Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121514323 T>G
Position: (GRCh37/hg19):Chr11:121385032 T>G
dbSNP ID: NA
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Intron 8

Findings

This intronic variant was found in a single Alzheimer’s patient in a study of 484 French early onset AD cases from the Centre National de Référence - Malades Alzheimer Jeunes (CNR-MAJ, the French national reference center for young Alzheimer’s patients) and 498 ethnically matched controls (Nicolas et al., 2016). Subsequently, the patient was found to carry two additional heterozygous variants in SORL1, in trans with c.1211+2T>G: a single-nucleotide insertion in intron 28 (c.3947-3insG) and a point mutation in exon 31 (c.4265A>G) (Le Guennec et al., 2018). Ex vivo splicing assays confirmed in silico predictions that both intronic variants affect splicing, generating aberrant transcripts containing premature stop codons (Le Guennec et al., 2018). (While the c.4265A>G variant would cause an arginine-to-serine substitution at amino acid 1422 [p.N1422S] in the absence of other changes in SORL1, it occurs downstream of the premature stop codons created by the c.3947-3insG variant.) Thus the two intronic variants occurring in trans in this patient are expected to result in a bi-allelic loss of function of SORL1.

A family history of dementia was reported (Le Guennec et al., 2018; Schramm et al., 2022). The patient’s mother, who died at age 91, was not able to live independently after age 78, although the age of symptom onset was not recorded. His father developed symptoms prior to age 70 and died at 76, and his paternal grandfather was also reported to have suffered from dementia, with symptom onset at 64. The patient himself developed symptoms at 55 years of age.

Archived blood from the patient’s mother was available for genotyping, and she was found to carry the c.3947-3insG and c.4265A>G mutations and to be homozygous for the E3 allele of APOE (Le Guennec et al., 2018). Although genotype data were not available from the father, paternal inheritance of the c.1211+2T>G SORL1 allele and an APOE E4 allele was inferred.

In a European-American cohort genotyped for variants reported by Nicolas et al., this variant was not seen in 217 sporadic early onset AD cases or 169 controls (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, this allele was observed once among the AD cases (Holstege et al., 2022).

Functional Consequences

The consequences of this variant were investigated through in silico predictions and ex vivo splicing assays (Le Guennec et al., 2018).

The variant is predicted to disrupt the canonical 5’ splice site of exon 8, causing exon skipping and a frameshift that introduces a premature stop codon. Two cryptic 5’ splice sites were also identified in silico, both of which would lead to premature stop codons.

A minigene splicing assay tested the effect of this variant in a cell-based system. A genomic fragment containing exon 8 and surrounding intronic sequences was amplified from the patient’s DNA and inserted into a plasmid used to transfect HeLa cells. This cell-based assay confirmed the in silico predictions: The c.1211+2T>G variant generated three aberrant transcripts, caused by exon skipping or the use of the cryptic splice sites. All three of these transcripts contain frameshifts that introduce premature stop codons. Should these transcripts escape nonsense-mediated decay and be translated, they would lead to proteins truncated within the VPS10P domain of SORL1—p.Glu348Valfs*5, created by total skipping of exon 8; p.Arg404Phefs*4, created when one of the cryptic splice sites caused the deletion of the last five nucleotides of exon 8; and p.Tyr405Glufs*28, created when the second cryptic splice site caused the insertion of the first 11 nucleotides of intron 8.

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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. Le Guennec K, Tubeuf H, Hannequin D, Wallon D, Quenez O, Rousseau S, Richard AC, Deleuze JF, Boland A, Frebourg T, Gaildrat P, Campion D, Martins A, Nicolas G. Biallelic Loss of Function of SORL1 in an Early Onset Alzheimer's Disease Patient. J Alzheimers Dis. 2018;62(2):821-831. 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.
5. 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