Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS4, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73173583 C>T
Position: (GRCh37/hg19):Chr14:73640291 C>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ACA to ATA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 5

Findings

This variant has been identified in two kindreds and three individual patients with Alzheimer’s disease (AD). Reported symptoms include cognitive decline typical of AD, as well as psychological and behavioral abnormalities.

The mutation was first reported in a Korean individual with early onset AD (Bagyinszky et al., 2016). It was subsequently identified and characterized in an Argentine family of Italian descent, spanning four generations, with 13 individuals affected by autosomal dominant AD (Itzcovich et al., 2019). Age of onset varied widely (49-71), with a median of 56. The mutation was present in the proband, an affected cousin, and a sibling whose neuropsychological profile was unavailable. It was absent from three of the proband’s children who had no cognitive complaints, but had yet to reach the median age of onset (43 to 54 years old). 

The mutation was also found in a Chinese kindred spanning four generations, including eight affected individuals (Zhang et al., 2020). In this case, the variant was identified by whole-genome sequencing followed by successive variant filtering, with a final focus on 106 dementia-associated genes. Two affected members were genotyped and found to carry the mutation. Age of onset in this family was late, with dementia surfacing when patients were in their late 60s or early 70s. Of note, psycho-behavioral symptoms were prominent. The proband, for example, presented with apathy, social withdrawal, verbal aggression, and irritability, in addition to memory loss, at age 68. At 72, her memory suddenly worsened and she began having hallucinations and delusions. Other affected family members also developed hallucinations and delusions, in addition to memory impairment. The authors described the disorder as “a frontal variant of AD.”

The mutation was also reported in two additional Korean individuals with early onset AD. The original Korean patient had no known family history of the disease and may be a de novo mutation (Giau et al., 2019; Bagyinszky et al., 2020). Memory loss was her first symptom, surfacing in her early 60s, followed by continued memory decline, language impairment, and personality changes. She was homozygous for the APOE 3 allele. Another Korean woman had a family history of AD and her symptoms, including memory impairment, visuospatial dysfunction, depression, and apathy, began at 50 years of age (Kim et al., 2020). The Korean man suffered from short-term memory impairment starting at 49 years of age, and developed language deficits (Bagyinszky et al., 2020). His mother was diagnosed with dementia. Of note, in addition to PSEN1 T119I, this patient carried a SORL1 variant previously associated with AD (R528T), as well as rare variants in the ABCA7 (V1729M) and SORL1 (N828S and G1524R) genes.

The PSEN1 T119I mutation was absent from several variant databases, including gnomAD, Exome Variant Server,  ExAC, KRGDB, and 1000 Genomes.

Neuropathology
Post-mortem neuropathological data are unavailable. However, PiB-PET revealed amyloid deposition in frontal, parietal, and temporal cortices in three cases, with two also including the precuneus and posterior cingulate, and one including the striatum (Itzcovich et al., 2019; Zhang et al., 2020; Bagyinszky et al., 2020). In addition, PET-FDG demonstrated mild bilateral hypometabolism in the parietal lobe, precuneus, anterior cingulate, dorsal frontal lobe, and lateral temporal lobe with left predominance in one patient. In addition, bilateral hypometabolism in parietal and/or temporal cortices was observed in another two (Giau et al., 2019; Kim et al., 2020). Brain MRI scans of two patients revealed mild hippocampal atrophy. One of the latter also had frontal and temporal atrophy (Kim et al., 2020; Zhang et al., 2020). Another patient had bilateral atrophy in the parietal cortex with minimal hippocampal damage (Bagyinszky et al., 2020). Interestingly, the Korean man carrying multiple gene variants had no detectable atrophy, but was PiB-PET positive. Amyloid β42 levels in cerebrospinal fluid were reduced in one mutation carrier, and phospho-tau levels were elevated in another (Itzcovich et al., 2019).

Biological Effect
In silico analyses yielded variable results, but overall suggested deleterious effects (Itzcovich et al., 2019; Giau et al., 2019; Kim et al., 2020; Zhang et al., 2020, Xiao et al., 2021). Itzcovich and colleagues reported the mutation to be possibly damaging (PolyPhen2) or damaging (SIFT), Giau et al.’s predictions included damaging (PolyPhen2), tolerated (SIFT), and neutral (Provean), Kim et al. reported the mutation was probably damaging (PolyPhen2) and tolerable (SIFT), and Zhang et al. found it was probably damaging (PANTHER and PolyPhen2), had a medium impact (Mutation Assessor), and was disease-causing (Mutation Taster). Moreover, Giau et al. reported the mutation is predicted to result in major helical torsion in the conserved HL-I loop, and Bagyinszky et al. reported increased hydrophobicity and bulkiness, with reduced polarity, based on ExPASY analysis (Bagyinszky et al., 2020). These effects were predicted to also affect nearby residues Y115 to E123, and a three-dimensional model predicted abnormal HL-1 orientation and altered intramolecular interactions. Furthermore, Zhang et al. noted a likely conformational effect based on cryo-electron microscopy structural data  (Zhou et al., 2019; Jan 2019 news). Giau also noted that other threonine to isoleucine substitutions in this loop are associated with aggressive AD phenotypes. Lastly, the CADD-PHRED score reported by Itzcovich et al. and Kim et al. was 24, suggesting it is in the top one percent of most deleterious variants in the genome. The site is evolutionarily conserved (GERP score = 4.74).

Following guidelines from the American College of Medical Genetics and Genomics (Richards et al., 2015), Itzcovich and colleagues classified the variant  as “likely pathogenic."

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.

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References

News Citations

1. CryoEM γ-Secretase Structures Nail APP, Notch Binding 11 Jan 2019

Paper Citations

1. Bagyinszky E, Park YH, Wang MJ, Park SY, Jang JW, Youn YC, An SS, Kim SY. Novel PSEN1 T119I mutation in an early-onset Alzheimer’s disease patient. Alzheimer Dement. J. Alzheimer Assoc. 2016
2. Itzcovich T, Chrem-Méndez P, Vázquez S, Barbieri-Kennedy M, Niikado M, Martinetto H, Allegri R, Sevlever G, Surace EI. A novel mutation in PSEN1 (p.T119I) in an Argentine family with early- and late-onset Alzheimer's disease. Neurobiol Aging. 2019 May 9; PubMed.
3. Zhang S, Li X, Zhang L, Meng X, Ma L, Zhang G, Wu H, Liang L, Cao M, Mei F. Identification of a Rare PSEN1 Mutation (Thr119Ile) in Late-Onset Alzheimer's Disease With Early Presentation of Behavioral Disturbance. Front Psychiatry. 2020;11:347. Epub 2020 May 14 PubMed.
4. Giau VV, Bagyinszky E, Yang YS, Youn YC, An SS, Kim SY. Genetic analyses of early-onset Alzheimer's disease using next generation sequencing. Sci Rep. 2019 Jun 10;9(1):8368. PubMed.
5. Bagyinszky E, Lee H, Pyun JM, Suh J, Kang MJ, Vo VG, An SS, Park KH, Kim S. Pathogenic PSEN1 Thr119Ile Mutation in Two Korean Patients with Early-Onset Alzheimer's Disease. Diagnostics (Basel). 2020 Jun 14;10(6) PubMed.
6. Kim YE, Cho H, Kim HJ, Na DL, Seo SW, Ki CS. PSEN1 variants in Korean patients with clinically suspicious early-onset familial Alzheimer's disease. Sci Rep. 2020 Feb 26;10(1):3480. PubMed.
7. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. 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.
8. Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
9. 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.

Further Reading