title: Variants Within TSC2 Exons 25 and 31 Are Very Unlikely to Cause Clinically Diagnosable Tuberous Sclerosis.
abstract: Inactivating mutations in TSC1 and TSC2 cause tuberous sclerosis complex (TSC). The 2012 international consensus meeting on TSC diagnosis and management agreed that the identification of a pathogenic TSC1 or TSC2 variant establishes a diagnosis of TSC, even in the absence of clinical signs. However, exons 25 and 31 of TSC2 are subject to alternative splicing. No variants causing clinically diagnosed TSC have been reported in these exons, raising the possibility that such variants would not cause TSC. We present truncating and in-frame variants in exons 25 and 31 in three individuals unlikely to fulfil TSC diagnostic criteria and examine the importance of these exons in TSC using different approaches. Amino acid conservation analysis suggests significantly less conservation in these exons compared with the majority of TSC2 exons, and TSC2 expression data demonstrates that the majority of TSC2 transcripts lack exons 25 and/or 31 in many human adult tissues. In vitro assay of both exons shows that neither exon is essential for TSC complex function. Our evidence suggests that variants in TSC2 exons 25 or 31 are very unlikely to cause classical TSC, although a role for these exons in tissue/stage specific development cannot be excluded.
authors.affiliation: Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Ekong
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, 3015CN, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Nellist
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, 3015CN, The Netherlands.
authors.forename: Marianne
authors.initials: M
authors.lastname: Hoogeveen-Westerveld
authors.affiliation: Department of Clinical Genetics, Erasmus MC, Rotterdam, 3015CN, The Netherlands.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Wentink
authors.affiliation: Department of Pediatrics, Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104-4318.|Department of Neurology Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, 19104.
authors.forename: Jessica
authors.initials: J
authors.lastname: Panzer
authors.affiliation: Texas Scottish Rite Hospital for Children, Dallas, Texas, 75219.
authors.forename: Steven
authors.initials: S
authors.lastname: Sparagana
authors.affiliation: University College London Genetics Institute, Darwin building, Gower Street, London, WC1E 6BT, UK.
authors.forename: Warren
authors.initials: W
authors.lastname: Emmett
authors.affiliation: Institute of Structural and Molecular Biology, University College London, London, WC1E 6BT, UK.
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Dawson
authors.affiliation: UF de Génétique Moléculaire, Département de Biochimie Génétique PBMM, Institut de Biologie en Santé CHU Angers, 49933 Angers, Cedex 9, France.
authors.forename: Marie Claire
authors.initials: MC
authors.lastname: Malinge
authors.affiliation: Centre de Référence des Epilepsies Rares, Hôpital Universitaire Necker - Enfants Malades, 75015, Paris, France.
authors.forename: Rima
authors.initials: R
authors.lastname: Nabbout
authors.affiliation: Neonatology and Neonatal Intensive Care Unit, S. Anna Hospital, 10126, Torino, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Carbonara
authors.affiliation: Laboratory of Molecular Genetics, Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Presidio OIRM S. Anna, 10126, Torino, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Barberis
authors.affiliation: CNR-IBB UOS-TO at MBC, Molecular Biotechnology Center for University of Turin, 10126, Torino, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Padovan
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, University College London, London, UK.
authors.forename: Marta
authors.initials: M
authors.lastname: Futema
authors.affiliation: University College London Genetics Institute, Darwin building, Gower Street, London, WC1E 6BT, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, University College London, London, UK.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.affiliation: Department of Medical Sciences, University of Turin, 10126, Torino, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Migone
authors.affiliation: Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, UK.
authors.forename: Sue
authors.initials: S
authors.lastname: Povey
mesh_terms: D000328:Adult; D000483:Alleles; D017398:Alternative Splicing; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology / Q000379:methods; D030541:Databases, Genetic; D005091:Exons; D015870:Gene Expression; D056726:Genetic Association Studies; D014644:Genetic Variation; D006801:Humans; D009154:Mutation; D010641:Phenotype; D014402:Tuberous Sclerosis / Q000175:diagnosis* / Q000235:genetics*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
keywords: TSC2; alternative splicing; diagnosis; tuberous sclerosis; variants