Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2–21.3

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are both relentlessly progressive and ultimately fatal neurological disorders. ALS is familial in ∼10% of cases and FTD in ∼30%. Inheritance is usually autosomal dominant with variable penetrance. Phenotypic overlap between ALS and FTD can occur within the same kindred. Mutations in copper/zinc superoxide dismutase 1 (SOD1) are found in ∼20% of familial and ∼3% of sporadic ALS cases but are not associated with dementia. Mutations in microtubule associated protein tau (MAPT) are detected in ∼30% of familial FTD kindreds. Dominant ALS with FTD has previously been linked to 9q21 and pure ALS to loci on 16q21, 18q21, 20p13. Here we report the results of a genome-wide linkage study in a large ALS and FTD kindred using Affymetrix 10K GeneChip microarrays. Linkage analysis of single nucleotide polymorphism (SNP) data identified consistently positive log of the odds (LOD) scores across chromosome 9p (maximal LOD score of 2.4). Fine mapping the region with microsatellite markers generated a maximal multipoint LOD score of 3.02 (𝛉 = 0) at D9S1878. Recombination narrowed the conserved haplotype to 12 cM (11 Mb) at 9p13.2–21.3 (flanking markers D9S2154 and D9S1874). Bioinformatic analysis of the region has identified 103 known genes.