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Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS.

ABSTRACT: 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.

SUBMITTER: Smith BN

PROVIDER: S-EPMC4521390 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS.

Smith Bradley N BN Ticozzi Nicola N Fallini Claudia C Gkazi Athina Soragia AS Topp Simon S Kenna Kevin P KP Scotter Emma L EL Kost Jason J Keagle Pamela P Miller Jack W JW Calini Daniela D Vance Caroline C Danielson Eric W EW Troakes Claire C Tiloca Cinzia C Al-Sarraj Safa S Lewis Elizabeth A EA King Andrew A Colombrita Claudia C Pensato Viviana V Castellotti Barbara B de Belleroche Jacqueline J Baas Frank F ten Asbroek Anneloor L M A AL Sapp Peter C PC McKenna-Yasek Diane D McLaughlin Russell L RL Polak Meraida M Asress Seneshaw S Esteban-Pérez Jesús J Muñoz-Blanco José Luis JL Simpson Michael M van Rheenen Wouter W Diekstra Frank P FP Lauria Giuseppe G Duga Stefano S Corti Stefania S Cereda Cristina C Corrado Lucia L Sorarù Gianni G Morrison Karen E KE Williams Kelly L KL Nicholson Garth A GA Blair Ian P IP Dion Patrick A PA Leblond Claire S CS Rouleau Guy A GA Hardiman Orla O Veldink Jan H JH van den Berg Leonard H LH Al-Chalabi Ammar A Pall Hardev H Shaw Pamela J PJ Turner Martin R MR Talbot Kevin K Taroni Franco F García-Redondo Alberto A Wu Zheyang Z Glass Jonathan D JD Gellera Cinzia C Ratti Antonia A Brown Robert H RH Silani Vincenzo V Shaw Christopher E CE Landers John E JE

Neuron 20141022 2

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. An ...[more]

PMID: 25374358

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Project description:Endometrial cancer is the fourth most commonly diagnosed cancer in women. Family history is a known risk factor for endometrial cancer. The incidence of endometrial cancer in a first-degree relative elevates the relative risk to range between 1.3 and 2.8. It is unclear to what extent or what other novel germline variants are at play in endometrial cancer. We aim to address this question by utilizing whole exome sequencing as a means to identify novel, rare variant associations between exonic regions and endometrial cancer. The MyCode community health initiative is an excellent resource for this study with germline whole exome data for 60,000 patients available in the first phase, and further 30,000 patients independently sequenced in the second phase as part of DiscovEHR study. We conducted exome-wide rare variant association using 472 cases and 4,110 controls in 60,000 patients (discovery cohort); and 261 cases and 1,531 controls from 30,000 patients (replication cohort). After binning rare germline variants into genes, case-control association tests performed using Optimal Unified Approach for Rare-Variant Association, SKAT-O. Seven genes, including RBM12, NDUFB6, ATP6V1A, RECK, SLC35E1, RFX3 (Bonferroni-corrected P < 0.05) and ATP8A1 (suggestive P < 10-5), and one long non-coding RNA, DLGAP4-AS1 (Bonferroni-corrected P < 0.05), were associated with endometrial cancer. Notably, RECK, and ATP8A1 were replicated from the replication cohort (suggestive threshold P < 0.05). Additionally, a pathway-based rare variant analysis, using pathogenic and likely pathogenic variants, identified two significant pathways, pyrimidine metabolism and protein processing in the endoplasmic reticulum (Bonferroni-corrected P < 0.05). In conclusion, our results using the single-source electronic health records (EHR) linked to genomic data highlights candidate genes and pathways associated with endometrial cancer and indicates rare variants involvement in endometrial cancer predisposition, which could help in personalized prognosis and also further our understanding of its genetic etiology.

Dataset Information

Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS.

Publications

Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS.

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