Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM2, PP1, BP4
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226895650 C>A
Position: (GRCh37/hg19):Chr1:227083351 C>A
dbSNP ID: rs537889666
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 13, 3'UTR

Findings

This variant, located in the 3’ untranslated region of the PSEN2 transcript, was reported in a pedigree from the Chinese Familial Alzheimer’s Disease Network (Pang et al., 2021, Jia et al., 2020). Five family members carrying the variant were diagnosed with AD with an age at onset between 52 and 55 years. In contrast, one member who was cognitively healthy at age 59 did not carry the variant, indicating cosegregation with disease. The mutation was also absent from four healthy spouses within the family, 100 controls, and 100 patients with sporadic AD.

The proband was a 58-year-old woman who began experiencing short-term memory loss at age 53. Two years after onset, her cognitive ability had declined, and she had language impairment, spatial disorientation, and personality changes. Her family history included five members with dementia spanning two generations.
One East Asian heterozygote was reported in the gnomAD variant database and the global frequency was 0.00003184 (v2.1.1, Oct 2021).

Neuropathology
Neuropathological data are unavailable, but an MRI scan of the proband’s brain revealed widening of the sulcus, fissure, and temporal horn, with decreased hippocampal volume (Pang et al., 2021). Also, FDG-PET showed hypometabolism in the bilateral frontal, parietal, and temporal lobes. Moreover, five affected carriers had cerebrospinal fluid levels of Aβ42, total tau, and phospho-tau consistent with AD.

Biological Effect
In vitro studies revealed this variant disrupts the interaction of the 3’UTR of PSEN2 with the micro RNA miR-183-5p, a suppressor of PSEN2 expression (Pang et al., 2021). Consistently, PSEN2 levels measured in cerebrospinal fluid were moderately increased in the affected members of the reported family compared with those of unrelated AD patients and healthy controls. These altered PSEN2 levels may result in an increased Aβ42/Aβ40 ratio, as suggested by experiments in cultured cells showing that applying a miR-183-5p inhibitor modestly increased the Aβ42/Aβ40 ratio and, conversely, applying a mimic of the miRNA decreased the ratio.

This variant’s PHRED-scaled CADD score, however, did not reach 20, a commonly used threshold to predict deleteriousness (CADD v.1.6, Oct 2021).

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-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. c.*71C>A: Assessment of effect on Aβ42/Aβ40 ratio was indirect.

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.

PP1-S

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease: *Alzforum requires at least one affected carrier and one unaffected non-carrier from the same family to fulfill this criterion. c.*71C>A: Family with >=3 affected carriers and >=1 unaffected noncarriers.

BP4-P

Multiple lines of computational evidence suggest no impact on 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 less than 20.

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

Last Updated: 22 Feb 2022

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References

Paper Citations

Pang Y, Li T, Wang Q, Qin W, Li Y, Wei Y, Jia L. A Rare Variation in the 3' Untranslated Region of the Presenilin 2 Gene Is Linked to Alzheimer's Disease. Mol Neurobiol. 2021 Sep;58(9):4337-4347. Epub 2021 May 19 PubMed.
Jia L, Fu Y, Shen L, Zhang H, Zhu M, Qiu Q, Wang Q, Yan X, Kong C, Hao J, Wei C, Tang Y, Qin W, Li Y, Wang F, Guo D, Zhou A, Zuo X, Yu Y, Li D, Zhao L, Jin H, Jia J. PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease. Alzheimers Dement. 2020 Jan;16(1):178-191. PubMed.

Mutations

PSEN2 c.*71C>A

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