Abstract Details

Title Novel Stop-gain SORL1 Mutation in a Peruvian Family with Alzheimer's Disease of the PeADI Study

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P6 - Poster Session 6 (8:00 AM-9:00 AM)

Poster/Presentation
Number 9-017

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.

Authors/Disclosures
Mario R. Cornejo Olivas, MD (INSTITUTO NACIONAL DE CIENCIAS NEUROLOGICAS) PRESENTER	Dr. Cornejo Olivas has received research support from UNIVERSIDAD CIENTIFICA DEL SUR. The institution of Dr. Cornejo Olivas has received research support from CHDI. The institution of Dr. Cornejo Olivas has received research support from NIH. The institution of Dr. Cornejo Olivas has received research support from GP2/ASAP/MJFF. Dr. Cornejo Olivas has a non-compensated relationship as a Secretary elect with MDS-PAS that is relevant to AAN interests or activities.
Anthony J. Griswold, PhD (University of Miami)	Dr. Griswold has received research support from National Institutes of Health.
Ana Saldarriaga-Mayo (Universidad Científica del Sur)	Ana Saldarriaga-Mayo has nothing to disclose.
Pedro Mena (University of Miami)	Pedro Mena has nothing to disclose.
Richard S. Rodriguez (Neurogenetics Research Center, Instituto Nacional de Ciencias Neurológicas, Lima)	No disclosure on file
Larry Adams	No disclosure on file
Patrice Whitehead	No disclosure on file
Rosario Isasi (Dpt Human Genetics University of Miami Miller School of Medicine)	No disclosure on file
Maryenela Z. Illanes-Manrique, MD, Atlantic Fellow (Instituto Nacional de Ciencias Neurologicas)	The institution of Dr. Illanes-Manrique has received research support from GLOBAL BRAIN HEALTH INSTITUTE.
Elison Sarapura-Castro, MD (Instituto Nacional De Ciencias Neurologicas)	Dr. Sarapura-Castro has nothing to disclose.
Farid Rajabli, PhD (University of Miami)	Farid Rajabli has nothing to disclose.
Katalina McInerney (Fellow, Division of Movement Disorders)	Katalina McInerney has nothing to disclose.
Karina Milla-Neyra (Instituto Nacional De Ciencias Neurologicas)	No disclosure on file
Carla Manrique Enciso (INCN)	No disclosure on file
Gary W. Beecham, PhD (University of Miami, Hussman Institute for Human Genomics)	The institution of Dr. Beecham has received research support from NIH. The institution of an immediate family member of Dr. Beecham has received research support from NIH.
Sheila C. Suarez, MD (Instituto Nacional De Ciencias Neurologicas)	Dr. Suarez has nothing to disclose.
Peter H. St George-Hyslop, MD, PhD (University of Toronto)	Dr. St George-Hyslop has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for TransitionBio. The institution of Dr. St George-Hyslop has received research support from NIH. Dr. St George-Hyslop has received intellectual property interests from a discovery or technology relating to health care.
Ismael Araujo-Aliaga (Instituto Nacional de Ciencias Neurologicas)	No disclosure on file
Michael L. Cuccaro	No disclosure on file
Jeffery Vance, MD, PhD (University of Miami)	Dr. Vance has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for neurology genetics.
Margaret A. Pericak-Vance, PhD (University of Miami Miller School of Medicine)	Dr. Pericak-Vance has nothing to disclose.

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