Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3, BS4
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy
Position: (GRCh38/hg38):Chr14:73198040 C>G
Position: (GRCh37/hg19):Chr14:73664748 C>G
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCT to GGT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This amino acid substitution was first reported in a family with Alzheimer’s disease, including eight affected members with a mean age of onset of 53 and a mean disease duration of 13 years (Ryman et al., 2014). The underlying genetic alteration was not reported.

Subsequently, the mutation was found in an Italian family that included two symptomatic carriers and one asymptomatic carrier, suggesting incomplete penetrance (Piaceri et al., 2020). The proband was a woman who experienced memory deficits beginning at age 53 and whose cognitive abilities deteriorated rapidly after age 55. She developed severe behavioral disturbances, including delusions and aggression. The proband’s mother and one of the proband’s aunts suffered from rapidly progressive dementia with parkinsonism leading to death in less than five years. Another aunt also suffered from dementia, but progression was slower.

Two of three of the proband’s siblings carried the mutation, but only one was symptomatic. The symptomatic carrier, a 54-year-old woman, developed cognitive deficits at 54, with left-sided rigidity and bradykinesia. Like her sister, she deteriorated rapidly, developing overt dementia, behavioral disturbances, parkinsonism, and myoclonus. Strikingly, the other sibling carrying the mutation remained healthy until the end of the study, at which time he was 64. The noncarrier sibling, a 67-year-old woman, also remained healthy. All genotyped members were APOE3 homozygotes.

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

Neuropathology
Neuropathology is unavailable, but cerebrospinal fluid biomarkers for AD, including Aβ42, total tau, and phospho-tau, were consistent with AD in two patients (Piaceri et al., 2020). Moreover, brain MRI of one patient revealed mild cortical and hippocampal atrophy, severe vascular leukencephalopathy, multiple microbleeds, and superficial siderosis. The patient was diagnosed with cerebral amyloid angiopathy. In another patient at an early stage of disease, no significant atrophy was detected by MRI, but vascular leukencephalopathy without microbleeds or superficial siderosis was reported.

Biological effect
Amyloid β production was disrupted in HEK293 cells expressing this variant (Schultz et al., 2023). While the Aβ42/Aβ40 ratio was increased, the ratio of short to long Aβ species was decreased, indicating a damaging effect. An indicator of γ-secretase function as a percentage of wildtype activity was developed combining the Aβ (37 + 38 + 40) / (42 + 43) ratio—a measure of γ-processivity—with the commonly used Aβ42/Aβ40 ratio—a measure of the relative production of aggregation-prone Aβ. This composite score, 36.45 for A260G, was strongly associated with AD age at onset, as well as biomarker and cognitive trajectories across multiple PSEN1 variants.

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021). These authors classified the variant as likely pathogenic using the ACMG-AMP guidelines (Richards et al., 2015).

Pathogenicity

Alzheimer's Disease : Likely Pathogenic

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

PS3-S

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

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.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

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.

BS4-S

Lack of segregation in affected members of a family.

	Pathogenic (PS, PM, PP)			Benign (BA, BS, BP)
Criteria Weighting	Strong (-S)	Moderate (-M)	Supporting (-P)	Supporting (-P)	Strong (-S)	Strongest (BA)

Last Updated: 16 Oct 2023

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References

Paper Citations

Ryman DC, Acosta-Baena N, Aisen PS, Bird T, Danek A, Fox NC, Goate A, Frommelt P, Ghetti B, Langbaum JB, Lopera F, Martins R, Masters CL, Mayeux RP, McDade E, Moreno S, Reiman EM, Ringman JM, Salloway S, Schofield PR, Sperling R, Tariot PN, Xiong C, Morris JC, Bateman RJ, Dominantly Inherited Alzheimer Network. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology. 2014 Jul 15;83(3):253-60. Epub 2014 Jun 13 PubMed.
Piaceri I, Chiari A, Galli C, Bagnoli S, Ferrari C, Saavedra ST, Molinari MA, Vinceti G, Sorbi S, Nacmias B. Incomplete penetrance in familial Alzheimer's disease with PSEN1 Ala260Gly mutation. Neurol Sci. 2020 Aug;41(8):2263-2266. Epub 2020 Apr 23 PubMed.
Schultz S, Liu L, Schultz A, Fitzpatrick C, Levin R, Bellier J-P, Shirzadi Z, Mathurin N, Chen C, Benzinger T, Day G, Farlow M, Gordon B, Hassenstab J, Jack C, Jucker M, Karch C, Lee J, Levin J, Perrin R, Schofield P, Xiong C, Johnson K, McDade E, Bateman R, Sperling R, Selkoe D, Chhatwal J, theDominantlyInheritedAlzheimer'sNetworkInvestigators. Functional variations in gamma-secretase activity are critical determinants of the clinical, biomarker, and cognitive progression of autosomal dominant Alzheimer's disease. 2023 Jul 25 10.1101/2023.07.04.547688 (version 2) bioRxiv.
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.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

Mutations

PSEN1 A260G

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