Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121554082 G>A
Position: (GRCh37/hg19):Chr11:121424791 G>A
dbSNP ID: rs766534267
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Nonsense
Codon Change: TGG to TGA
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 17

Findings

This variant was identified in two families enrolled in the French National Reference Center for Young Alzheimer Patients (Centre National de Référence Malades Alzheimer Jeunes, CNR-MAJ) (Schramm et al., 2022).

In the first family, the proband (APOE genotype E3/E4) was diagnosed with probable AD with age of onset 63 years. An affected sibling—age of onset 74 years, APOE E3/E3—was also found to be a carrier of the variant. Two other siblings, cognitively intact at ages 65 and 69 years, respectively, do not carry the variant; both are APOE E3/E3. Genotype information was not available from another sibling, cognitively intact at age 72.

In the second family, genotype information was available only from the proband, who was diagnosed with probable AD with symptom onset at 64 years; their APOE genotype is E3/E4. One parent and the parent’s sibling were also diagnosed with AD, both with symptom onset at 60 years. A half-sibling of the proband was cognitively intact at age 50.

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

Functional Consequences

Introduces a premature stop codon.

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References

Paper Citations

1. 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.
2. 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

No Available Further Reading