Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex

Mark Nellist (1) , Marianne Hoogeveen-Westerveld (2) , Marjolein Wentink (2) , Diana van den Heuvel (2) , Melika Mozaffari (2) , Rosemary Ekong (3) , Sue Povey (3) , Johan T. den Dunnen (4) , Kay Metcalfe (5) , Stephanie Vallee (6) , Stefan Krüger (7) , Vandana Shashi (8) , Joann Bergoffen (9) , Frances Elmslie (10) , David J Kwiatkowski (11) , Julian Sampson (12) , Concha Vidales (13) , Jacinta Dzarir (14) , Javier Garcia-Planells (15) , Kira Dies (16) , Anneke Maat-Kievit (17) , Ans M.W. van den Ouweland (18) , Dicky Jj Halley (2)

1 Clinical Genetics
2 Erasmus MC - Erasmus University Medical Center [Rotterdam]
3 University College
4 Human & Clinical Genetics
5 Central Manchester University Hospitals NHS Foundation Trust
6 DHMC - Dartmouth Hitchcock Medical Center
7 Center for Human Genetics
8 Duke University [Durham]
9 Kaiser Permanente
10 St. George's Hospital
11 Medicine
12 Medical Genetics
13 Policlinica Gipuzka
14 The Prince of Wales Hospital
15 University of Valencia
16 Boston Children's Hospital
17 Department of Clinical Genetics
18 Clinical Genetics

The effects of missense changes and small in-frame deletions and insertions on protein function are not easy to predict and the identification of such variants in individuals at risk of a genetic disease can complicate genetic counselling. One option is to perform functional tests to assess whether the variants affect protein function. We have used this strategy to characterise variants identified in the TSC1 and TSC2 genes in individuals with, or suspected of having, Tuberous Sclerosis Complex (TSC). Here we present an overview of our functional studies on 45 TSC1 and 107 TSC2 variants. Using a standardised protocol we classified 16 TSC1 variants and 70 TSC2 variants as pathogenic. In addition we identified 8 putative splice site mutations (5 TSC1 and 3 TSC2). The remaining 24 TSC1 and 34 TSC2 variants were classified as probably neutral.

Mots clés: Life Sciences

Mark Nellist, Marianne Hoogeveen-Westerveld, Marjolein Wentink, Diana van den Heuvel, Melika Mozaffari, et al.. Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with Tuberous Sclerosis Complex. Human Mutation, 2011, 32 (4), pp.424. ⟨10.1002/humu.21451⟩. ⟨hal-00620580⟩