Overview

Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr11:121589256_121589257 ->G
Position: (GRCh37/hg19):Chr11:121459965_121459966 ->G
dbSNP ID: NA
Coding/Non-Coding: Non-Coding
DNA Change: Insertion
Reference Isoform: SORL1 Isoform 1 (2214 aa)
Genomic Region: Intron 28

Findings

This variant—a single-nucleotide insertion in intron 28 (c.3947-3insG)—was identified in a French patient with early onset Alzheimer’s disease, in a cohort of 852 early onset AD cases, 927 late-onset cases and 1,273 controls from the Alzheimer Disease Exome Sequencing France (ADESFR) cohort (Bellenguez et al., 2017). Subsequently, this patient was found to carry three heterozygous mutations in SORL1: the c.3947-3insG variant, a point mutation in exon 31 (c.4265A>G) occurring in cis, and an in-trans point mutation (c.1211+2T>G) in intron 8 (Le Guennec et al., 2018). Both intronic variants affect splicing, generating aberrant transcripts containing premature stop codons. Thus, the two intronic variants occurring in trans in this patient are expected to result in a bi-allelic loss of function of SORL1 (see Functional Consequences below).

A family history of dementia was reported (Le Guennec et al., 2018; Schramm et al., 2022). The proband’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 proband himself developed symptoms at 55 years of age.

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

Functional Consequences

The consequences of the c.3947-3insG variant were investigated through in silico predictions and in vitro splicing assays (Le Guennec et al., 2018).

The variant was predicted to disrupt the canonical 3’ splice site of exon 29, causing exon skipping and the introduction of a premature stop codon at the aberrant exon 28/30 junction. A cryptic 3’ splice site, 43-44 nucleotides upstream of the natural 3’ site, was also identified in silico.

A minigene splicing assay tested the effect of this variant in a cell-based system. HeLa cells were transfected with a genomic fragment containing exon 29 and surrounding intronic sequences amplified from the patient’s DNA. Two aberrant transcripts were detected. Both retained the last 44 nucleotides of intron 28, the consequence of using of the cryptic 3’ splice site identified in silico, but one used the canonical 5’ splice site of exon 29 while the other was generated by a cryptic exonic 5’ splice site that caused the deletion of 109 nucleotides from exon 29. Should these transcripts escape nonsense-mediated decay and be translated, they would lead to a protein truncated at the beginning of the seventh of SORL1’s 11 complement-type repeat-domains (also called “LDLR-type A repeats”), p.Gln1317Trpfs*39.

It should be noted that, 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 is located downstream of the premature stop codons created by the c.3947-3insG variant.

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References

Paper Citations

1. 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.
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. 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

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