2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Accelerating novel gene discovery utilizing a constraint-based method on exome sequencing data of 23,670 patients

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Researchers from 3billion, Inc in South Korea have developed a constraint-based method to accelerate the discovery of novel genes from exome sequencing data. They focused on predicted loss-of-function (LoF) variants in a dataset of 1.5 billion variants from 23,670 patients with various phenotypes. The study aimed to overcome the bottleneck of the diagnostic odyssey caused by the lack of gene-disease association.<br /><br />The researchers dumped all internal variants into a MySQL database to optimize the search query. They then performed several filtering steps to select rare variants based on the disease inheritance pattern. For potential autosomal dominant genes, they selected variants with gnomAD pLI > 0.8, gnomAD allele count < 2, and in-house allele count < 10. For potential autosomal recessive or X-linked genes, they chose variants with gnomAD allele frequency < 0.05 and in-house allele count < 40.<br /><br />The next step involved removing variants confirmed as in-cis relationships with cis-trans phasing data for potential compound heterozygous variants. They then selected high-quality protein truncating variants (PTV) such as nonsense, frameshift, and essential splice site variants. Finally, they removed genes associated with a disease on OMIM/Orphanet and variants from samples already reported as diagnosed.<br /><br />In the results and discussion, the researchers found novel gene candidates using their discovery method. They also mentioned the importance of external collaboration, particularly for genes with n-of-1 cases or incomplete evidence.<br /><br />Overall, this study demonstrates a genotype-driven approach to accelerate the discovery of novel genes from exome sequencing data. The researchers provide detailed steps for variant selection and highlight the potential for external collaboration in identifying gene candidates. This method could contribute to the molecular diagnosis and discovery of novel genes for rare Mendelian diseases.

Asset Subtitle

Presenting Author - Won Chan Jeong, BS; Co-Author - Kisang Kwon, MS; Co-Author - Seung Woo Ryu, Ph.D.; Co-Author - Heonjong Han, Ph.D; Co-Author - Jungsul Lee, Ph.D.; Co-Author - Go Hun Seo, MD, Ph.D.; Co-Author - Hane Lee, Ph.D;

Meta Tag

Bioinformatics

Databases

Exome sequencing

Genetic Testing

Genotype-Phenotype Correlations

Identification of Disease Genes

Methodology

NextGen Sequencing

Variant Detection

Co-Author Kisang Kwon, MS

Co-Author Seung Woo Ryu, Ph.D.

Co-Author Heonjong Han, Ph.D

Co-Author Jungsul Lee, Ph.D.

Co-Author Go Hun Seo, MD, Ph.D.

Co-Author Hane Lee, Ph.D

Presenting Author Won Chan Jeong, BS

Keywords

3billion, Inc

South Korea

constraint-based method

novel genes

exome sequencing data

loss-of-function variants

diagnostic odyssey

gene-disease association

variant selection

rare Mendelian diseases