
Autistic Disorder
Base Sequence
Biological and medical sciences
Calcium channels (L-type)
Calcium channels (voltage-gated)
Calcium Channels, L-Type - genetics
Cardiac dysrhythmias
Cardiology. Vascular system
channelopathy
Electrocardiography
Emergency and intensive care: neonates and children. Prematurity. Sudden death
Exons
Exons - genetics
Female
Genotype
Genotyping
Heart
Humans
Infant, Newborn
Infant, Premature
Intensive care medicine
Long QT Syndrome - genetics
Long QT Syndrome - pathology
Lymphocytes
Male
Medical genetics
Medical sciences
Missense mutation
Molecular Sequence Data
Mosaicism
Peripheral blood
Phenotype
Prognosis
Sequence Analysis, DNA
sudden death
Syndactyly - genetics
Syndactyly - pathology
Timothy syndrome
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Summary:Timothy syndrome type 1 (TS‐1) is a rare disorder that affects multiple organ systems and has a high incidence of sudden death due to profound QT prolongation and resultant ventricular arrhythmias. All previously described cases of TS‐1 are the result of a missense mutation in exon 8A (p.G406R), an alternatively spliced variant of the L‐type calcium channel gene (Cav1.2, CACNA1C). Most patients reported in the literature represent highly affected individuals who present early in life with severe cardiac and neurological manifestations. Here, we describe somatic mosaicism in TS‐1 patients with less severe manifestations than the typical TS‐1 patient. These findings suggest that the TS prognosis may not be as dismal as previously reported. Moreover, our findings have implications for genetic counseling in that previously described de novo TS mutations may represent cases of parental mosaicism and warrant careful genotyping of parental tissue other than peripheral blood lymphocytes. © 2011 Wiley‐Liss, Inc.
ISSN:1552-4825
1552-4833
1552-4833
DOI:10.1002/ajmg.a.34223