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Yuji Takahashi, MD, PhD; Naomi Seki, MD, PhD; Hiroyuki Ishiura, MD; Jun Mitsui, MD; Takashi Matsukawa, MD; Atsushi Kishino, MD; Osamu Onodera, MD, PhD; Masashi Aoki, MD, PhD; Nobuyuki Shimozawa, MD, PhD; Shigeo Murayama, MD, PhD; Yasuto Itoyama, MD, PhD; Yasuyuki Suzuki, MD, PhD; Gen Sobue, MD, PhD; Masatoyo Nishizawa, MD, PhD; Jun Goto, MD, PhD; Shoji Tsuji, MD, PhD

Arch Neurol. 2008;65(10):1326-1332.

Background  Comprehensive resequencing of the causative and disease-related genes of neurodegenerative diseases is expected to enable (1) comprehensive mutational analysis of familial cases, (2) identification of sporadic cases with de novo or low-penetrant mutations, (3) identification of rare variants conferring disease susceptibility, and ultimately (4) better understanding of the molecular basis of these diseases.

Objective  To develop a microarray-based high-throughput resequencing system for the causative and disease-related genes of amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases.

Design  Validation of the system was conducted in terms of the signal-to-noise ratio, accuracy, and throughput. Comprehensive gene analysis was applied for patients with ALS.

Subjects  Ten patients with familial ALS, 35 patients with sporadic ALS, and 238 controls.

Results  The system detected point mutations with 100% accuracy and completed the resequencing of 270 kilobase pairs in 3 working days with greater than 99.9% accuracy of base calls, or the determination of base(s) at each position. Analysis of patients with familial ALS revealed 2 SOD1 mutations. Analysis of the 35 patients with sporadic ALS revealed a previously known SOD1 mutation, S134N, a novel putative pathogenic DCTN1 mutation, R997W, and 9 novel variants including 4 nonsynonymous heterozygous variants consisting of 2 in ALS2, 1 in ANG, and 1 in VEGF that were not found in the controls.

Conclusion  The DNA microarray–based resequencing system is a powerful tool for high-throughput comprehensive analysis of causative and disease-related genes. It can be used to detect mutations in familial and sporadic cases and to identify numerous novel variants potentially associated with genetic risks.

Author Affiliations: Departments of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo (Drs Takahashi, Seki, Ishiura, Mitsui, Matsukawa, Kishino, Goto, and Tsuji), Brain Research Institute, Niigata University, Niigata (Drs Onodera and Nishizawa), and Tohoku University Graduate School of Medicine, Sendai (Drs Aoki and Itoyama); Division of Genomics Research, Life Science Research Center, Gifu University, Gifu (Dr Shimozawa); Geriatric Neuroscience (Neuropathology), Tokyo Metropolitan Institute of Gerontology, Tokyo (Dr Murayama); Department of Pediatrics, Gifu University School of Medicine, Gifu (Dr Suzuki); and Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan (Dr Sobue).

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