2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Application of ACMG/AMP variant classification guidelines to Alzheimer's disease-associated genetic variation

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The Dominantly Inherited Alzheimer Network (DIAN) is conducting clinical trials to test new therapies for autosomal dominant Alzheimer's disease (AD). A list of 220 trial-eligible genetic variants in three genes associated with AD has been curated by the DIAN clinical genetics committee. However, these variants have not been assessed using standardized variant classification guidelines. Therefore, the researchers developed adult-onset neurodegenerative disease-specific variant classification guidelines based on American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) evidence codes.<br /><br />The application of these guidelines to the DIAN trial-eligible variants showed that 90% of the variants classified as pathogenic or likely pathogenic, with 23 variants remaining as variants of uncertain significance (VUS). Four variants were upgraded to likely pathogenic using biomarker data collected by DIAN. The discordance in variant classification between DIAN and other databases highlights the need for refined ACMG/AMP guidelines for AD-associated variation. Collaboration and data sharing efforts among researchers and clinical genetics laboratories would benefit the field.<br /><br />The researchers also provided guidelines for allele frequency, computational prediction, segregation, protein consequence, and functional studies to assess the criteria for trial-eligible variant list inclusion. Of the 220 variants on the DIAN trial-eligible list, 78 were classified as pathogenic, 119 as likely pathogenic, and 23 as VUS according to the refined ACMG/AMP guidelines. Using AD biomarker data, four VUSs were upgraded to likely pathogenic. The classifications of the DIAN variants were compared to those in ALZFORUM and ClinVar databases, showing a 60% and 45% concordance rate, respectively. However, when the pathogenic and likely pathogenic categories were collapsed, the concordance rates increased to 84% and 83% respectively.<br /><br />In conclusion, the application of refined ACMG/AMP criteria to AD-associated genetic variants identified through the DIAN clinical trials suggests high clinical relevance. The discordance in classification highlights the need for collaboration and refinement of disease-specific ACMG/AMP guidelines for AD and other neurodegenerative disorders.

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Presenting Author - Alexa M. Dickson, PhD, MB (ASCP); Co-Author - Meagan M. Corliss, Master; Co-Author - Jonathan W. Heusel, MD, PhD; Co-Author - Ellen Ziegemeier, MA; Co-Author - Jorge J. Llibre-Guerra, MD; Co-Author - Alison M. Goate, Dphil; Co-Author - Carlos Cruchaga, PhD; Co-Author - Alan E. Renton, PhD; Co-Author - Celeste M. Karch, PhD; Co-Author - Victoria Fernandez Hernandez, PhD; Co-Author - Gregory S. Day, MD; Co-Author - Laura Courtney, BS; Co-Author - Eric McDade, DO; Co-Author - Randall J. Bateman, MD; Co-Author - Kevin M. Bowling;

Meta Tag

Brain/Nervous System

Databases

Genetic Testing

Methodology

Neuroscience

Co-Author Meagan M. Corliss, Master

Co-Author Jonathan W. Heusel, MD, PhD

Co-Author Ellen Ziegemeier, MA

Co-Author Jorge J. Llibre-Guerra, MD

Co-Author Alison M. Goate, Dphil

Co-Author Carlos Cruchaga, PhD

Co-Author Alan E. Renton, PhD

Co-Author Celeste M. Karch, PhD

Co-Author Victoria Fernandez Hernandez, PhD

Co-Author Gregory S. Day, MD

Co-Author Laura Courtney, BS

Co-Author Eric McDade, DO

Co-Author Randall J. Bateman, MD

Co-Author Kevin M. Bowling

Presenting Author Alexa M. Dickson, PhD, MB (ASCP)

Keywords

Dominantly Inherited Alzheimer Network

clinical trials

autosomal dominant Alzheimer's disease

genetic variants

AD-associated variation

variant classification

ACMG/AMP guidelines

DIAN trial-eligible variants

discordance in variant classification

neurodegenerative disorders