PROJECT 2 Project 2 of the CREATE RDCRC will explore the genetic determinants of ALS and related disorders using a novel and innovative approach in which we capitalize on shared phenotypic elements across this group of disorders. For Project-2 we will enroll and deeply phenotype 500 patients with ALS and related disorders in whom the genetic cause of disease is not currently known. These data will be combined with the deep phenotypic data collected on 200 patients with ALS and related disorders in which the primary genetic cause has already been identified (Project-1). Genetic studies will identify novel genes for ALS and related disorders, and begin to illuminate the factors that modify the natural course of disease and define endophenotypic features/phenotypic elements that cut cross the boundaries of classic disease entities. This will be achieved by examining both common and rare variation in the context of novel gene discovery in familial and sporadic cases and genetic modifiers in the case of established genetic mutations. All genetic analyses will be based on whole exome sequencing and genome-wide array genotyping as a backbone for the genetic architecture of each sample. In addition to the ~700 exomes we will generate from our deeply phenotyped cohort, we have or expect to have access to ~2,500 exomes from patients with ALS and related disorders, which will be used to confirm/validate the findings in our cohort.

Public Health Relevance

The genetic factors identified in our studies will enhance our ability to predict disease onset, course and outcome;will help guide molecular and drug discovery studies;and will be critical to the success of our future efforts to undertake clinical trials in genetically defined populations. This study will also lay a foundation of deep phenotypic and deep genetic data for use by the broader research community.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZTR1-CI-8 (01))
Program Officer
Gubitz, Amelie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Miami School of Medicine
Coral Gables
United States
Zip Code
Benatar, Michael; Boylan, Kevin; Jeromin, Andreas et al. (2016) ALS biomarkers for therapy development: State of the field and future directions. Muscle Nerve 53:169-82
Rebelo, Adriana P; Abrams, Alexander J; Cottenie, Ellen et al. (2016) Cryptic Amyloidogenic Elements in the 3' UTRs of Neurofilament Genes Trigger Axonal Neuropathy. Am J Hum Genet 98:597-614
Esanov, Rustam; Belle, Kinsley C; van Blitterswijk, Marka et al. (2016) C9orf72 promoter hypermethylation is reduced while hydroxymethylation is acquired during reprogramming of ALS patient cells. Exp Neurol 277:171-7
van Blitterswijk, Marka; Gendron, Tania F; Baker, Matthew C et al. (2015) Novel clinical associations with specific C9ORF72 transcripts in patients with repeat expansions in C9ORF72. Acta Neuropathol 130:863-76
Gendron, Tania F; van Blitterswijk, Marka; Bieniek, Kevin F et al. (2015) Cerebellar c9RAN proteins associate with clinical and neuropathological characteristics of C9ORF72 repeat expansion carriers. Acta Neuropathol 130:559-73
van Blitterswijk, Marka; Rademakers, Rosa (2015) Neurodegenerative disease: C9orf72 repeats compromise nucleocytoplasmic transport. Nat Rev Neurol 11:670-2
Rossor, Alexander M; Oates, Emily C; Salter, Hannah K et al. (2015) Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2. Brain 138:293-310
Turner, Martin R; Benatar, Michael (2015) Ensuring continued progress in biomarkers for amyotrophic lateral sclerosis. Muscle Nerve 51:14-8