Genetic screening in early-onset Alzheimer's disease identified three novel presenilin mutations

Neurobiology of Aging
Tsz Hang WongJohn C van Swieten

Abstract

Mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) are major genetic causes of early-onset Alzheimer's disease (EOAD). Clinical heterogeneity is frequently observed in patients with PSEN1 and PSEN2 mutations. Using whole exome sequencing, we screened a Dutch cohort of 68 patients with EOAD for rare variants in Mendelian Alzheimer's disease, frontotemporal dementia, and prion disease genes. We identified 3 PSEN1 and 2 PSEN2 variants. Three variants, 1 in PSEN1 (p.H21Profs*2) and both PSEN2 (p.A415S and p.M174I), were novel and absent in control exomes. These novel variants can be classified as probable pathogenic, except for PSEN1 (p.H21Profs*2) in which the pathogenicity is uncertain. The initial clinical symptoms between mutation carriers varied from behavioral problems to memory impairment. Our findings extend the mutation spectrum of EOAD and underline the clinical heterogeneity among PSEN1 and PSEN2 mutation carriers. Screening for Alzheimer's disease-causing genes is indicated in presenile dementia with an overlapping clinical diagnosis.

Citations

Dec 19, 2019·Journal of Neuropathology and Experimental Neurology·Diego IaconoDaniel P Perl
Apr 7, 2020·Reviews in the Neurosciences·Diana Marcela Cuestas Torres, Fernando P Cardenas
Jun 10, 2019·Journal of Alzheimer's Disease : JAD·Fiammetta MonacelliMassimo Tabaton
Dec 15, 2020·Journal of Neurochemistry·Nofar Stolero, Dan Frenkel

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