Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121595687 C>A
Position: (GRCh37/hg19):Chr11:121466396 C>A
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected Protein Consequence: Nonsense
Codon Change: TGC to TGA
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 32

Findings

This protein-truncating variant was identified in a French early onset Alzheimer’s patient from the Centre National de Référence - Malades Alzheimer Jeunes (CNR-MAJ), the French national reference center for young Alzheimer patients (Pottier et al., 2012; Nicolas et al., 2016). The carrier—56 years old at symptom onset, APOE genotype E3/E4—had a family history consistent with an autosomal dominant pattern of inheritance, but she did not carry mutations in APP, PSEN1, or PSEN2. Subsequently, updated information was published about this family (Schramm et al., 2022): An affected sibling of the proband (age of onset 66 years, APOE E3/E3) and two other siblings unaffected at ages 66 and 69 years (both APOE E3/E3) all carried the C1478Ter variant. Two cousins of the proband—one affected (age of onset 68 years, APOE E3/E4) and one unaffected at 72 years (APOE E3/E3)—did not carry the mutation. The proband’s mother and one of her siblings (the parent of the genotyped cousins) were affected, with ages of onset 64 years and 80 years, respectively, but of unknown genotype.

The C1478Ter variant was not found in 1,500 controls of matched ancestry in the original study describing this variant (Pottier et al., 2012, 22472873). Nor were any additional carriers found among a group of 1,273 controls, 927 late-onset Alzheimer disease cases, and 852 early onset AD cases from the Alzheimer Disease Exome Sequencing France (ADESFR) project (Bellenguez et al., 2017).

This variant was selected for genotyping in a North American cohort of 217 early onset AD cases and 169 controls. The variant was not found in this cohort. Nor was it found by whole- exome or genome sequencing of 866 familial late-onset AD cases and 324 controls in the same study (Fernández et al., 2016).

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

Functional Consequences

Allele-specific expression was quantified in blood cells from the carrier of the C1478Ter variant (Pottier et al., 2012). There was a clear difference in expression between the wild-type and mutant alleles that was consistent with nonsense-mediated mRNA decay of the mutant transcript.

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References

Paper Citations

1. Pottier C, Hannequin D, Coutant S, Rovelet-Lecrux A, Wallon D, Rousseau S, Legallic S, Paquet C, Bombois S, Pariente J, Thomas-Anterion C, Michon A, Croisile B, Etcharry-Bouyx F, Berr C, Dartigues JF, Amouyel P, Dauchel H, Boutoleau-Bretonnière C, Thauvin C, Frebourg T, Lambert JC, Campion D. High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Mol Psychiatry. 2012 Apr 3; 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. 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.
4. 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.
5. 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.
6. 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