Discovery and validation of dominantly inherited Alzheimer’s disease mutations in populations from Latin America
Year: 2022
Type: article
Study design: Observational Study
Abstract: BACKGROUND: In fewer than 1% of patients, AD is caused by autosomal dominant mutations in either the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes. The full extent of familial AD and frequency of these variants remains understudied in Latin American (LatAm) countries. Due to the rare nature of these variants, determining the pathogenicity of a novel variant in these genes can be challenging. Here, we use a systematic approach to assign the likelihood of pathogenicity in variants from densely affected families in Latin American populations. METHODS: Clinical data was collected from LatAm families at risk for DIAD. Symptomatic family members were identified and assessed by local clinicians and referred for genetic counseling and testing. To determine the likelihood of pathogenicity among variants of unknown significance from LatAm populations, we report pedigree information, frequency in control populations, in silico predictions, and cell-based models of amyloid-beta ratios. RESULTS: We identified five novel variants in the presenilin1 (PSEN1) gene from Brazilian and Mexican families. The mean age at onset in newly identified families was 43.5 years (range 36-54). PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, p.Ala275Thr, and p.Ile414Thr variants have not been reported in PubMed, ClinVar, and have not been reported in dominantly inherited AD (DIAD) families. We found that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr produce Aβ profiles consistent with known AD pathogenic mutations. PSEN1 p.Ile414Thr did not alter Aβ in a manner consistent with a known pathogenic mutation. CONCLUSIONS: Our study provides further insights into the genetics of AD in LatAm. Based on our findings, including clinical presentation, imaging, genetic, segregations studies, and cell-based analysis, we propose that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr are likely pathogenic variants resulting in DIAD, whereas PSEN1 p.Ile414Thr is likely a risk factor. This report is a step forward to improving the inclusion/engagement of LatAm families in research. Family discovery is of great relevance for the region, as new initiatives are underway to extend clinical trials and observational studies to families living with DIAD.
Source: Alzheimer s Research & Therapy
Authors: Leonel Tadao Takada, Carmen Aláez-Verson, Bhagyashri D. Burgute, Ricardo Nitrini, Ana Luisa Sosa, Raphael Machado Castilhos, Marcia Fagundes Chaves, Erika-Mariana Longoria, Karol Carrillo-Sánchez, Sonia Maria Dozzi Brucki, Luis Leonardo Flores-Lagunes, Carolina Molina, Marcos Jimenez Olivares, Ellen Ziegemeier, Jennifer Petranek, Alison M. Goate, Carlos Cruchaga, Alan E. Renton, Maria Victoria Fernández, Gregory S. Day, Eric McDade, Randall J. Bateman, Celeste M. Karch, Jorge J. Llibre-Guerra, for the Dominantly Inherited Alzheimer Network
Institutions: Universidade de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, National Institute of Genomic Medicine, Washington University in St. Louis, Instituto Nacional de Neurología y Neurocirugía, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Icahn School of Medicine at Mount Sinai, Mayo Clinic in Florida
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,590
OpenAlex ID: W4289889028