Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121606859 C>T
Position: (GRCh37/hg19):Chr11:121477568 C>T
dbSNP ID: rs1482991048
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Nonsense
Codon Change: CGA to TGA
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 36

Findings

This protein-truncating variant was identified in a patient enrolled in the Centre National de Référence Malades Alzheimer Jeunes (CNR-MAJ), the French National Reference Center for Young Alzheimer Patients (Bellenguez et al., 2017; Schramm et al., 2022). The proband (APOE genotype E3/E3) was diagnosed with probable Alzheimer’s disease, with age of onset 53 years. There is a family history of AD: One of the proband’s parents and four of the parent’s siblings were also affected, with ages of onset ranging from 70 to 75 years. Genotype information was available from four family members in addition to the proband: A cousin cognitively intact at age 52 (APOE E4/E4) also carries the variant, while two cousins unaffected at ages 56 and 62 (both APOE E3/E3) and an affected aunt or uncle (age of onset, 70; APOE E3/E3) do not.

A second carrier of the R1655Ter variant was found in an American study of 6,965 AD cases and 13,232 controls from the Washington Heights-Inwood Community Aging Project (WHICAP), the Alzheimer’s Disease Sequencing Project (ADSP) and the Institute of Genomic Medicine at Columbia University (Raghavan et al., 2018). This carrier was described as a non-Hispanic white male.

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

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References

Paper Citations

1. 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.
2. 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.
3. Raghavan NS, Brickman AM, Andrews H, Manly JJ, Schupf N, Lantigua R, Wolock CJ, Kamalakaran S, Petrovski S, Tosto G, Vardarajan BN, Goldstein DB, Mayeux R, Alzheimer's Disease Sequencing Project. Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease. Ann Clin Transl Neurol. 2018 Jul;5(7):832-842. Epub 2018 May 24 PubMed.
4. 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.

Further Reading

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