Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121557345 C>-
Position: (GRCh37/hg19):Chr11:121428054 C>-
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Deletion
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Exon 19

Findings

This single-nucleotide deletion results in a frame shift. It 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 was 50 years old at the time of symptom onset, and her APOE genotype is E3/E4. No additional carriers were found when the dataset was expanded to include 927 late-onset cases, 852 early onset cases, and 1273 controls from the Alzheimer Disease Exome Sequencing-France project (ADESFR) (Campion et al., 2019).

Subsequently, the pedigree of the French carrier was published (Schramm et al., 2022). One of her parents was also diagnosed with AD, with symptom onset at age 59 but unknown genotype. Two siblings, unaffected at ages 63 (APOE E3/E3) and 70 years (APOE E3/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).

Functional Consequences

This deletion, resulting in a frame shift, is predicted to be protein truncating.

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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. 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.
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. 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