Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2, PM4, PP1, PP3
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
Reference Assembly: GRCh37/hg19
dbSNP ID: NA
Coding/Non-Coding: Both
DNA Change: Deletion
Expected RNA Consequence: Deletion
Expected Protein Consequence: Deletion-Insertion
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Intron 8, Exon 9, Intron 9

Findings

This mutation involves the deletion of 4,555 nucleotides including exon 9 and intronic sequences on either side. With the exception of the amino acids encoded by exon 9, an otherwise full-length protein is expressed with an amino acid substitution, S290C, at the splice junction between exons 8 and 10. This was the first deletion mutation in PSEN1 reported to be pathogenic for AD (Crook et al., 1998; Prihar et al., 1999). There are now several known mutations that result in the exclusion of exon 9 due to deletion events as well as splice-site mutations. These mutations are variously referred to as ΔE9, Δ9, delE9, or deltaE9.

This mutation has been observed in two Finnish families. It was first described in a pedigree known as Finn2, which previously had been shown to be affected by early onset Alzheimer's disease due to an unidentified genomic change that resulted in the exclusion of exon 9 from PSEN1 transcripts (Crook et al., 1998). The reported pedigree contains 17 affected individuals over three generations. Disease in this family was characterized by progressive dementia frequently preceded by spastic paraparesis (SP). In this family, onset of SP ranged from 45 to 55 years old and cognitive decline at 45 to 57 years. Death typically occurred five to 12 years after onset. Additional clinical and neuroimaging data for this family, as well as an extended pedigree, are reported in Verkkoniemi et al., 2000.

In the second Finnish family, the same 4.6 kb deletion was found to be associated with disease over two generations (Hiltunen et al., 2000). In contrast to the Finn2 family, the clinical presentation of the four affected patients was typical for AD without indications of spastic paraparesis or any other major motor disturbance. The mean age at onset was 43.5 years. The E318G polymorphism in exon 9 of PSEN1 was also detected in two affected and eight healthy family members. The deletion mutation segregated with disease in this family and was absent in 102 unrelated AD patients and 51 control subjects from Finland.

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

Neuropathology

Neuropathological examination of two patients from the Finn2 pedigree revealed unusual plaques in addition to the typical amyloid plaques and neurofibrillary tangles of AD. The plaques were described as “reminiscent of loosely packed cotton-wool balls” that were large (100-150 μM in diameter) and not congophilic, suggesting a lack of amyloid at the core (Crook et al., 1998). Cotton-wool plaques have since been associated with multiple other PSEN1 mutations, such as I83_M84del, G217D, G217R, V261F, P264L, E280G, P284L, A431E, and DelT440.

Neuropathological findings were reported in one individual from the other Finnish family. In accordance with the clinical features, the pathology was typical of AD with numerous congophilic amyloid plaques, neurofibrillary tangles, neuritic plaques, and reactive astrocytes and microglia near plaques. Cerebral amyloid angiopathy was observed both in the parenchyma and in the leptomeninges. Cotton-wool plaques were not observed. Overall, the neuropathology supported the diagnosis of definite AD according to CERAD criteria (Hiltunen et al., 2000).

Biological Effect

This is a deletion of 4.6 kb including the entire exon 9 and extending into the flanking intronic sequences. It results in an in-frame skipping of exon 9 and an amino acid change (S290C) at the splice junction of exons 8 and 10. Several in silico algorithms predicted it is damaging (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.

PS3-S

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. S290_S319delinsC: 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.

PM4-M

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

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. S290_S319delinsC: At least one family with >=3 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)

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

Crook R, Verkkoniemi A, Perez-Tur J, Mehta N, Baker M, Houlden H, Farrer M, Hutton M, Lincoln S, Hardy J, Gwinn K, Somer M, Paetau A, Kalimo H, Ylikoski R, Pöyhönen M, Kucera S, Haltia M. A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat Med. 1998 Apr;4(4):452-5. PubMed.
Prihar G, Verkkoniem A, Perez-Tur J, Crook R, Lincoln S, Houlden H, Somer M, Paetau A, Kalimo H, Grover A, Myllykangas L, Hutton M, Hardy J, Haltia M. Alzheimer disease PS-1 exon 9 deletion defined. Nat Med. 1999 Oct;5(10):1090. PubMed.
Verkkoniemi A, Somer M, Rinne JO, Myllykangas L, Crook R, Hardy J, Viitanen M, Kalimo H, Haltia M. Variant Alzheimer's disease with spastic paraparesis: clinical characterization. Neurology. 2000 Mar 14;54(5):1103-9. PubMed.
Hiltunen M, Helisalmi S, Mannermaa A, Alafuzoff I, Koivisto AM, Lehtovirta M, Pirskanen M, Sulkava R, Verkkoniemi A, Soininen H. Identification of a novel 4.6-kb genomic deletion in presenilin-1 gene which results in exclusion of exon 9 in a Finnish early onset Alzheimer's disease family: an Alu core sequence-stimulated recombination?. Eur J Hum Genet. 2000 Apr;8(4):259-66. 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 (ΔE9Finn)

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