2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Clinical relevance of mosaic variants detected from exome sequencing data.

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In this study, the authors focused on detecting mosaic variants in genes associated with immune disorders. They utilized a specific mosaic variant calling method to identify these variants in blood samples from a primary immunodeficiency cohort undergoing research exome sequencing. By employing this method, they were able to identify clinically relevant variants that would not have been detected through a traditional germline variant analysis and reporting pipeline.<br /><br />The authors found that predicted loss of function variants in genes such as ASXL1, STAG2, and DNMT3A were more prevalent in patients with GATA2 deficiency, a type of autoimmune lymphoproliferative syndrome (ALPS). These findings indicate a potential link between these specific genetic variants and the development of GATA2 deficiency.<br /><br />The study involved a cohort of 2837 individuals who underwent research exome sequencing at the NIAID. Whole blood samples were used for DNA extraction, and variant calling was performed using the Lofreq2 method on an 85.6 Mb genomic region. Variants in regions with segmental duplications, decoy, and low complexity were filtered out, while those with a minor allele frequency of <0.001 in gnomAD, variant allele fraction <0.35, read depth >9, genotype quality >90, and a cohort frequency of <0.007 were retained.<br /><br />In the end, the authors identified a set of 145,955 candidate mosaic variants that had not been verified by orthogonal testing. They developed a somatic variant burden testing pipeline to further analyze these variants and assess their clinical relevance. Ongoing work involves validating the variants detected using orthogonal methods in corresponding cell types and understanding the clinical implications of somatic variants with uncertain significance.<br /><br />The implementation of the Lofreq2 method in this study highlights its ability to detect somatic variants that may be missed by traditional germline analysis pipelines. The authors also discuss the importance of extending this analysis to other patient cohorts with different inborn errors of immunity. Overall, the study contributes to the understanding of mosaic variants in immune disorders and their potential impact on disease development.

Asset Subtitle

Presenting Author - Rajarshi Ghosh, PhD, FACMG; Co-Author - Andrew J. Oler, PhD; Co-Author - Mark D. Rustad, PhD; Co-Author - Samuel Li, PhD; Co-Author - Jia Yan, MS, PhD, CGC; Co-Author - Morgan N. Similuk, ScM, CGC; Co-Author - Steven M. Holland, MD; Co-Author - Magdalena A. Walkiewicz-Yvon, PhD;

Meta Tag

Genetic Testing

Genome sequencing

Genomic Methodologies

Identification of Disease Genes

Oncogenesis

Sequencing

Variant Detection

Co-Author Andrew J. Oler, PhD

Co-Author Mark D. Rustad, PhD

Co-Author Samuel Li, PhD

Co-Author Jia Yan, MS, PhD, CGC

Co-Author Morgan N. Similuk, ScM, CGC

Co-Author Steven M. Holland, MD

Co-Author Magdalena A. Walkiewicz-Yvon, PhD

Presenting Author Rajarshi Ghosh, PhD, FACMG

Keywords

mosaic variants

immune disorders

genetic variants

primary immunodeficiency

research exome sequencing

variant calling method

GATA2 deficiency

somatic variants

Lofreq2 method

inborn errors of immunity