Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121558809_121558812 CGCA>----
Position: (GRCh37/hg19):Chr11:121429518_121429521 CGCA>----
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Deletion
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 20

Findings

This four-nucleotide deletion introduces a frameshift and a premature stop codon. A 52-year-old Alzheimer’s patient was found to be a heterozygous carrier in a Dutch cohort of 640 AD cases and 1268 controls (Holstege et al., 2017).

No additional carriers were found among 5198 AD cases and 4491 controls from the Alzheimer’s Disease Sequencing Project from whom whole-exome sequencing data were available, 1779 AD cases and 1273 controls from the Alzheimer Disease Exome Sequencing France project, 332 cases and 676 controls of European ancestry from the United Kingdom and North America (Campion et al., 2019), or 1256 cases and 1938 controls from the European Early Onset Dementia Consortium (Holstege et al., 2017).

The variant is classified as pathogenic by the criteria of Holstege et al., 2017 (Holstege et al., 2017).

Functional Consequences

Induced pluripotent stem cells (iPSCs) were generated from fibroblasts obtained from the H962Pfs mutation carrier and differentiated into neurons. Compared with iPSC-derived neurons from a control subject, cells from the mutation carrier expressed half the amount of SORL1 protein and exhibited enlarged endosomes (Hung et al., 2021).

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References

Paper Citations

1. Holstege H, van der Lee SJ, Hulsman M, Wong TH, van Rooij JG, Weiss M, Louwersheimer E, Wolters FJ, Amin N, Uitterlinden AG, Hofman A, Ikram MA, van Swieten JC, Meijers-Heijboer H, van der Flier WM, Reinders MJ, van Duijn CM, Scheltens P. Characterization of pathogenic SORL1 genetic variants for association with Alzheimer's disease: a clinical interpretation strategy. Eur J Hum Genet. 2017 Aug;25(8):973-981. Epub 2017 May 24 PubMed.
2. Campion D, Charbonnier C, Nicolas G. SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data. Acta Neuropathol. 2019 Aug;138(2):173-186. Epub 2019 Mar 25 PubMed.
3. Hung C, Tuck E, Stubbs V, van der Lee SJ, Aalfs C, van Spaendonk R, Scheltens P, Hardy J, Holstege H, Livesey FJ. SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network. Cell Rep. 2021 Jun 15;35(11):109259. PubMed.

Further Reading

No Available Further Reading