2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Disease burden of DCM genes newly added to ACMG secondary findings via population genomic screening: Impact of <em>TTN</em> and <em>FLNC</em>

Pdf Summary

This study focused on the disease burden associated with dilated cardiomyopathy (DCM) genes, particularly titin (TTN) and filamin C (FLNC), which were recently added to the American College of Medical Genetics and Genomics (ACMG) Secondary Findings (SF) list. The researchers conducted a population genomic screening of participants in Geisinger's MyCode Community Health Initiative and identified individuals with pathogenic/likely pathogenic (P/LP) variants in these genes. They compared the demographics, diagnoses, and echocardiogram data of variant-positive participants to the rest of the MyCode cohort. <br /><br />The results showed that participants with P/LP variants in TTN and FLNC had an increased disease burden, consistent with previous studies. Truncating variants in TTN were not equally distributed across the gene, with the highest risk for DCM observed in the A-band. Furthermore, TTNtv in high percentage spliced in (PSI) exons in the I-band also showed increased disease risk. The addition of TTNtv to population genomic screening is expected to significantly increase results, highlighting the importance of identifying individuals at highest risk for disease.<br /><br />In terms of demographics, individuals with TTNtv were slightly younger and less likely to be of European ancestry compared to the rest of the MyCode cohort. The study also identified a few individuals with variants in other DCM genes (BAG3, RBM20, and TNNC1), most of whom had DCM or idiopathic cardiomyopathy.<br /><br />Overall, this study highlights the importance of considering TTN and FLNC variants in population genomic screening for the evaluation of disease burden, especially in relation to DCM. It emphasizes the need to identify those at highest risk for disease and suggests that further consideration should be given to the inclusion of other high PSI exons of TTN in genomic screening.

Asset Subtitle

Presenting Author - Melissa A. Kelly, MS, CGC; Co-Author - Eric D. Carruth, PhD; Co-Author - Juliann M. Savatt, MS, CGC; Co-Author - Christopher M. Haggerty, PhD; Co-Author - Natasha T. Strande, PhD;

Meta Tag

Cardiac/circulatory disorders

Genetic Testing

Genotype-Phenotype Correlations

Population Genetics

Risk Assessment

Co-Author Eric D. Carruth, PhD

Co-Author Juliann M. Savatt, MS, CGC

Co-Author Christopher M. Haggerty, PhD

Co-Author Natasha T. Strande, PhD

Presenting Author Melissa A. Kelly, MS, CGC

Keywords

dilated cardiomyopathy

TTN

FLNC

ACMG

population genomic screening

pathogenic variants

demographics

echocardiogram data

truncating variants

high PSI exons