Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121513057 C>T
Position: (GRCh37/hg19):Chr11:121383766 C>T
dbSNP ID: rs772110877
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Missense
Codon Change: CGG to TGG
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 7

Findings

In a study that included 15,808 Alzheimer’s cases and 16,097 control subjects from multiple European and American cohorts, this allele was observed once among the AD cases (Holstege et al., 2022).

The R332W variant was identified in one of 484 cases from the Centre National de Référence-Malades Alzheimer Jeunes (CNR-MAJ), the French National Reference Center for Young Alzheimer Patients, but none of 498 ethnically matched controls (Nicolas et al., 2016). The carrier’s age of onset was 60 years, and his APOE genotype is E3/E4. No additional carriers were found when this French cohort was expanded to 852 early onset AD cases, 927 late-onset cases, and 1,273 controls from the Alzheimer Disease Exome Sequencing France (ADESFR) project (Bellenguez et al., 2017). The CNR-MAJ and ADESFR datasets contributed to the 2022 study cited above.

Subsequently, additional information was published about the family of this carrier (Schramm et al., 2022). One of the proband’s parents was also diagnosed with dementia, with age of onset 70 years, as were two of this parent’s siblings (ages of onset 60 and 85 years) and one of their parents (age of onset 60 years). The proband has five surviving siblings, one of whom is also affected by AD, with age of onset 55 years. The other four siblings were unaffected at ages ranging from 54 to 69 years. Genotype information is available from these siblings: The affected individual also carries the R332W variant and is APOE E3/E4; the four unaffected siblings are all noncarriers of the R332W mutation and are APOE E3/E3.

An additional two carriers—one Swedish case and one Spanish case, with ages of onset 53 and 54 years—were found in a pan-European cohort of 1255 early onset AD cases and 1938 age-matched controls from the European Early Onset Dementia Consortium (Verheijen, et al., 2016). The Swedish carrier reported by Verheijen et al. was also reported by Thonberg et al. (Thonberg et al., 2017).

The R332W variant was not seen in a Dutch sample consisting of 640 AD cases and 1268 controls (Holstege et al., 2017). The cohorts comprising this sample also contributed to the 2022 study.

The variant was among 54 selected for genotyping in a North American cohort of 217 sporadic early onset AD cases and 169 controls. It was not found in this cohort. Nor was it found by whole- exome or genome sequencing of 875 familial late-onset AD cases and 328 controls in the same study (Fernández et al., 2016).

The R332W variant is classified as likely pathogenic by the criteria of Holstege et al. (Holstege et al., 2017) and of uncertain significance by the criteria of the American College of Medical Genetics and Genomics (Thonberg et al., 2017).

Functional Consequences

The R332W variant impaired maturation (glycosylation) and trafficking to the plasma membrane of SORL1 overexpressed in HEK293 cells (Rovelet-Lecrux et al., 2021). Defects in SORL1 maturation and cell-surface expression—with retention of the protein in the endoplasmic reticulum—were also observed when the variant was introduced into the endogenous SORL1 gene in human iPSCs. These changes in SORL1 localization were accompanied by increased release of Aβ.

The variant was predicted to be deleterious by SIFT, probably damaging by PolyPhen-2, and disease-causing by Mutation Taster (Nicolas et al., 2016).

Table

^aAllele frequencies as reported by study authors or calculated by Alzforum curators from data provided in the study, assuming heterozygosity if not explicitly stated in the paper.
^bThis carrier also reported in Nicolas et al., 2016; Schramm et al., 2022.
^cOne carrier (Swedish) also reported in Thonberg et al., 2017.

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References

Paper Citations

1. Holstege H, Hulsman M, Charbonnier C, Grenier-Boley B, Quenez O, Grozeva D, van Rooij JG, Sims R, Ahmad S, Amin N, Norsworthy PJ, Dols-Icardo O, Hummerich H, Kawalia A, Amouyel P, Beecham GW, Berr C, Bis JC, Boland A, Bossù P, Bouwman F, Bras J, Campion D, Cochran JN, Daniele A, Dartigues JF, Debette S, Deleuze JF, Denning N, DeStefano AL, Farrer LA, Fernández MV, Fox NC, Galimberti D, Genin E, Gille JJ, Le Guen Y, Guerreiro R, Haines JL, Holmes C, Ikram MA, Ikram MK, Jansen IE, Kraaij R, Lathrop M, Lemstra AW, Lleó A, Luckcuck L, Mannens MM, Marshall R, Martin ER, Masullo C, Mayeux R, Mecocci P, Meggy A, Mol MO, Morgan K, Myers RM, Nacmias B, Naj AC, Napolioni V, Pasquier F, Pastor P, Pericak-Vance MA, Raybould R, Redon R, Reinders MJ, Richard AC, Riedel-Heller SG, Rivadeneira F, Rousseau S, Ryan NS, Saad S, Sanchez-Juan P, Schellenberg GD, Scheltens P, Schott JM, Seripa D, Seshadri S, Sie D, Sistermans EA, Sorbi S, van Spaendonk R, Spalletta G, Tesi N, Tijms B, Uitterlinden AG, van der Lee SJ, Visser PJ, Wagner M, Wallon D, Wang LS, Zarea A, Clarimon J, van Swieten JC, Greicius MD, Yokoyama JS, Cruchaga C, Hardy J, Ramirez A, Mead S, van der Flier WM, van Duijn CM, Williams J, Nicolas G, Bellenguez C, Lambert JC. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease. Nat Genet. 2022 Dec;54(12):1786-1794. Epub 2022 Nov 21 PubMed.
2. Nicolas G, Charbonnier C, Wallon D, Quenez O, Bellenguez C, Grenier-Boley B, Rousseau S, Richard AC, Rovelet-Lecrux A, Le Guennec K, Bacq D, Garnier JG, Olaso R, Boland A, Meyer V, Deleuze JF, Amouyel P, Munter HM, Bourque G, Lathrop M, Frebourg T, Redon R, Letenneur L, Dartigues JF, Génin E, Lambert JC, Hannequin D, Campion D, CNR-MAJ collaborators. SORL1 rare variants: a major risk factor for familial early-onset Alzheimer's disease. Mol Psychiatry. 2016 Jun;21(6):831-6. Epub 2015 Aug 25 PubMed.
3. Bellenguez C, Charbonnier C, Grenier-Boley B, Quenez O, Le Guennec K, Nicolas G, Chauhan G, Wallon D, Rousseau S, Richard AC, Boland A, Bourque G, Munter HM, Olaso R, Meyer V, Rollin-Sillaire A, Pasquier F, Letenneur L, Redon R, Dartigues JF, Tzourio C, Frebourg T, Lathrop M, Deleuze JF, Hannequin D, Genin E, Amouyel P, Debette S, Lambert JC, Campion D, CNR MAJ collaborators. Contribution to Alzheimer's disease risk of rare variants in TREM2, SORL1, and ABCA7 in 1779 cases and 1273 controls. Neurobiol Aging. 2017 Nov;59:220.e1-220.e9. Epub 2017 Jul 14 PubMed.
4. Schramm C, Charbonnier C, Zaréa A, Lacour M, Wallon D, CNRMAJ collaborators, Boland A, Deleuze JF, Olaso R, ADES consortium, Alarcon F, Campion D, Nuel G, Nicolas G. Penetrance estimation of Alzheimer disease in SORL1 loss-of-function variant carriers using a family-based strategy and stratification by APOE genotypes. Genome Med. 2022 Jun 28;14(1):69. PubMed. Correction.
5. Verheijen J, Van den Bossche T, van der Zee J, Engelborghs S, Sanchez-Valle R, Lladó A, Graff C, Thonberg H, Pastor P, Ortega-Cubero S, Pastor MA, Benussi L, Ghidoni R, Binetti G, Clarimon J, Lleó A, Fortea J, de Mendonça A, Martins M, Grau-Rivera O, Gelpi E, Bettens K, Mateiu L, Dillen L, Cras P, De Deyn PP, Van Broeckhoven C, Sleegers K. A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer's disease. Acta Neuropathol. 2016 Aug;132(2):213-24. Epub 2016 Mar 30 PubMed.
6. 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.
7. 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.
8. Fernández MV, Black K, Carrell D, Saef B, Budde J, Deming Y, Howells B, Del-Aguila JL, Ma S, Bi C, Norton J, Chasse R, Morris J, Goate A, Cruchaga C, NIA-LOAD family study group, NCRAD. SORL1 variants across Alzheimer's disease European American cohorts. Eur J Hum Genet. 2016 Dec;24(12):1828-1830. Epub 2016 Sep 21 PubMed.
9. 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.
10. Rovelet-Lecrux A, Feuillette S, Miguel L, Schramm C, Pernet S, Quenez O, Ségalas-Milazzo I, Guilhaudis L, Rousseau S, Riou G, Frébourg T, Campion D, Nicolas G, Lecourtois M. Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease. Acta Neuropathol Commun. 2021 Dec 18;9(1):196. PubMed.

Further Reading

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