Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PS2, PS3, PM1, PM2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73206384 A>G
Position: (GRCh37/hg19):Chr14:73673092 A>G
dbSNP ID: NA
Coding/Non-Coding: Both
DNA Change: Substitution
Expected RNA Consequence: Splicing Alteration
Expected Protein Consequence: Deletion-Insertion
Genomic Region: Intron 8, Exon 9

Findings

This point mutation in intron 8 of PSEN1 is one of several mutations in this region that affect splicing. It occurs in a splice acceptor site, which results in the exclusion of exon 9 from transcripts, and is thus referred to as ΔE9 or Δ9. Due to the exclusion of exon 9, the predicted presenilin-1 protein lacks a stretch of about 30 amino acids.

The mutation was originally identified in a French patient with Alzheimer’s disease. The mutation is thought to have occurred de novo, as it was not present in the DNA of either parent (Rovelet-Lecrux et al., 2015).

The mutation was also identified in a German individual of European descent who presented with progressive aphasia, memory decline, and changes in interests and behavior at the age of 48 (Blauwendraat et al., 2016, Blauwendraat et al., 2017). The collection of symptoms was consistent with frontal-variant AD, and closely resembled behavioral variant frontotemporal dementia. Although segregation with disease could not be determined, this individual did have a positive family history, including a mother and sister with unspecified dementia, beginning at age 80 and 47, respectively.

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

Neuropathology

Neuropathological data are unavailable, but MRI of the German patient showed supratentorial atrophy, particularly of parietal and occipital cortex (Blauwendraat et al., 2015). In addition, the levels of Aβ42 in cerebrospinal fluid were reduced.

Biological Effect

This point mutation abrogates a splice acceptor site in PSEN1, such that exon 9, which encodes residues 290-319, is excluded from mature transcripts. The skipping of exon 9 occurs in-frame, but introduces a missense mutation at the splice junction of exon 8 and exon 10, S290C. In silico, Mutation Taster, CADD, and DANN predict the point mutation to be disease-causing (Rovelet-Lecrux et al., 2015, Blauwendraat et al., 2017, Xiao et al., 2021).

A summary of the biological effects of PSEN1 mutants that result in the exclusion of exon 9 can be found at: PSEN1 ΔE9 Mutants (below the table).

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.

PS1-S

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.

PS2-S

De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. S290_S319delinsC A>G: Functional data derive from assays involving exon 9 deletion mutants, not necessarily this specific variant.

PM1-M

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

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.

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)

Research Models

A summary of research models that express PSEN1 lacking exon 9 can be found at: PSEN1 ΔE9 Mutants (below the table).

Last Updated: 14 Oct 2023

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References

Paper Citations

Rovelet-Lecrux A, Charbonnier C, Wallon D, Nicolas G, Seaman MN, Pottier C, Breusegem SY, Mathur PP, Jenardhanan P, Le Guennec K, Mukadam AS, Quenez O, Coutant S, Rousseau S, Richard AC, Boland A, Deleuze JF, Frebourg T, Hannequin D, Campion D, CNR-MAJ collaborators. De novo deleterious genetic variations target a biological network centered on Aβ peptide in early-onset Alzheimer disease. Mol Psychiatry. 2015 Sep;20(9):1046-56. Epub 2015 Jul 21 PubMed.
Blauwendraat C, Wilke C, Jansen IE, Schulte C, Simón-Sánchez J, Metzger FG, Bender B, Gasser T, Maetzler W, Rizzu P, Heutink P, Synofzik M. Pilot whole-exome sequencing of a German early-onset Alzheimer's disease cohort reveals a substantial frequency of PSEN2 variants. Neurobiol Aging. 2016 Jan;37:208.e11-7. Epub 2015 Sep 30 PubMed.
Blauwendraat C, Wilke C, Simón-Sánchez J, Jansen IE, Reifschneider A, Capell A, Haass C, Castillo-Lizardo M, Biskup S, Maetzler W, Rizzu P, Heutink P, Synofzik M. The wide genetic landscape of clinical frontotemporal dementia: systematic combined sequencing of 121 consecutive subjects. Genet Med. 2017 Jul 27; 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 S290_S319delinsC A>G (ΔE9)

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