Mutations

PSEN1 R269H

Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PP2, PP3, BS1
Clinical Phenotype: Alzheimer's Disease, Cerebral Amyloid Angiopathy, Myoclonus
Position: (GRCh38/hg38):Chr14:73198067 G>A
Position: (GRCh37/hg19):Chr14:73664775 G>A
dbSNP ID: rs63750900
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGT to CAT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

This variant has been identified in multiple families and individuals of European and East Asian ancestries with Alzheimer's disease. Age at onset is variable, ranging from mid-40s to late 60s, with some carriers belonging to a cohort of late-onset AD (LOAD) cases. In the gnomAD variant database, the variant was reported at a global frequency of 0.0000093, including 15 heterozygotes (gnomAD v4.0.0, Jan 2024). Although most of these carriers (10) were of non-Finnish European ancestry, the variant's frequency was higher in other groups, with 3 carriers of African ancestry corresponding to an allele frequency of 0.000040 in that population.

R269H was first described in a Caucasian American man who developed memory impairment at the age of 46. He died after a nine-year course of progressive dementia and met CERAD criteria for AD. His clinical phenotype included visual and auditory hallucinations and myoclonus He did not have seizures or extrapyramidal signs. His APOE genotype was ε4/ε4. The patient’s father died at the age of 61 after a five-year history of dementia. There was no further family history of dementia and segregation with disease could not be assessed (Gómez-Isla et al., 1997).

Several additional Caucasian carriers were subsequently reported. For example, a U.K. family (Family 226) was identified with four affected individuals over three generations. The mean age of onset in this family was 53 years of age (range: 50 to 56). At least one member of this family had autopsy-confirmed AD (Janssen et al., 2003). Moreover, a second U.K. family was reported with nine affected individuals over three generations in a pattern consistent with autosomal-dominant transmission. The proband presented with forgetfulness at the age of 66 and was diagnosed with probable AD. He later developed prominent visual agnosia. His mother had been diagnosed with AD at the age of 67 and died two years later. She was one of seven sisters, five of whom were reported to have had AD, as had the maternal grandfather. At the age of 69, the proband’s sister also developed memory impairment consistent with AD. The proband was determined to carry the R269H mutation, but segregation with disease could not be assessed due to lack of DNA from family members (Larner et al., 2007).

The mutation was also identified in four patients from three U.K. families in a retrospective analysis of genotypic and phenotypic data from individuals with autosomal-dominant familial AD due to APP or PSEN1 mutations seen at the Dementia Research Centre in London (Ryan et al., 2016). Age at onset ranged from 50 to 62. One of two patients examined had behavioral alterations, and one of two had myoclonus. A previous report from the same group described a 59-year-old man with cognitive decline starting at age 58 (Ryan et al., 2012). The man presented with a pronounced dysexecutive syndrome, mild episodic memory impairment, and relative preservation of parietal lobe function. Finger myoclonus was also reported. The family history of disease was unknown.

Moreover, a French carrier with a family history of AD and onset at age 60 was also reported (Lanoiselée et al., 2017), as well as a Belgian carrier with AD onset before age 66 (Perrone et al., 2020).

Several carriers of East Asian ancestry have also been identified. The earliest report described two members of a Japanese family (Mat-1) who met NINCDS-ADRDA criteria for AD and had an average age at onset of 50 years (Kamimura et al., 1998). Subsequently, the mutation was found in a screen involving whole-exome sequencing of 15 unrelated Chinese patients with familial AD (Jiang et al., 2019). The proband presented with cognitive deficits typical of AD, without any atypical neurological features. In addition, a large cohort study from Southern China in which 14 genes associated with neurodegenerative dementias were sequenced identified two carriers with a family history of dementia and ages at onset of 45 and 60 years (Jiao et al., 2021). Symptoms included memory decline and, in one case, language impairment.

Of note, this variant was also reported in a preprint that analyzed data from the U.S.-based Alzheimer’s Disease Sequencing Project (ADSP), including whole-exome and whole-genome sequences from 13,825 late-onset AD cases and 14,715 controls. The variant was identified in four AD cases and was absent from controls (Wang et al., 2023, suppl table e-5).

Neuropathology

Postmortem analysis in the first mutation carrier showed a high burden of Aβ and neurofibrillary tangles in cortical areas compared with other cases of similar age and APOE genotype (Gómez-Isla et al., 1997). In another case, MRI revealed prominent cerebellar, parieto-occipital and temporal lobar microbleeds sufficient to fulfill criteria for probable cerebral amyloid angiopathy (Ryan et al., 2012). The authors hypothesized that the patient’s atypical phenotype, with early dysexecutive syndrome, could be related to this pathology. In addition, mild generalized volume loss, without predominance of medial temporal lobe atrophy, and moderate white matter disease were observed. MRI in another patient showed global brain atrophy and white-matter changes thought to be associated with the patient’s visual agnosia (Larner et al., 2007).

In another carrier, Aβ40, Aβ42, Aβ43, sAPPα, sAPPβ levels in cerebrospinal fluid (CSF) were found to be reduced, as was the Aβ42/Aβ40 ratio, while tau and phospho-tau levels were elevated (Perrone et al., 2020).

Biological Effect

This variant was found to  moderately decrease the Aβ (37 + 38 + 40) / (42 + 43) ratio in mouse embryonic fibroblasts expressing A431E on a PSEN null background and transduced with human APP-C99 (Petit et al., 2022; Apr 2022 news). Based on analyses of multiple PSEN mutants, this ratio was reported to outperform the Aβ42/Aβ40 ratio as an indicator of AD pathogenicity and correlated with AD age at onset. Moreover, a follow-up study reported in a preprint, combined the two ratios to yield a composite measure which reflects γ-secretase function as a percentage of wildtype activity (Schulz et al., 2023). This composite score (53.34 for R269H) was strongly associated, not only with age at onset, but with biomarker and cognitive trajectories.

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted it is damaging (Xiao et al., 2021). 

This variant has been classified as definitely pathogenic following the guidelines of Guerreiro et al. 2010 (Lanoiselée et al., 2017), deleterious following modified guidelines from Richards et al., 2015 (Koriath et al., 2018), and likely pathogenic following Richards et al., 2015 guidelines (Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Likely 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.

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.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

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.

BS1-S

Allele frequency is greater than expected for disorder. *Alzforum uses the gnomAD variant database.  R269H: Most carriers were of European ancestry, but allele frequency was higher in individuals of African ancestry.

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

Last Updated: 25 Jan 2024

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References

News Citations

  1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40?

Paper Citations

  1. . A novel presenilin-1 mutation: increased beta-amyloid and neurofibrillary changes. Ann Neurol. 1997 Jun;41(6):809-13. PubMed.
  2. . Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
  3. . The R269H mutation in presenilin-1 presenting as late-onset autosomal dominant Alzheimer's disease. J Neurol Sci. 2007 Jan 31;252(2):173-6. Epub 2006 Dec 26 PubMed.
  4. . Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. Lancet Neurol. 2016 Dec;15(13):1326-1335. Epub 2016 Oct 21 PubMed.
  5. . Cerebral microbleeds in familial Alzheimer's disease. Brain. 2011 Jun 17; PubMed.
  6. . APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med. 2017 Mar;14(3):e1002270. Epub 2017 Mar 28 PubMed.
  7. . Amyloid-β1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. Alzheimers Res Ther. 2020 Sep 11;12(1):108. PubMed.
  8. . Familial Alzheimer's disease genes in Japanese. J Neurol Sci. 1998 Sep 18;160(1):76-81. PubMed.
  9. . Mutation screening in Chinese patients with familial Alzheimer's disease by whole-exome sequencing. Neurobiol Aging. 2019 Apr;76:215.e15-215.e21. Epub 2018 Dec 6 PubMed.
  10. . The role of genetics in neurodegenerative dementia: a large cohort study in South China. NPJ Genom Med. 2021 Aug 13;6(1):69. PubMed.
  11. . Frequency of Variants in Mendelian Alzheimer's Disease Genes within the Alzheimer's Disease Sequencing Project (ADSP). 2023 Oct 25 10.1101/2023.10.24.23297227 (version 1) medRxiv.
  12. . Aβ profiles generated by Alzheimer's disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset. Mol Psychiatry. 2022 Jun;27(6):2821-2832. Epub 2022 Apr 1 PubMed.
  13. . Functional variations in gamma-secretase activity are critical determinants of the clinical, biomarker, and cognitive progression of autosomal dominant Alzheimer's disease. 2023 Jul 25 10.1101/2023.07.04.547688 (version 2) bioRxiv.
  14. . 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.
  15. . 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.
  16. . 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.
  17. . 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.

Further Reading

Papers

  1. . The impact of different presenilin 1 andpresenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain: evidence for other phenotype-modifying factors. Brain. 1999 Sep;122 ( Pt 9):1709-19. PubMed.
  2. . Genetic determinants of white matter hyperintensities and amyloid angiopathy in familial Alzheimer's disease. Neurobiol Aging. 2015 Dec;36(12):3140-3151. Epub 2015 Sep 4 PubMed.

Protein Diagram

Primary Papers

  1. . A novel presenilin-1 mutation: increased beta-amyloid and neurofibrillary changes. Ann Neurol. 1997 Jun;41(6):809-13. PubMed.

Other mutations at this position

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