Overview

Pathogenicity: Alzheimer's Disease : Uncertain Significance, Frontotemporal Dementia : Not Classified
ACMG/AMP Pathogenicity Criteria: PP3, BS1
Clinical Phenotype: Alzheimer's Disease, Frontotemporal Dementia, Progressive Nonfluent Aphasia
Reference Assembly: GRCh37/hg19
Position: Chr1:227075798 C>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CAT to AAT
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 7

Findings

This mutation has been found in several individuals of East Asian ancestry. Its global frequency in the gnomAD variant database is relatively low (0.0001874), but all 53 heterozygote carriers reported are of East Asian ancestry, bringing the frequency in this population up to 0.002656 (gnomAD v2.1.1, Nov 2021).

The variant was first identified in two unrelated Chinese individuals, one affected by familial late-onset Alzheimer’s disease and the other by apparently sporadic frontotemporal dementia. Segregation with disease was not established (Shi et al., 2015). One mutation carrier experienced progressive memory loss starting at age 68. She met clinical criteria for probable AD. Her APOE genotype was E3/E4. Her brother developed dementia at age 64 and died at 66. The other mutation carrier had apparently sporadic FTD. At age 62, he developed behavioral changes and progressive language disturbance, including word-finding difficulty, nonfluent and sparse speech, and stuttering. His symptoms were consistent with Progressive Nonfluent Aphasia (PNFA), a subtype of primary progressive aphasia (PPA). In addition, he became withdrawn and apathetic, and later developed global cognitive impairment.

The mutation was subsequently found in a Chinese patient diagnosed with AD at age 59 (Xu et al., 2018), and a Korean woman with early onset AD who developed cognitive decline, memory problems, and language impairment starting at age 59 (Giau et al., 2018; Giau et al., 2019). 

Neuropathology

Unknown. Neuroimaging of one of the AD cases showed diffuse cortical atrophy, especially in the bilateral temporal lobe (Shi et al., 2015). FDG-PET showed hypometabolism in bilateral frontal lobe, lateral temporal lobe, parietal lobe, and insular cortex, in addition to the cingulate cortex, precuneus, and caudate nucleus. PIB-PET showed amyloid deposition in the bilateral frontal lobe, lateral temporal lobe, parietal lobe, cingulate cortex, and precuneus.

Neuroimaging in the mutation carrier with FTD showed mild symmetrical cerebral atrophy. FDG-PET showed hypometabolism in the left frontal cortex, anterior cingulate cortex, thalamus, and caudate nucleus. He was amyloid-negative by PiB-PET.

Biological Effect

The biological effects of this variant are unknown, but most in silico algorithms tested predicted a damaging effect (Xu et al., 2018, Giau et al., 2018) and, consistently, its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (CADD v.1.6, Nov 2021). Moreover, results of 3D in silico modelling predicted the substitution may cause helical torsion and  additional stress due to hydrophobic residues on the surface interacting with transmembrane domain III (Giau et al., 2018).

Pathogenicity

Alzheimer's Disease : Uncertain Significance

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. Shi Z, Wang Y, Liu S, Liu M, Liu S, Zhou Y, Wang J, Cai L, Huo YR, Gao S, Ji Y. Clinical and neuroimaging characterization of Chinese dementia patients with PSEN1 and PSEN2 mutations. Dement Geriatr Cogn Disord. 2015;39(1-2):32-40. Epub 2014 Oct 15 PubMed.
2. Xu Y, Liu X, Shen J, Tian W, Fang R, Li B, Ma J, Cao L, Chen S, Li G, Tang H. The Whole Exome Sequencing Clarifies the Genotype- Phenotype Correlations in Patients with Early-Onset Dementia. Aging Dis. 2018 Aug;9(4):696-705. PubMed.
3. Giau VV, Pyun JM, Bagyinszky E, An SS, Kim S. A pathogenic PSEN2 p.His169Asn mutation associated with early-onset Alzheimer's disease. Clin Interv Aging. 2018;13:1321-1329. Epub 2018 Jul 31 PubMed.
4. Giau VV, Bagyinszky E, Yang YS, Youn YC, An SS, Kim SY. Genetic analyses of early-onset Alzheimer's disease using next generation sequencing. Sci Rep. 2019 Jun 10;9(1):8368. PubMed.

Further Reading

No Available Further Reading