Abstract
Alzheimer’s disease (AD) is the most common form of neurodegenerative dementia. In this study, whole genome sequencing identifies one rare and likely pathogenic mutation in the presenilin 1 (PSEN1) gene (c.356C > T, p.T119I) associated with a frontal variant of AD. Affected individuals in the kindred developed late-onset cognitive decline accompanied with early presentation of psychiatric symptoms. Positive amyloid PiB PET tracing suggested presence of pathophysiological biomarker for AD. Whole genome sequencing analysis evaluated rare coding mutations in susceptible genes for various types of dementia and supported the role of PSEN1 as a causal gene. Identification of this T119I variant in PSEN1 might broaden the spectrum of genetic basis and clinical diversity of familial AD.
Highlights
Cognitive deficits resulting in compromised social and occupational function are typical features of dementia
We report a rare missense presenilin 1 (PSEN1) mutation (c.356C > T, p.T119I) in a late-onset Alzheimer’s disease (AD) pedigree with early presentation of behavioral disturbance
We performed whole genome sequencing and proved that PSEN1 but not other susceptible genes for dementia contributing to the genetic cause of the frontal variant of AD
Summary
Cognitive deficits resulting in compromised social and occupational function are typical features of dementia. Alzheimer’s disease (AD) is the most common form of dementia [1]. An estimated 6%–14% of AD cases exhibit different clinical features from the typical amnestic form [4, 5]. The most common AD variants include posterior cortical atrophy, logopenic aphasia and the frontal variant [6]. Posterior cortical atrophy is characterized by visuospatial agnosia and visual disorientation [7]. Clinical features of logopenic aphasia include prolonged word-finding and impaired auditory verbal short-term memory [8]. The frontal variant of AD mainly presents as impairments of behavior and executive function, and overlaps with psychiatric disorders and a behavioral variant of frontotemporal dementia [9].
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