title: Mosaic and Intronic Mutations in TSC1/TSC2 Explain the Majority of TSC Patients with No Mutation Identified by Conventional Testing.
abstract: Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor gene syndrome due to germline mutations in either TSC1 or TSC2. 10-15% of TSC individuals have no mutation identified (NMI) after thorough conventional molecular diagnostic assessment. 53 TSC subjects who were NMI were studied using next generation sequencing to search for mutations in these genes. Blood/saliva DNA including parental samples were available from all subjects, and skin tumor biopsy DNA was available from six subjects. We identified mutations in 45 of 53 subjects (85%). Mosaicism was observed in the majority (26 of 45, 58%), and intronic mutations were also unusually common, seen in 18 of 45 subjects (40%). Seventeen (38%) mutations were seen at an allele frequency < 5%, five at an allele frequency < 1%, and two were identified in skin tumor biopsies only, and were not seen at appreciable frequency in blood or saliva DNA. These findings illuminate the extent of mosaicism in TSC, indicate the importance of full gene coverage and next generation sequencing for mutation detection, show that analysis of TSC-related tumors can increase the mutation detection rate, indicate that it is not likely that a third TSC gene exists, and enable provision of genetic counseling to the substantial population of TSC individuals who are currently NMI.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Magdalena E
authors.initials: ME
authors.lastname: Tyburczy
authors.affiliation: Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Kira A
authors.initials: KA
authors.lastname: Dies
authors.affiliation: Department of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Glass
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Susana
authors.initials: S
authors.lastname: Camposano
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Chekaluk
authors.affiliation: Center for Cancer Genome Discovery, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Thorner
authors.affiliation: Center for Cancer Genome Discovery, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America.
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: Darcy
authors.initials: D
authors.lastname: Krueger
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors.forename: David N
authors.initials: DN
authors.lastname: Franz
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Thiele
authors.affiliation: Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Sahin
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
mesh_terms: D006801:Humans; D007438:Introns; D009030:Mosaicism; D009154:Mutation; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins