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
Reference Assembly: GRCh37/hg19
Position: 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.

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References

News Citations

1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40? 20 Apr 2022

Paper Citations

1. Gómez-Isla T, Wasco W, Pettingell WP, Gurubhagavatula S, Schmidt SD, Jondro PD, McNamara M, Rodes LA, DiBlasi T, Growdon WB, Seubert P, Schenk D, Growdon JH, Hyman BT, Tanzi RE. A novel presenilin-1 mutation: increased beta-amyloid and neurofibrillary changes. Ann Neurol. 1997 Jun;41(6):809-13. PubMed.
2. Janssen JC, Beck JA, Campbell TA, Dickinson A, Fox NC, Harvey RJ, Houlden H, Rossor MN, Collinge J. Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003 Jan 28;60(2):235-9. PubMed.
3. Larner AJ, Ray PS, Doran M. 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. Ryan NS, Nicholas JM, Weston PS, Liang Y, Lashley T, Guerreiro R, Adamson G, Kenny J, Beck J, Chavez-Gutierrez L, de Strooper B, Revesz T, Holton J, Mead S, Rossor MN, Fox NC. 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. Ryan NS, Bastos-Leite AJ, Rohrer JD, Werring DJ, Fox NC, Rossor MN, Schott JM. Cerebral microbleeds in familial Alzheimer's disease. Brain. 2011 Jun 17; PubMed.
6. Lanoiselée HM, Nicolas G, Wallon D, Rovelet-Lecrux A, Lacour M, Rousseau S, Richard AC, Pasquier F, Rollin-Sillaire A, Martinaud O, Quillard-Muraine M, de la Sayette V, Boutoleau-Bretonniere C, Etcharry-Bouyx F, Chauviré V, Sarazin M, le Ber I, Epelbaum S, Jonveaux T, Rouaud O, Ceccaldi M, Félician O, Godefroy O, Formaglio M, Croisile B, Auriacombe S, Chamard L, Vincent JL, Sauvée M, Marelli-Tosi C, Gabelle A, Ozsancak C, Pariente J, Paquet C, Hannequin D, Campion D, collaborators of the CNR-MAJ project. 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.
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10. 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.
11. Wang D, Scalici A, Wang Y, Lin H, Pitsillides A, Heard-Costa N, Cruchaga C, Ziegemeier E, Bis JC, Fornage M, Boerwinkle E, DeJager PL, Wijsman E, Dupuis J, Renton AE, Seshadri S, Goate AM, TheAlzheimer'sDiseaseSequencingProject, DeStefano AL, Peloso GM. 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. Petit D, Fernández SG, Zoltowska KM, Enzlein T, Ryan NS, O'Connor A, Szaruga M, Hill E, Vandenberghe R, Fox NC, Chávez-Gutiérrez L. 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. Schultz S, Liu L, Schultz A, Fitzpatrick C, Levin R, Bellier J-P, Shirzadi Z, Mathurin N, Chen C, Benzinger T, Day G, Farlow M, Gordon B, Hassenstab J, Jack C, Jucker M, Karch C, Lee J, Levin J, Perrin R, Schofield P, Xiong C, Johnson K, McDade E, Bateman R, Sperling R, Selkoe D, Chhatwal J, theDominantlyInheritedAlzheimer'sNetworkInvestigators. 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.
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Further Reading