• Motor neuron disease
• amyotrophic lateral sclerosis
• genetic epidemiology
• epidemiology
• neurogenetics

We recently published that a large hexanucleotide repeat expansion within the C9ORF72 gene is the cause of chromosome 9p-linked amyotrophic lateral sclerosis (ALS)/fronto-temporal dementia (FTD). Here, I describe how the chromosome 9p21 locus was first identified, the growing excitement (and frustration) over attempts to pinpoint the underlying genetic lesion, and how we and our collaborators ultimately cloned it. In many ways, this behind-the-scenes account showcases the various technological advances that have been driving the genomics field over the last few years, and which ultimately were responsible for finding the pathogenic repeat expansion.

Our story begins in 2006 with the publication of two papers that used traditional linkage analysis to identify a region on the short arm of chromosome 9 in two large ALS/FTD families.1 2 The overlap between these studies (plus several similar studies) was about 7 million base pairs (bp). In terms of genetics, this was equivalent in size to a large city, such as New York.

Moving on a few years, genomics technology has advanced at a rapid pace, and we are in the middle of the genome-wide association study revolution. Several such studies of both ALS and …