Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PM5, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr1:226888978 T>C
Position: (GRCh37/hg19):Chr1:227076679 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATG to ACG
Reference Isoform: PSEN2 Isoform 1 (448 aa)
Genomic Region: Exon 8

Findings

This variant has been reported in several Chinese individuals with Alzheimer’s disease. It was initially described in three reports published in 2021.

One report described a Han Chinese man diagnosed with posterior cortical atrophy, a clinical variant of sporadic early onset Alzheimer’s disease characterized by visual impairments (Li et al., 2021). The mutation was identified by whole-exome sequencing focusing on rare variants in 35 dementia-associated genes. The carrier developed progressive visual impairment and short-term memory loss at age 59. His initial symptoms were object agnosia, right-left confusion, and impaired episodic memory. His APOE genotype was APOE E3/E4.

Two Chinese women with AD were also found to carry this mutation (Jiao et al., 2021, Mao et al., 2021, Dong et al., 2022). One was from a large cohort study in South China in which 14 genes associated with neurodegenerative dementias from 1795 patients were sequenced (Jiao et al., 2021). Her age at onset was 50 years and her APOE genotype was APOE E3/E4. She had no known family history of AD. Memory impairment was the only clinical phenotype reported.

The other carrier, from the Peking Union Medical College Hospital (PUMCH) cohort in Beijing, presented with memory loss with an age at onset of 47 years (Mao et al., 2021). This carrier had a family history of dementia. A subsequent report from this same research group described a carrier who is likely the same individual: a woman from the PUMCH cohort with memory loss, dressing apraxia, visuospatial agraphia, dyscalculia, visual mislocalization, and disrupted sleep (Dong et al., 2022). Like the previously described carrier, her age at onset was 47-48 years and she also had a family history of cognitive impairment that included her mother, maternal uncle, and maternal aunt, all of whom developed cognitive deficits in their 70s. In addition, the descriptions of the MRI and biomarker findings for both probands (see Neuropathology below) were very similar.

An additional carrier with sporadic early onset AD was identified in a group of Han Chinese patients (Liu et al., 2022). The only symptom described in this case was progressive memory impairment.

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

Neuropathology
Neuropathological data are unavailable, but brain imaging information is available for two or three carriers. In the carrier with posterior cortical atrophy, brain MRI showed bilateral parietal and occipital cortex atrophy and brain 18F-FDG-PET suggested hypometabolism in parietal, temporal, and occipital cortices. Florbetapir F18 positron emission tomography (AV-45-PET) revealed extensive Aβ deposition (Li et al., 2021).

Another carrier also had brain atrophy, but only of the parietal lobe. This mutation carrier had cerebrospinal fluid (CSF) biomarker levels consistent with AD (Mao et al., 2021). Consistent with this carrier being the same individual as the one subsequently reported by Dong and colleagues, the more recent paper described left predominant parietal atrophy as revealed by MRI, as well as CSF markers consistent with AD (Dong et al., 2022).

Biological Effect
HEK293 cells transfected with APP carrying the Swedish mutation (APP/SW) and PSEN2 carrying the M239T variant generated more Aβ42 and had a greater Aβ42/Aβ40 ratio compared to cells transfected with APP/SW and wild-type PSEN2 (Dong et al., 2022).

Moreover, several in silico algorithms predicted it was damaging (Li et al., 2021, Mao et al., 2021, Dong et al., 2022) and its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, suggesting a deleterious effect (CADD v.1.6, Oct 2021). Li and colleagues classified this mutation as likely pathogenic.

Dong and colleagues classified this variant as pathogenic following the ACMG-AMP guidelines (Dong et al., 2022).

Pathogenicity

Alzheimer's Disease : 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.

PS4-M

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. M239T: The variant was reported in 3 or more unrelated patients with AD, and absent from controls.

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. M239T: Variant located in the predicted proteolytic active site.

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.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

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.

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

Research Models

A human induced pluripotent stem cell (iPSC) line has been generated from skin fibroblasts of an early onset AD carrier (Zhu et al., 2024).

Last Updated: 01 Jul 2024

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References

Mutations Citations

Paper Citations

Zhu W, Zhou J, Shang L, Zhou Y, Wang Q, Yu Y, Dong L, Mao C, Chu S, Jin W, Li J, Gao J. Generation and characterization of an iPS cell line (PUMCi006-A) from skin fibroblasts of a patient with an M239T mutation in PSEN2 gene. Stem Cell Res. 2024 Jun;77:103391. Epub 2024 Mar 14 PubMed.
Li XY, Cui Y, Jing D, Xie K, Zhong X, Kong Y, Wang Y, Chu M, Wang C, Wu L. Novel PSEN1 and PSEN2 Mutations Identified in Sporadic Early-onset Alzheimer Disease and Posterior Cortical Atrophy. Alzheimer Dis Assoc Disord. 2021 Jul-Sep 01;35(3):208-213. PubMed.
Jiao B, Liu H, Guo L, Xiao X, Liao X, Zhou Y, Weng L, Zhou L, Wang X, Jiang Y, Yang Q, Zhu Y, Zhou L, Zhang W, Wang J, Yan X, Li J, Tang B, Shen L. The role of genetics in neurodegenerative dementia: a large cohort study in South China. NPJ Genom Med. 2021 Aug 13;6(1):69. PubMed.
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.
Dong L, Liu C, Sha L, Mao C, Li J, Huang X, Wang J, Chu S, Peng B, Cui L, Xu Q, Gao J. PSEN2 Mutation Spectrum and Novel Functionally Validated Mutations in Alzheimer's Disease: Data from PUMCH Dementia Cohort. J Alzheimers Dis. 2022;87(4):1549-1556. PubMed.
Liu C, Cong L, Zhu M, Wang Y, Tang S, Han X, Zhang Q, Tian N, Liu K, Liang X, Fa W, Wang N, Hou T, Du Y. Screening for Genetic Mutations Associated with Early-Onset Alzheimer's Disease in Han Chinese. Curr Alzheimer Res. 2022;19(10):724-733. PubMed.

Mutations

PSEN2 M239T

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