Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73198050 T>G
Position: (GRCh37/hg19):Chr14:73664758 T>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TGT to TGG
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This variant was identified in an Italian family with variable phenotypes of Alzheimer’s disease and variable ages of onset (Tortelli et al., 2021). The family spanned five generations, including three affected mutation carriers, spanning two generations: the proband, his mother, and his maternal aunt. It also included an unaffected individual, the proband’s father, who lacked the mutation, indicating the variant co-segregates with disease. However, the father’s age was not reported and it is unclear if he was past the late age of onset described for most family members. Genetic analysis of the proband involved sequencing of the PSEN1 gene and APOE genotyping which revealed homozygosity for the APOE3 allele.

The proband presented with attention deficit, followed by spatial disorientation, psychiatric symptoms, and parkinsonism, beginning at age 45. His onset of disease was described as characteristic of frontal neuropathology, including behavioral symptoms such as apathy, disinhibition, personality changes, and irritability. About a year later, he began experiencing memory loss followed by episodes of spatial disorientation. In contrast, his mother and maternal aunt had depression and anxiety for several years before developing memory loss characteristic of AD, at ages 68 and 72, respectively. Subsequently, the proband’s mother developed visual hallucinations, arousal disruption, and parkinsonism, resembling the symptoms of Lewy body dementia. The maternal aunt developed pyramidal motor impairment. Of note, like the mother and aunt, most affected members of the family experienced late disease onset.

Disease duration, from symptom onset to complete loss of independence, also varied between the carriers, ranging from four years in the proband’s maternal aunt, to five years in the proband, and nine years in the proband’s mother.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, September 2021).

Neuropathology
Neuropathological data are unavailable, and a brain MRI scan of the proband showed only slight diffuse cortical atrophy (Tortelli et al., 2021). However, analyses of cerebrospinal fluid biomarkers revealed decreased levels of A42, and increased levels of total tau and p181-tau, typical of AD. CT scans of the proband’s mother’s brain and aunt’s brain showed moderate, diffuse cortical atrophy and diffuse fronto-parietal atrophy, respectively. Moreover, electroencephalography of the mother revealed bilateral theta waves in frontotemporal regions.

Biological Effect
The biological effect of this variant is unknown, but Tortelli and colleagues noted it involves the substitution of a polar amino acid having a small thiol side chain, with a much less polar amino acid having a large indole side chain (Tortelli et al., 2021). Three-dimensional modeling suggested the different steric sizes could alter PSEN1 tertiary and quaternary conformation. Moreover, the PHRED-scaled CADD score, which integrates diverse information, was above 20 suggesting a deleterious effect (CADD v.1.6, Sep 2021). Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates C263 may help stabilize the structural re-arrangement of PSEN1 upon APP binding (Zhou et al., 2019; Jan 2019 news).

Pathogenicity

Alzheimer's Disease : Pathogenic*

*Carriers of this variant had heterogenous phenotypes.

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

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. C263W: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP1-S

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. C263W: At least one family with >=3 affected carriers and >=1 unaffected noncarriers.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

	Pathogenic (PS, PM, PP)			Benign (BA, BS, BP)
Criteria Weighting	Strong (-S)	Moderate (-M)	Supporting (-P)	Supporting (-P)	Strong (-S)	Strongest (BA)

Last Updated: 22 Feb 2022

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References

News Citations

Paper Citations

Tortelli R, Seripa D, Zecca C, Dell'Abate MT, Bisceglia P, Barulli MR, De Blasi R, Logroscino G. A New Presenilin 1 (Psen1) Mutation (p.Cys263Trp) as a Cause of Both Early and Late-Onset Alzheimer's Disease in a Large Italian Family. Int J Mol Sci. 2021 Jun 9;22(12) PubMed.
Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.

Mutations

PSEN1 C263W

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