Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121470017 A>G
Position: (GRCh37/hg19):Chr11:121340726 A>G
dbSNP ID: rs766916904
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: AAT to AGT
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 2

Findings

This variant was identified in a Chinese woman who developed behavioral and psychological symptoms of dementia at age 60 (Li et al., 2020). The patient was initially diagnosed with late-onset schizophrenia, but this diagnosis later was changed to Parkinson’s disease based on signs of bradykinesia and hypermyotonia. Longitudinal MRIs showed progressive frontotemporal atrophy, and FDG-PET revealed hypometabolism in the frontal cortex and caudate nucleus. A diagnosis of frontotemporal dementia was ruled out, as she did not display signs typical of behavioral variant frontotemporal dementia, semantic variant primary progressive aphasia, or non-fluent/agrammatic variant primary progressive aphasia. The patient did show impairments in episodic memory. Eventually, she was diagnosed with early onset Alzheimer’s disease.

The patient was found to be a heterozygous carrier of a mutation in SORL1, leading to an asparagine-to-serine substitution at amino acid 99. No mutations were found in an additional 52 genes associated with neurodegenerative diseases, including APP, GRN, MAPT, PSEN1, PSEN2, SNCA, TARDBP, and TREM2.

Subsequently, a second carrier was identified among a group of dementia patients seen at the Shanghai Mental Health Center (Sun et al., 2021). This carrier was clinically diagnosed with Alzheimer’s disease, with an age of onset of 55 years and a family history of AD. Her APOE genotype is E3/E4.

This variant is classified as of uncertain significance by the criteria of the American College of Medical Genetics and Genomics (Sun et al., 2021).

Functional Consequences

The N99S variant was predicted to be deleterious by PolyPhen-2 and Mutation Taster, but likely benign by M-CAP (Mendelian Clinically Applicable Pathogenicity) (Sun et al., 2021).

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References

Paper Citations

1. Li X, Xiong Z, Liu Y, Yuan Y, Deng J, Xiang W, Li Z. Case report of first-episode psychotic symptoms in a patient with early-onset Alzheimer's disease. BMC Psychiatry. 2020 Mar 17;20(1):128. PubMed.
2. Sun L, Zhang J, Su N, Zhang S, Yan F, Lin X, Yu J, Li W, Li X, Xiao S. Analysis of Genotype-Phenotype Correlations in Patients With Degenerative Dementia Through the Whole Exome Sequencing. Front Aging Neurosci. 2021;13:745407. Epub 2021 Oct 14 PubMed.

Further Reading

No Available Further Reading