Frontiers in Molecular Neuroscience 01 frontiersin.org TYPE Brief Research Report PUBLISHED 16 February 2023 DOI 10.3389/fnmol.2023.1104585 Co-occurring pathogenic variants in 6q27 associated with dementia spectrum disorders in a Peruvian family Karla Lucia F. Alvarez 1 , Jorge Alberto Aguilar-Pineda 1 , Michelle M. Ortiz-Manrique 1 , Marluve F. Paredes-Calderon 2 , Bryan C. Cardenas-Quispe 2 , Karin Jannet Vera-Lopez 1 , Luis D. Goyzueta-Mamani 1 , Miguel Angel Chavez-Fumagalli 1 , Gonzalo Davila-Del-Carpio 3 , Antero Peralta-Mestas 2 , Patricia L. Musolino 4,5 and Christian Lacks Lino Cardenas 6 * 1 Laboratory of Genomics and Neurovascular Diseases, Universidad Católica de Santa María, Arequipa, Peru, 2 Division of Neurology, Psychiatry and Radiology of the National Hospital ESSALUD-HNCASE, Arequipa, Peru, 3 Vicerrectorado de Investigación, Universidad Católica de Santa María, Arequipa, Peru, 4 Department of Neurology, Massachusetts General Hospital, Boston, MA, United States, 5 Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States, 6 Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, Boston, MA, United States Evidence suggests that there may be racial diferences in risk factors associated with the development of Alzheimer’s disease and related dementia (ADRD). We used whole-genome sequencing analysis and identifed a novel combination of three pathogenic variants in the heterozygous state (UNC93A: rs7739897 and WDR27: rs61740334; rs3800544) in a Peruvian family with a strong clinical history of ADRD. Notably, the combination of these variants was present in two generations of afected individuals but absent in healthy members of the family. In silico and in vitro studies have provided insights into the pathogenicity of these variants. These studies predict that the loss of function of the mutant UNC93A and WDR27 proteins induced dramatic changes in the global transcriptomic signature of brain cells, including neurons, astrocytes, and especially pericytes and vascular smooth muscle cells, indicating that the combination of these three variants may afect the neurovascular unit. In addition, known key molecular pathways associated with dementia spectrum disorders were enriched in brain cells with low levels of UNC93A and WDR27. Our fndings have thus identifed a genetic risk factor for familial dementia in a Peruvian family with an Amerindian ancestral background. KEYWORDS unbiased gene discovery, whole genome sequencing, family-specifc genetic factor, Amerindian ancestral background, Alzheimer’s disease 1. Introduction Neurological disorders are an important cause of disability and death around the world. Interestingly, Alzheimer’s disease, dementia, Parkinson’s disease, epilepsy, schizophrenia, and autism spectrum disorder share common anatomical alterations and cognitive defects (Kochunov et al., 2021). Certainly, Alzheimer’s disease is the main cause of dementia, contributes 50 to 75% of cases (Report, 2021), and can be presented in two forms as defned by age: early-onset Alzheimer’s disease (EOAD), which occurs before 65 years of age, and late-onset Alzheimer’s disease (LOAD), which is mostly present afer 65 years OPEN ACCESS EDITED BY Gal Bitan, University of California, Los Angeles, United States REVIEWED BY Xiaopu Zhou, Hong Kong University of Science and Technology, Hong Kong SAR, China Maria Bullido, Autonomous University of Madrid, Spain *CORRESPONDENCE Christian Lacks Lino Cardenas clinocardenas@mgh.harvard.edu SPECIALTY SECTION This article was submitted to Brain Disease Mechanisms, a section of the journal Frontiers in Molecular Neuroscience RECEIVED 21 November 2022 ACCEPTED 18 January 2023 PUBLISHED 16 February 2023 CITATION Alvarez KLF, Aguilar-Pineda JA, Ortiz-Manrique MM, Paredes-Calderon MF, Cardenas-Quispe BC, Vera-Lopez KJ, Goyzueta-Mamani LD, Chavez-Fumagalli MA, Davila-Del-Carpio G, Peralta-Mestas A, Musolino PL and Lino Cardenas CL (2023) Co-occurring pathogenic variants in 6q27 associated with dementia spectrum disorders in a Peruvian family. Front. Mol. Neurosci. 16:1104585. doi: 10.3389/fnmol.2023.1104585 COPYRIGHT © 2023 Alvarez, Aguilar-Pineda, Ortiz- Manrique, Paredes-Calderon, Cardenas- Quispe, Vera-Lopez, Goyzueta-Mamani, Chavez-Fumagalli, Davila-Del-Carpio, Peralta- Mestas, Musolino and Lino Cardenas. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.