Overview

Pathogenicity: Alzheimer's Disease : Not Classified, Spastic Paraparesis : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM4
Clinical Phenotype: Alzheimer's Disease, Dementia, Spastic Paraparesis
dbSNP ID: NA
Coding/Non-Coding: Both
DNA Change: Deletion
Expected RNA Consequence: Deletion
Expected Protein Consequence: Deletion
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 9, Introns 8 and 9

Findings

This mutation is a 5.7 kb deletion that removes exon 9, as well as sequences from the 3’end of intron 8 and the 5’ end of intron 9 (Fukuda et al., 2023). It is one of several  mutations in PSEN1 that are notable for exclusion of exon 9, which are variously referred to as ΔE9, Δ9, delE9, or deltaE9. This particular mutation was identified in a 55-year-old Japanese woman with spasticity and dementia.  Her spastic symptoms started at age 45. MRI revealed a spinal cystic mass on her right side, but the mass remained stable in size and her symptoms progressed, involving both lower and upper limbs and both sides of her body. Cognitive impairment emerged one year after onset of motor symptoms.
The patient was diagnosed with complex hereditary spastic paraplegia with dementia or pure hereditary spastic paraplegia with Alzheimer’s disease. Of note, her father, who died at age 72, also developed an abnormal gait and cognitive impairment.

This deletion is absent from the gnomAD variant database (v2.1.1, Oct 2023).

Neuropathology
Neuropathological data are unavailable, but brain MRI of the proband showed slight atrophy, and SPECT indicated right-dominant bilateral hypoperfusion of the parietal lobes, precuneus, and posterior cingulate cortex (Fukuda et al., 2023).

Biological Effect

The biological effect of this specific variant is unknown, but many studies of other PSEN1 variants that result in the exclusion of exon 9 (PSEN1ΔE9) have revealed this type of deletion is pathogenic (see PSEN1 ΔE9 Mutants, below the table).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it is not classified by Alzforum because the AD diagnosis was uncertain, only one affected carrier has been reported, and the variant was absent from the gnomAD database. However, note that multiple mutations resulting in the same consequence (deletion of exon 9) are 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. Fukuda H, Mizuguchi T, Doi H, Kameyama S, Kunii M, Joki H, Takahashi T, Komiya H, Sasaki M, Miyaji Y, Ohori S, Koshimizu E, Uchiyama Y, Tsuchida N, Fujita A, Hamanaka K, Misawa K, Miyatake S, Tanaka F, Matsumoto N. Long-read sequencing revealing intragenic deletions in exome-negative spastic paraplegias. J Hum Genet. 2023 Oct;68(10):689-697. Epub 2023 Jun 12 PubMed.

Other Citations

1. PSEN1 ΔE9 Mutants

Further Reading

No Available Further Reading