Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121545316 A> -
Position: (GRCh37/hg19):Chr11:121416025 A> -
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Deletion
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 14

Findings

This variant, a single-nucleotide deletion resulting in a frameshift, was identified in a single Alzheimer’s patient in a French cohort composed of 484 early onset Alzheimer’s cases and 498 controls (Nicolas et al., 2016). The carrier’s age of symptom onset was 60 years, and her APOE genotype was E4/E4. No additional carriers were found when the French dataset was expanded to include 927 late-onset AD cases, 852 early onset cases, and 1,273 controls (Bellenguez et al., 2017; Campion et al., 2019).

Subsequently, the pedigree of this carrier and genotype information from her descendants were reported (Schramm et al., 2022). A sibling of the proband was diagnosed with AD with symptom onset at 60 years of age, as was one of her parents (age of onset 58 years) and a grandparent (age of onset 60 years). Of the proband’s six children, unaffected at ages ranging from 53 to 70 years, three were genotyped: one carried the variant (unaffected at age 63, APOE E4/E4) and two did not (unaffected at ages 69 and 70, both APOE E2/E4). A grandchild of the proband (unaffected at age 48, APOE E4/E4) did not carry the variant.

This variant was among 54 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).

Note that Fernández et al. and Nicolas et al. refer to this variant as "p.(Gly646fs)."

Functional Consequences

This single-nucleotide deletion results in a frameshift.

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References

Paper Citations

1. 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.
2. 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.
3. 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.
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. 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.

Further Reading

No Available Further Reading