Biallelic Loss of Function of SORL1 in an Early Onset Alzheimer’s Disease Patient

Article type: Research Article

Authors: Le Guennec, Kilan^a | Tubeuf, Hélène^b | Hannequin, Didier^c | Wallon, David^c | Quenez, Olivier^a | Rousseau, Stéphane^a | Richard, Anne-Claire^a | Deleuze, Jean-François^d | Boland, Anne^d | Frebourg, Thierry^b | Gaildrat, Pascaline^b | Campion, Dominique^{a; e} | Martins, Alexandra^b | Nicolas, Gaël^{a; *}

Affiliations: [a] Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and CNR-MAJ, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France | [b] Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France | [c] Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics, Department of Neurology and CNR-MAJ, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France | [d] Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Evry, France | [e] Department of Research, Rouvray Psychiatric Hospital, Sotteville-lès-Rouen, France

Correspondence: [*] Correspondence to: Gaël Nicolas, Department of Genetics, Rouen University Hospital, 1, rue de Germont, 76031 Rouen, France. Tel.: +33 235148280; Fax: +33 235148237; E-mail: gaelnicolas@hotmail.com.

Abstract: Heterozygous SORL1 protein truncating variants (PTV) are a strong risk factor for early-onset Alzheimer’s disease (EOAD). In case control studies performed at the genome-wide level, PTV definition is usually straightforward. Regarding splice site variants, only those affecting canonical sites are typically included. Some other variants, not annotated as PTV, could, however, affect splicing and hence result in a loss of SORL1 function. We took advantage of the whole exome sequencing data from the 9/484 patients with a previously reported SORL1 PTV in the French EOAD series and searched for a second variant which may affect splicing and eventually result in more than 50% loss of function overall. We found that one patient, known to carry a variant predicted to disrupt the canonical 5’ splice site of exon 8, also carried a second novel intronic variant predicted to affect SORL1 splicing of exon 29. Segregation analysis showed that the second variant was located in trans from the known PTV. We performed ex vivo minigene splicing assays and showed that both variants led to the generation of transcripts containing a premature stop codon. This is therefore the first evidence of a human carrying biallelic SORL1 PTV. This patient had a family history of dementia in both maternal and paternal lineages with later ages of onset than the proband himself. However, his 55 years age at onset was in the same ranges as previously published SORL1 heterozygous PTV carriers. This suggests that biallelic loss of SORL1 function is an extremely rare event that was not associated with a dramatically earlier age at onset than heterozygous SORL1 loss-of-function variant carriers, in this single patient.

Keywords: Compound heterozygous, early-onset Alzheimer’s disease, haploinsufficiency, knockout, recessive, SORL1

DOI: 10.3233/JAD-170981

Journal: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 821-831, 2018