A novel <i>SORL1</i> mutation in a pedigree affected by early-onset Alzheimer's disease

Familial cases of Alzheimer's disease (AD) with autosomal dominant transmission and early onset have a prevalence around 1%. Since only a small fraction of them has a monogenic inheritance due to <i>APP, PSEN1</i>, and <i>PSEN2</i> genes, genetic studies are ongoing to unravel the missing heritability. By sequencing panels including multiple dementia-related genes, we identified a novel likely pathogenic mutation in <i>SORL1</i> in a pedigree including five members affected by AD. This loss of function mutation may lead to a reduction of SORL1 receptor, worsening amyloidogenic burden. As the contribution of <i>SORL1</i> mutations to heritability of AD is presently not well established, we think that it is very important to signal new familial (likely) pathogenic <i>SORL1</i> mutations in order to define the actual genetic involvement of <i>SORL1</i> in AD pathogenesis.