Overview

Pathogenicity: Alzheimer's Disease : Benign
ACMG/AMP Pathogenicity Criteria: PP3, BS1, BS2, BS3
Clinical Phenotype: Alzheimer's Disease, None
Position: (GRCh38/hg38):Chr1:226883747 C>T
Position: (GRCh37/hg19):Chr1:227071448 C>T
dbSNP ID: rs150400387
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to TGC
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 5

Findings

This variant has been reported in several patients with neurodegenerative disease, as well as in two healthy controls. It was first identified in one of 283 control subjects from an Alzheimer’s disease (AD) study in the Netherlands (Sleegers et al., 2004), and subsequently in a healthy first-degree relative of a patient with late-onset AD (Ertekin-Taner et al., 2008).

Carriers with degenerative disease include at least five individuals with AD and one with frontotemporal dementia. Most of the AD carriers had late-onset disease, including two Belgian patients (Brouwers et al., 2008; Perrone et al., 2020), a Caucasian individual (Sassi et al., 2014), and a Han Chinese man (Mao et al., 2021).

However, the variant was also reported in a 49-year-old Korean man diagnosed with probable early onset AD (Park et al., 2017; An et al., 2016). His symptoms included memory loss, personality changes including obsessive-compulsive behavior, and disorientation. He was tested for mutations in APP, PSEN1, PSEN2, PGRN, MAPT, and PRNP. He had no family history of dementia.

In one case, a European carrier with AD whose brother was also affected, age at onset was not reported (Sala Frigerio et al., 2015).

The variant was also identified in a genetic screen of 421 patients in the U.K. with early onset frontotemporal dementia (Koriath et al., 2018).

The variant was present in the gnomAD variant database at a frequency of 0.00022 and an allele count of 62 (gnomAD v2.1.1, Nov 2021). All carriers in gnomAD were heterozygotes, most of European ancestry (43).

Neuropathology

Neuropathological data are unavailable, but one carrier had reduced Aβ43 and Aβ42 levels in CSF, and increased Aβ40 levels, resulting in a decreased Aβ42/Aβ40 ratio (Perrone et al., 2020). This carrier also had decreased levels of sAPPα and sAPPβ. In another carrier, mild cortical atrophy was revealed by MRI, and SPECT showed hypoperfusion in the frontal, temporal, and limbic lobes (Park et al., 2017).

Biological Effect

As described above, this variant was associated with reduced Aβ43 and Aβ42, and increased Aβ40, levels in the CSF of one carrier (Perrone et al., 2020). However, Aβ40 and Aβ42 secretion were unaffected in an experimental assay using transfected mouse neuroblastoma cells (Hsu et al., 2020). In silico algorithms predicted the R62C substitution is possibly damaging (PolyPhen) or damaging (SIFT) or neutral (LRT), and R62 is conserved between PSEN1 and PSEN2 (Hsu et al., 2020; Sala Frigerio et al., 2015; Mao et al., 2021). Its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021). Moreover, structural prediction analyses suggested the variant may cause large conformational alterations (Park et al., 2017).

Hardy and colleagues classified the variant as likely benign (Sassi et al., 2014) and, similarly, Karch and colleagues classified it as not pathogenic (Hsu et al., 2020). However, Mead and co-workers considered it possibly deleterious, predicting it is most likely fully penetrant (Koriath et al., 2018).

Pathogenicity

Alzheimer's Disease : Benign

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. Sleegers K, Roks G, Theuns J, Aulchenko YS, Rademakers R, Cruts M, van Gool WA, Van Broeckhoven C, Heutink P, Oostra BA, van Swieten JC, van Duijn CM. Familial clustering and genetic risk for dementia in a genetically isolated Dutch population. Brain. 2004 Jul;127(Pt 7):1641-9. Epub 2004 May 6 PubMed.
2. Ertekin-Taner N, Younkin LH, Yager DM, Parfitt F, Baker MC, Asthana S, Hutton ML, Younkin SG, Graff-Radford NR. Plasma amyloid beta protein is elevated in late-onset Alzheimer disease families. Neurology. 2008 Feb 19;70(8):596-606. Epub 2007 Oct 3 PubMed.
3. Brouwers N, Sleegers K, Van Broeckhoven C. Molecular genetics of Alzheimer's disease: an update. Ann Med. 2008;40(8):562-83. PubMed.
4. Perrone F, Bjerke M, Hens E, Sieben A, Timmers M, De Roeck A, Vandenberghe R, Sleegers K, Martin JJ, De Deyn PP, Engelborghs S, van der Zee J, Van Broeckhoven C, Cacace R, BELNEU Consortium. Amyloid-β1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. Alzheimers Res Ther. 2020 Sep 11;12(1):108. PubMed.
5. Sassi C, Guerreiro R, Gibbs R, Ding J, Lupton MK, Troakes C, Al-Sarraj S, Niblock M, Gallo JM, Adnan J, Killick R, Brown KS, Medway C, Lord J, Turton J, Bras J, Alzheimer's Research UK Consortium, Morgan K, Powell JF, Singleton A, Hardy J. Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease. Neurobiol Aging. 2014 Dec;35(12):2881.e1-2881.e6. Epub 2014 Jun 16 PubMed.
6. Mao C, Li J, Dong L, Huang X, Lei D, Wang J, Chu S, Liu C, Peng B, Román GC, Cui L, Gao J. Clinical Phenotype and Mutation Spectrum of Alzheimer's Disease with Causative Genetic Mutation in a Chinese Cohort. Curr Alzheimer Res. 2021;18(3):265-272. PubMed.
7. Park KW, An SS, Bagyinszky E, Kim S. A case of possibly pathogenic PSEN2 R62C mutation in a patient with probable early-onset Alzheimer's dementia supported by structure prediction. Clin Interv Aging. 2017;12:367-375. Epub 2017 Feb 13 PubMed.
8. An SS, Park SA, Bagyinszky E, Bae SO, Kim YJ, Im JY, Park KW, Park KH, Kim EJ, Jeong JH, Kim JH, Han HJ, Choi SH, Kim S. A genetic screen of the mutations in the Korean patients with early-onset Alzheimer's disease. Clin Interv Aging. 2016;11:1817-1822. Epub 2016 Dec 15 PubMed.
9. Koriath C, Kenny J, Adamson G, Druyeh R, Taylor W, Beck J, Quinn L, Mok TH, Dimitriadis A, Norsworthy P, Bass N, Carter J, Walker Z, Kipps C, Coulthard E, Polke JM, Bernal-Quiros M, Denning N, Thomas R, Raybould R, Williams J, Mummery CJ, Wild EJ, Houlden H, Tabrizi SJ, Rossor MN, Hummerich H, Warren JD, Rowe JB, Rohrer JD, Schott JM, Fox NC, Collinge J, Mead S. Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Mol Psychiatry. 2018 Oct 2; PubMed.
10. Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, Goate AM, Karch CM. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020 Jun;139:104817. Epub 2020 Feb 19 PubMed.

Other Citations

1. Sala Frigerio et al., 2015

Further Reading

No Available Further Reading