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Homozygosity of the autosomal dominant Alzheimer disease presenilin 1 E280A mutation

We identified several families in Antioquia, Colombia, with early-onset Alzheimer disease (AD) due to the mendelian autosomal dominant inheritance of a PSEN1 E280A gene mutation. Extended family members were interviewed and parish baptism certificates in Antioquian municipalities examined.1 The size of these extended families (including carriers and noncarriers) approaches 5,000 individuals. Full genomes in carriers proved a single founder.2 To support an AD prevention clinical trial, we established a registry in 2010 of all family members over age 8 years.3 Since then we genotyped 3,407 family members and identified 823 (24%) carriers of the PSEN1 E280A mutation. The Comite de Bioetica de la Sede de Investigacion Universitaria, SIU Universidad de Antioquia, approved this study. All participants provided written informed consent. Despite the size of this exceptionally large family and frequent consanguinity, homozygosity at this gene locus had not been reported. The apparent absence of homozygous PSEN1 mutations led to the speculation that E280A homozygosity could be lethal. Generally, homozygous dominant mutations are more severely affected than heterozygotes in both humans and model systems.4 However, human cases in which dominant point mutations are homozygous are rare.