Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM4, PP1, PP3
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Position: (GRCh38/hg38):Chr14:73173693_73173694 ------>TTATAT
Position: (GRCh37/hg19):Chr14:73640401_73640402 ------>TTATAT
dbSNP ID: rs63750631
Coding/Non-Coding: Coding
DNA Change: Insertion
Expected RNA Consequence: Insertion
Expected Protein Consequence: Insertion; Missense
Codon Change: TAC to TTT.ATA.TAC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation is a six-nucleotide insertion (TTATAT) predicted to result in a missense substitution at codon 156 (Y156F), and an insertion of an isoleucine and tyrosine immediately after codon 156. It was found in a screen for variants in the open reading frame of the PSEN1 gene in participants from the U.S., Germany, and Canada who had been referred for AD diagnostic testing (Rogaeva et al., 2001). The cohort included 372 patients with AD and 42 asymptomatic individuals with a strong family history of AD.

Symptoms and neuropathology were subsequently described for two carriers of the mutation in a Michigan family with five affected individuals spanning four generations (Moretti et al., 2004). The disease was characterized by very early onset (28 years of age in the proband), rapidly progressing dementia, and early presentation of spastic paraparesis, dystonia, and motor speech changes. Like typical AD, patients developed cognitive problems first.

The mutation was absent from the proband's mother who was unaffected. It is also absent from the gnomAD database (gnomAD v2.1.1, May 2021).

Neuropathology
Neuropathology in one case was typical of AD, but more severe and widespread. Classic AD plaques, as well as cotton-wool plaques, were present in neocortex, limbic regions, and to a lesser extent, the striatum. Moreover, sequential FDG-PET scans from two individuals revealed rapidly progressing hypo-metabolism starting in the posterior temporo-parietal cortex, and subsequently spreading to other areas, including the posterior cingulate, primary motor, and frontal association cortices (Moretti et al., 2004).

Biological Effect
The biological effects of this mutation are unknown. Codon 156 is in a highly conserved region of the PSEN1 gene. Although one study reported that in silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Xiao et al., 2021), its PHRED-scaled CADD score was above 20, suggesting a deleterious effect (CADD v1.6, Sep 2021).

Pathogenicity

Alzheimer's Disease : Likely Pathogenic

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

PM1-P

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. Y156delinsFIY: Variant located at edge of mutational hot spot.

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.

PM4-M

Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.

PP1-M

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. Y156delinsFIY: At least one family with 2 affected carriers and >=1 unaffected noncarriers.

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: 25 Jan 2023

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References

Paper Citations

Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, Richard E, Rogaev EI, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss MA, Mayeux R, St George-Hyslop P. Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
Moretti P, Lieberman AP, Wilde EA, Giordani BI, Kluin KJ, Koeppe RA, Minoshima S, Kuhl DE, Seltzer WK, Foster NL. Novel insertional presenilin 1 mutation causing Alzheimer disease with spastic paraparesis. Neurology. 2004 May 25;62(10):1865-8. PubMed.
Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

Mutations

PSEN1 Y156delinsFIY

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