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Somatic mosaicism contributes to phenotypic variation in Timothy syndrome
Author(s) -
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.,
TristaniFirouzi Martin
Publication year - 2011
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.34223
Subject(s) - missense mutation , somatic cell , exon , genotyping , phenotype , mutation , long qt syndrome , genetics , sudden death , genetic counseling , biology , medicine , genotype , gene , qt interval
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 ( Ca v 1.2 , 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.