Overview

Pathogenicity: Dementia : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP2, PP3, BS3
Clinical Phenotype: Dementia
Position: (GRCh38/hg38):Chr14:73217237 T>C
Position: (GRCh37/hg19):Chr14:73683945 T>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATA to ACA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This variant was found in a Mexican family spanning four generations with six members affected by cognitive impairment (Takada et al., 2022). Mean age at onset was 54 or 59 years. The proband developed irritability and apathy at age 51, followed by progressive memory loss. Based on MMSE evaluations, dementia progressed from mild to moderate/severe within a year and a half. APOE genotype was APOE3/E4. Several family members, including one of the proband’s parents, developed progressive memory decline.

This variant was absent from 250 Mexican mestizo exomes and from both the gnomAD variant database and the exome variant server, and had not been reported in ClinVar as of December 2021.

Neuropathology
Neuropathological data are unavailable.

Biological Effect
An assay using neuroblastoma N2A cells lacking endogenous presenilin genes and expressing the I414T mutation suggested the mutation does not alter Aβ production in a damaging manner: the Aβ42/Aβ40 ratio was similar to cells expressing wildtype PSEN1, and both Aβ40 and Aβ42 levels were decreased (Takada et al., 2022).

I414 is highly conserved across species and between PSEN1 and PSEN2. Moreover, its PHRED-scaled CADD score (28.4), which integrates diverse information in silico, was above 20, suggesting a deleterious effect. The authors noted that two pathogenicity classification systems based on the ACMG guidelines classified this variant as likely pathogenic. However, based on the algorithm described by Hsu et al., 2018, the authors classified it as a likely risk factor.

Pathogenicity

Dementia : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum because data for either a pathogenic or benign classification are lacking: only one affected carrier with dementia has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database. In addition, AD diagnosis was unclear. 

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. Takada LT, Aláez-Verson C, Burgute BD, Nitrini R, Sosa AL, Castilhos RM, Chaves MF, Longoria EM, Carrillo-Sánchez K, Brucki SM, Flores-Lagunes LL, Molina C, Olivares MJ, Ziegemeier E, Petranek J, Goate AM, Cruchaga C, Renton AE, Fernández MV, Day GS, McDade E, Bateman RJ, Karch CM, Llibre-Guerra JJ, Dominantly Inherited Alzheimer Network. Discovery and validation of dominantly inherited Alzheimer's disease mutations in populations from Latin America. Alzheimers Res Ther. 2022 Aug 5;14(1):108. PubMed.
2. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.
3. Hsu S, Gordon BA, Hornbeck R, Norton JB, Levitch D, Louden A, Ziegemeier E, Laforce R Jr, Chhatwal J, Day GS, McDade E, Morris JC, Fagan AM, Benzinger TL, Goate AM, Cruchaga C, Bateman RJ, Dominantly Inherited Alzheimer Network (DIAN), Karch CM. Discovery and validation of autosomal dominant Alzheimer's disease mutations. Alzheimers Res Ther. 2018 Jul 18;10(1):67. PubMed.

External Citations

1. Takada et al., 2022

Further Reading

No Available Further Reading