Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PM4, PP1
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73171017_73171019 TCA>---
Position: (GRCh37/hg19):Chr14:73637725_ 73637727 TCA>---
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Deletion
Expected RNA Consequence: Deletion
Expected Protein Consequence: Deletion-Insertion
Codon Change: GTC to G--, AGC to -GC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This variant was found in a Brazilian family with a history of early onset dementia spanning three generations (Takada et al., 2022). The proband suffered from memory loss, difficulty finding words, and geographic disorientation which started at age 39. Cognitive impairment progressed and myoclonus developed, with seizures emerging in the last months before death at age 44. A sibling and two first-degree cousins were diagnosed with early onset Alzheimer’s disease.

Sequencing of the proband’s DNA revealed the deletion of three nucleotides resulting in an in-frame substitution of valine 103 and serine 104 with a glycine. The proband was homozygous for APOE3. The variant was also found in a symptomatic sibling and cousin, but not in an asymptomatic aunt who was over 60 years old, well past the mean age at onset of 37.8 years, suggesting co-segregation with disease.

The variant was absent from two large variant databases, gnomAD and the exome variant server.

Neuropathology
Neuropathological data are unavailable, but a year after symptom onset, a brain MRI of the proband revealed global atrophy, and FDG-PET showed hypometabolism in the posterior cingulate cortex, precuneus, and temporoparietal cortices (Takada et al., 2022).

Biological Effect
An assay using neuroblastoma N2A cells lacking endogenous presenilin genes and expressing the V103-S104delinsG mutation revealed an approximately 2.5-fold increase in the extracellular Aβ42/40 ratio compared with cells expressing wildtype PSEN1, although production of both peptides appeared to be reduced (Takada et al., 2022). Also of note, V103 is highly conserved between PSEN1 and PSEN2. The authors classified this variant as pathogenic based on the algorithm described by Hsu et al., 2018.

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-M

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. V103_S104delinsG: Aβ42/Aβ40 ratio increased, but production of both peptides decreased.

PM1-P

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. V103_S104delinsG: Variant located at edge of mutational hot spot.

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.

PM4-P

Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. V103_S104delinsG: Single amino acid loss.

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. V103_S104delinsG: At least one family with >=3 affected carriers and >=1 unaffected noncarriers.

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

Last Updated: 14 Dec 2022

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References

Paper Citations

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.
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.

Mutations

PSEN1 V103_S104delinsG

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