Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226888116 C>G
Position: (GRCh37/hg19):Chr1:227075817 C>G
dbSNP ID: rs775145486
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: TCT to TGT
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 7

Findings

This mutation was identified in an Italian kindred. The proband developed insidious memory loss at age 60, followed by progressive dementia and the diagnosis of probable Alzheimer's disease. There was a family history of dementia; the proband's mother had experienced dementia at age 60, and two of the mother's siblings had memory disturbances before the age of 65. The proband had two affected siblings who also carried the mutation. For the three siblings, the mean age of onset was 63 years.  In addition to progressive memory decline, the clinical course in the siblings was characterized by mood changes (primarily depression and apathy), and the proband experienced extrapyramidal signs, namely rigidity and bradykinesia. The mode of inheritance was consistent with autosomal-dominant transmission with high penetrance. The mutation was absent in 247 unrelated individuals (117 healthy controls and 130 individuals with AD) (Piscopo et al., 2010).

The mutation is found in the gnomAD variant database with a single allele count and a frequency of 0.000004805 (gnomAD v2.1.1 (non-neuro), Apr 2021).

Neuropathology

Unknown. MRI of the proband's brain showed focal atrophy in the medial temporal lobe; SPECT showed bilateral hypoperfusion in temporoparietal regions (Piscopo et al., 2010).

Biological Effect

Unknown. This mutation leads to a substitution of an evolutionarily conserved residue in the third transmembrane domain of PSEN2. In silico algorithms have predicted it is probably damaging (Polyphen) and deleterious (SIFT) (gnomAD v2.1.1 (non-neuro), Apr 2021) and, consistently, its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (CADD v.1.6, Nov 2021). The authors classified it as "definitely pathogenic" following the guidelines of Guerriero and colleagues (Guerreiro et al., 2010), however, their co-segregation assessment did not include genetic analysis of at least one non-affected family member to confirm that the mutation was present only in affected members. 

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: it was found in a single affected family without clear evidence of cosegregation or a functional effect, and it 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. Piscopo P, Talarico G, Crestini A, Gasparini M, Malvezzi-Campeggi L, Piacentini E, Lenzi GL, Bruno G, Confaloni A. A novel mutation in the predicted TMIII domain of the PSEN2 gene in an Italian pedigree with atypical Alzheimer's disease. J Alzheimers Dis. 2010;20(1):43-7. 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.

External Citations

1. gnomAD v2.1.1 (non-neuro), Apr 2021
2. gnomAD v2.1.1 (non-neuro), Apr 2021

Further Reading