Exome-wide Rare Variant Analysis Identifies TUBA4A Mutations Associated with Familial ALS

Bradley N Smith, Nicola Ticozzi, Claudia Fallini, Athina Soragia Gkazi, Simon Topp, Kevin P Kenna, Emma L Scotter, Jason Kost, Pamela Keagle, Jack W Miller, Daniela Calini, Caroline Vance, Eric W Danielson, Claire Troakes, Cinzia Tiloca, Safa Al-Sarraj, Elizabeth A Lewis, Andrew King, Claudia Colombrita, Viviana PensatoBarbara Castellotti, Jacqueline de Belleroche, Frank Baas, Anneloor Lma Ten Asbroek, Peter C Sapp, Diane McKenna-Yasek, Russell L McLaughlin, Meraida Polak, Seneshaw Asress, Jesús Esteban-Pérez, José Luis Muñoz-Blanco, Michael Simpson, Wouter van Rheenen, Frank P Diekstra, Giuseppe Lauria, Stefano Duga, Stefania Corti, Cristina Cereda, Lucia Corrado, Gianni Sorarù, Karen E Morrison, Kelly L Williams, Garth A Nicholson, Ian P Blair, Patrick A Dion, Claire S Leblond, Guy A Rouleau, Orla Hardiman, Ammar Al-Chalabi, Christopher E Shaw, SLAGEN Consortium

Research output: Contribution to journalArticlepeer-review

272 Citations (Scopus)


Exome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analysis.

Original languageEnglish
Pages (from-to)324-331
Number of pages8
Issue number2
Early online date22 Oct 2014
Publication statusPublished - 22 Oct 2014


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