PSEN1 I168dup


Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PP3
Clinical Phenotype: Alzheimer's Disease, Myoclonus
Reference Assembly: GRCh37/hg19
Position: Chr14:73653584_73653585 --->ATA
Coding/Non-Coding: Coding
Mutation Type: Duplicaton
Codon Change: ATA to ATA.ATA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 6


This mutation was identified in two siblings from a family spanning three generations and including five affected members with early onset, rapidly progressing cognitive impairment consistent with Alzheimer’s disease (O’Connor et al., 2021). The variant was found after DNA testing using the MRC Dementia Gene Panel, which includes 17 dementia genes. No additional variants were identified. The absence of the mutation in unaffected family members was not established.

Both carriers developed progressive impairments in episodic memory and executive function with symptom onset at age 36 and death in their early 40s. However, one of them experienced a generalized tonic-clonic seizure as their first symptom. This carrier also had prominent myoclonus and pathologically brisk reflexes on one side. The siblings’ mother suffered from gradual cognitive decline starting at age 32, followed by dementia, and death at age 42. In addition, two maternal aunts developed dementia in their 40s and their maternal grandmother died at a “young” age of a suspected brain tumor.

The mutation was absent from several genetic variant databases, including the Genome Aggregation Database v2.1.1, the 1000 Genomes Project, and the Exome Variant Server. As noted by the authors, this low population frequency suggests the mutation may be fully penetrant.

Neuropathology of the individual who suffered a tonic-clonic seizure was consistent with AD, including generalized cerebral atrophy, numerous amyloid plaques, neurofibrillary tangles, and cerebral amyloid angiopathy. Three years before death, a brain MRI showed relatively well-preserved parenchymal volumes. However, their affected sibling’s MRI revealed generalized cerebral atrophy at the same time before death. An electroencephalogram of this carrier showed bilateral slowing of brain activity, most notably over the left temporal region.

Biological Effect
The biological effect of this mutation is unknown. Its position on the α-helical surface of PSEN1’s third transmembrane domain fits the helix rule for pathogenic mutations, and it was predicted to be deleterious/damaging by in silico algorithms PROVEAN and SIFT. Moreover, it is predicted to be among the top 1 percent of most deleterious substitutions in the genome based on its scaled CADD score of 20.2. However, I168 is not conserved between PSEN1 and PSEN2.

The authors note that, according to the pathogenicity guidelines put forth by Guerreiro and colleagues (Guerreiro et al., 2010), this mutation is likely to be pathogenic, but they caution that segregation data are limited. 


Alzheimer's Disease : 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: it was found in a single affected family without clear evidence of cosegregation or a functional effect, and it is absent, or very rare, in the gnomAD database.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.


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


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.


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)

Last Updated: 22 Feb 2022


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Paper Citations

  1. . A novel presenilin 1 duplication mutation (Ile168dup) causing Alzheimer's disease associated with myoclonus, seizures and pyramidal features. Neurobiol Aging. 2021 Jul;103:137.e1-137.e5. Epub 2021 Feb 5 PubMed.
  2. . Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . A novel presenilin 1 duplication mutation (Ile168dup) causing Alzheimer's disease associated with myoclonus, seizures and pyramidal features. Neurobiol Aging. 2021 Jul;103:137.e1-137.e5. Epub 2021 Feb 5 PubMed.

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