Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP3
Clinical Phenotype: Alzheimer's Disease, Myoclonic seizure
Position: (GRCh38/hg38):Chr14:73186895_7386897 TTC>---
Position: (GRCh37/hg19):Chr14:73653603_73653605 TTC>---
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Deletion
Expected RNA Consequence: Deletion
Expected Protein Consequence: Deletion
Codon Change: TTC to ---
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6

Findings

This mutation was identified in a man diagnosed with AD who developed alterations in memory and personality at age 39 (Vöglein et al., 2019). He experienced rapid progressive dementia, seizures, and myoclonus. The patient’s mother developed dementia in her early 30s and died at 36, and his grandmother was diagnosed with AD before her death at age 50, suggesting autosomal dominant inheritance.

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

Neuropathology
Although neuropathological data are unavailable, MRI showed atrophy of the medial temporal lobe and FDG-PET revealed alterations typical of AD. Metabolism was markedly reduced in the precuneus/posterior cingulate and parietotemporal cortex, while perirolandic metabolism remained intact. Moreover, cerebrospinal fluid levels of Aβ42 were decreased, while those of total tau and phosphorylated tau were increased, as typically seen in AD patients.

Biological Effect
Cultured human embryonic kidney cells expressing APP with the Swedish mutation (APPswe) and the PSEN1 F175del mutation secreted more Aβ42 and less Aβ40, measured as a fraction of total Aβ, than cells expressing APPswe and wildtype PSEN1.  In addition, denaturing gel electrophoresis of conditioned media revealed increased levels of Aβ39, an alternative fragment generated from Aβ42. This observation was confirmed by MALDI-TOF mass spectrometry. Endoproteolysis of PSEN1 appeared unaffected. The authors considered the mutation probably pathogenic, in accordance with the Guerreiro et al. 2010 guidelines (Vöglein et al., 2019).

Several in silico algorithms predicted this variant is damaging (Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

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

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References

Paper Citations

1. Vöglein J, Willem M, Trambauer J, Schönecker S, Dieterich M, Biskup S, Giudici C, Utz K, Oberstein T, Brendel M, Rominger A, Danek A, Steiner H, Haass C, Levin J. Identification of a rare presenilin 1 single amino acid deletion mutation (F175del) with unusual amyloid-β processing effects. Neurobiol Aging. 2019 Dec;84:241.e5-241.e11. Epub 2019 Sep 20 PubMed.
2. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
3. 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.

External Citations

1. gnomAD v2.1.1

Further Reading

No Available Further Reading