Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM5, PP2, PP3, BS2
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173703 A>C
Position: (GRCh37/hg19):Chr14:73640411 A>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TAT to TCT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This variant was identified in a Chinese family with multiple members afflicted by neurological disorders, including early onset Alzheimer’s disease (Li et al., 2022). The proband was a woman who began experiencing progressive memory loss at 49 years of age. By 54, her cognitive function had decreased substantially, and she was diagnosed with probable AD. Her half-sister also suffered from AD with an age at onset of 58 years. Moreover, two of the proband’s siblings, 57 and 50 years old, had mild cognitive impairment (MCI) starting at ages 56 and 49, respectively. Four other family members, including the proband’s mother, had neuropsychiatric symptoms, including irritability and loss of emotional control, without signs of dementia.

Whole genome sequencing of multiple affected and unaffected family members failed to reveal a mutation that co-segregated with disease. The proband, her half-sister with AD, and her two siblings with MCI carried Y159S, but the proband’s mother also carried the mutation and died at 82 with neuropsychiatric, but not AD, symptoms. Two distant relatives who were unaffected at ages 74 and 54 were non-carriers.

To identify other genetic variants that might explain the apparent resilience of the proband’s mother and/or the vulnerability of her offspring to the Y159S variant, the authors performed a comparative whole-genome analysis to identify variants in PSEN1 and other genes that differed between the mother and her affected children. This search yielded thousands of genetic variations.

The Y159S variant was absent from the gnomAD variant database (Apr 2022).

Neuropathology
Neuropathological data are unavailable, but an MRI scan of the proband revealed mild bilateral atrophy of the temporal and parietal lobes (Li et al., 2022). Atrophy of the former was more pronounced on the left side. Moreover, hippocampal volume was also slightly reduced.

Biological Effect
In PC12 cells co-expressing the APP Swedish mutant, this variant increased the Aβ42/Aβ40 ratio approximately fourfold compared with wildtype PSEN1, mostly by reducing Aβ40 production, but also by moderately increasing Aβ42 production (Li et al., 2022). Moreover, it disrupted the processing of PSEN1, as revealed by decreased production of the PSEN1 C-terminal fragment.

The variant was predicted to be harmful by several in silico algorithms (SIFT, Polyphen 2, REVE) and, consistently, its PHRED-scaled CADD score was 27.1. In addition, the authors reported that the variant was predicted to be associated with AD in the professional version of the human gene mutation database (HGMD).

Pathogenicity

Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

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References

Paper Citations

1. Li H, Li Y, Liang W, Wei ZZ, Li X, Tian Y, Qiao S, Yang Y, Yang L, Wu D, Yin W, Liu H, Zhang W, Zhang Y, Wang Z. The identification of PSEN1 p.Tyr159Ser mutation in a non-canonic early-onset Alzheimer's disease family. Mol Cell Neurosci. 2022 May;120:103715. Epub 2022 Mar 3 PubMed.

Further Reading

No Available Further Reading