Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73640359 G>A
dbSNP ID: rs63751037
Coding/Non-Coding: Coding
Mutation Type: Point, Missense
Codon Change: GTC to ATC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This mutation was originally reported in a U.K. genetic screen of more than 3,000 samples of patients with dementia (Koriath et al., 2018). The carrier was a man diagnosed with AD who had one known relative with early onset dementia. Age at onset was 54 years. The mutation was absent from genetic variant databases, including ExAC, EVS, 1000G, and gnomAD.

The mutation was also found in a large cohort study in South China in which 14 genes associated with neurodegenerative dementias were sequenced in 1795 patients (Jiao et al., 2021). Two male mutation carriers, both diagnosed with AD, were identified with ages of onset of 54 and 52 years. Both had family histories of disease and homozygous APOE3 genotypes. Although both patients suffered from memory impairment, only one had language impairment and the other had mental and behavioral disturbances. Neither presented with sensory or movement dysfunction.

Neuropathology

Unknown

Biological Effect

The biological effect of this mutation is unknown. However, the affected site is highly conserved across species and in PSEN2. Based on their proposed pathogenicity algorithm, Koriath and colleagues classified the mutation as deleterious and Jiao and co-workers classified it as pathogenic or likely pathogenic.

Although some silico algorithms to predict the effects of this variant on protein function yielded conflicting results (Xiao et al., 2021), the CADD-PHRED tool, which integrates diverse information, gave it a high deleteriousness score above 20 (CADD v.1.6, Sep 2021).

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References

Paper Citations

1. 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.
2. 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.
3. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

External Citations

1. CADD v.1.6

Further Reading

No Available Further Reading