title: Somatic mosaicism contributes to phenotypic variation in Timothy syndrome.
abstract: 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.
authors: Division of Pediatric Cardiology, University of Utah, Salt Lake City, USA. pcsether@ihc.com
authors: Susan P
authors: SP
authors: Etheridge
authors: Neil E
authors: NE
authors: Bowles
authors: Cammon B
authors: CB
authors: Arrington
authors: Thomas
authors: T
authors: Pilcher
authors: Alan
authors: A
authors: Rope
authors: Arthur A M
authors: AA
authors: Wilde
authors: Marielle
authors: M
authors: Alders
authors: Elizabeth V
authors: EV
authors: Saarel
authors: Rene
authors: R
authors: Tavernier
authors: Katherine W
authors: KW
authors: Timothy
authors: Martin
authors: M
authors: Tristani-Firouzi
mesh_terms: D000293:Adolescent; D001321:Autistic Disorder; D001483:Base Sequence; D020746:Calcium Channels, L-Type / Q000235:genetics; D004562:Electrocardiography; D005091:Exons / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D008133:Long QT Syndrome / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008969:Molecular Sequence Data; D009030:Mosaicism; D010641:Phenotype; D017422:Sequence Analysis, DNA; D013576:Syndactyly / Q000235:genetics* / Q000473:pathology*
chemical_list: C079146:CACNA1C protein, human; D020746:Calcium Channels, L-Type