Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS1, PS3, PM1, PM2, PM4, PP1
Clinical Phenotype: Alzheimer's Disease, Spastic Paraparesis
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 deletion mutation in PSEN1 removes a 5.9 kb sequence involving intron 8, exon 9, and intron 9, resulting in the in-frame skipping of exon 9 and an amino acid substitution at the splice junction of exons 8 and 10. It is one of several known pathogenic mutations that involve exclusion of exon 9, which are variously known as ΔE9, Δ9, delE9, or deltaE9.

This mutation was identified in an Australian pedigree (Aus-1) with 13 affected individuals over three generations (Smith et al., 2001). The clinical and neuropathological phenotypes in this family were variable with instances of overlap of Alzheimer’s disease with spastic paraparesis (SP). The first known affected individual in this family developed cognitive symptoms at age 53. She died at age 58 with advanced dementia, but no motor symptoms. Seven of her 10 children also developed dementia, but none had SP. Spastic paraparesis appeared in the next generation; of four siblings, one had both dementia and SP (onset at 54 years) and three had SP but no dementia (onset at 46, 48, and 50 years). An affected cousin developed dementia at age 36 and died 10 years later without symptoms of SP. The mutation in this family was identified as a 5.9 kb deletion in the PSEN1 gene which juxtaposed intron 8 and 9 sequences and resulted in the in-frame skipping of exon 9. The break points did not match those of the previously reported deletion mutation in a Finnish AD pedigree (ΔE9Finn), which also involves deletion of exon 9 (Prihar et al., 1999).

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

Neuropathology

Like the clinical presentation in this family, the neuropathology was variable. Data were available for six affected individuals. Notably, some of the plaques observed were described as "variant." These were large, non-cored plaques with a cotton-wool appearance. These plaques were particularly noted in two cases (one with both Alzheimer's disease and spastic paraparesis and one with spastic paraparesis alone). Corticospinal tract degeneration was also present in these two cases (Smith et al., 2001).

Cotton-wool plaques were also noted in two additional cases carrying the exon 9 deletion, who had died at age 52 and 59 years. Overall, these cases had frequent plaques and neurofibrillary tangles (a Braak score of 5 in both). One of the cases also had Pick bodies in the dentate gyrus; no other brain regions were examined (Halliday et al., 2005).

Biological Effect

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.

Research Models

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

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References

Paper Citations

1. Smith MJ, Kwok JB, McLean CA, Kril JJ, Broe GA, Nicholson GA, Cappai R, Hallupp M, Cotton RG, Masters CL, Schofield PR, Brooks WS. Variable phenotype of Alzheimer's disease with spastic paraparesis. Ann Neurol. 2001 Jan;49(1):125-9. PubMed.
2. 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.
3. Halliday GM, Song YJ, Lepar G, Brooks WS, Kwok JB, Kersaitis C, Gregory G, Shepherd CE, Rahimi F, Schofield PR, Kril JJ. Pick bodies in a family with presenilin-1 Alzheimer's disease. Ann Neurol. 2005 Jan;57(1):139-43. PubMed.

Other Citations

1. PSEN1 ΔE9 Mutants

External Citations

1. gnomAD v2.1.1

Further Reading