Novel Stop-gain SORL1 Mutation in a Peruvian Family with Alzheimer's Disease of the PeADI Study
Mario Cornejo Olivas1, Anthony J. Griswold2, Ana Saldarriaga-Mayo1, Pedro Mena2, Richard Rodriguez1, Larry Adams2, Patrice Whitehead2, Rosario Isasi2, Maryenela Illanes-Manrique1, Elison Sarapura-Castro1, Farid Rajabli2, Katalina McInerney2, Karina Milla-Neyra3, Carla Manrique Enciso3, Gary Beecham2, Sheila Castro-Suarez4, Peter St. George-Hyslop5, Ismael Araujo-Aliaga1, Michael L. Cuccaro2, Jeffery Vance2, Margaret Pericak-Vance2
1Neurogenetics Working Group, Universidad Cientifica del Sur, 2Dpt Human Genetics University of Miami Miller School of Medicine, University of Miami, 3Neurogenetics Research Center, 4CBI en Demencias y Enfermedades Desmielinizantes del Sistema Nervioso, Instituto Nacional de Ciencias Neurologicas, 5Dpt of Neurology, Columbia University
Objective:
SORL1 risk variants have been reported in both early-onset and late-onset AD. The aim of this abstract is to report a SORL1 AD-risk variant within a Peruvian AD family.
Background:
Common and rare variants in SORL1 have been associated with increased risk of Alzheimer's disease (AD). Since 2019, we run an international collaborative research initiative to ascertain a Peruvian cohort for Alzheimer’s disease and other related dementias for genetic studies (PeADI) .
Design/Methods:
A Peruvian family (4 AD cases and two mild cognitive impairment (MCI) was recruited through the Peruvian Alzheimer Disease Initiative (PeADI) study. All six family-member completed a full cognitive assessment and underwent whole genome sequencing. Variants within AD risk genes as determined by the ADSP Gene Verification Committee were prioritized and variant interpretation was performed according to ACMG recommendations.
Results:
We identified a SORL1 c.5019G>A (p.Trp1673Ter) variant in the four AD diagnosed siblings within this family. The two MCI cases did not carry the novel variant. The identified SORL1 variant corresponded to a heterozygous stop-gain variant in exon 36 replacing tryptophan by a stop codon at position 1673 of the SORL1 protein. In-silico analysis predicts this variant promotes nonsense-mediated mRNA decay. This variant has not been previously reported in databases including gnomAD, LOVD and ClinVar. This variant is classified as likely pathogenic according to ACMG.
Conclusions:
We report the first Peruvian AD family carrying a likely pathogenic stop-gain SORL1 variant. Further cosegregation and functional assays are required to establish the risk size of this variant for AD.