Systematic validation of variants of unknown significance in PSEN1

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disease that is characterized by extracellular amyloid plaques, intracellular neurofibrillary tangles, and progressive cognitive decline. More than 200 mutations in APP, PSEN1, and PSEN2 cause autosomal dominant AD (ADAD). However, common and rare variants also exist within these genes that may be risk factors, protective factors or non‐pathogenic polymorphisms.MethodTo distinguish polymorphisms from pathogenic mutations, we have developed an algorithm for determining ADAD pathogenicity that weighs genetic, bioinformatic, clinical, imaging, and biofluid measures and in vitro analyses. Here, we evaluated 5 novel variants in PSEN1 identified in densely affected AD families in Latin America: p.Val103_Ser104delinsGly, K395I, P264T, A275T and I414T. PSEN1 p.Val103_Ser104delinsGly, K395I, and P264T produced a significant increase in the extracellular A42/40 ratio.ResultPSEN1 p.Val103_Ser104delinsGly, K395I, and P264T produced a significant increase in the extracellular A42/40 ratio. PSEN1 A275T produced a significant increase in A42 and A40 levels, without altering the ratio. PSEN1 I141I, however, failed to significantly alter A levels in a manner consistent with known pathogenic mutations.ConclusionThus, we propose that PSEN1 I414T is a risk factor or non‐pathogenic polymorphism, and PSEN1 p.Val103_Ser104delinsGly, K395I, and P264T represent novel likely pathogenic mutations.