Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121566938 A>G
Position: (GRCh37/hg19):Chr11:121437647 A>G
dbSNP ID: NA
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected Protein Consequence: Deletion
Codon Change: to
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Intron 21

Findings

This mutation, an adenine to guanine substitution, occurs two nucleotides upstream of exon 22 and was shown to cause exon 22 skipping (Thonberg et al., 2017). The variant was identified in a family with early onset Alzheimer’s disease, where it segregated with disease—being present in three affected family members but absent in one unaffected individual, who died at age 92 without signs of AD.

The age of onset of symptoms was 54 years in the proband. This person’s parent and two of the parent’s siblings also developed dementia, with symptom onset occurring between 60 and 72 years. Initial symptoms included memory and visuospatial deficits, with early neuropsychiatric symptoms reported in three of the four cases. The family history of cognitive and neuropsychiatric symptoms extended at least to the proband’s grandparents’ generation.

Among the four family members who were genotyped, the three affected individuals were heterozygous for the mutation, and the one unaffected person was not a carrier. The proband, who had the earliest onset of symptoms, was homozygous for the E4 allele of APOE, while the other three genotyped individuals were APOE E3/E4.

The mutation is classified as “likely pathogenic” according to the criteria of the American College of Medical Genetics and Genomics (ACMG).

Functional Consequences

The A to G nucleotide switch was predicted to lead to the loss of a splice-acceptor site by splice-site prediction software (MaxEnt, NNSPLICE, and HumanSplicingFinder). To test this prediction, cDNA from an affected family member was analyzed, and two transcripts were indeed detected—one corresponding to wild-type mRNA and the other lacking exon 22. At the protein level, the mutation is expected to result in an in-frame deletion of amino acids 1017–1074, which would completely remove the epidermal growth factor-like domain of SORL1.

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References

Paper Citations

1. Thonberg H, Chiang HH, Lilius L, Forsell C, Lindström AK, Johansson C, Björkström J, Thordardottir S, Sleegers K, Van Broeckhoven C, Rönnbäck A, Graff C. Identification and description of three families with familial Alzheimer disease that segregate variants in the SORL1 gene. Acta Neuropathol Commun. 2017 Jun 9;5(1):43. PubMed.

Further Reading

No Available Further Reading