2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Complete Resolution of Genes with Highly Homologous Gene Family Members or Pseudogenes Using Long-read PacBio HiFi Sequencing

Complete Resolution of Genes with Highly Homologous Gene Family Members or Pseudogenes Using Long-read PacBio HiFi Sequencing

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This document discusses the use of PacBio HiFi long-read sequencing to resolve genes with highly homologous gene family members or pseudogenes. Short read sequencing can struggle with accurately analyzing these challenging regions due to high sequence homology and frequent copy number variants. The authors developed an informatics method called Paraphase1, which accurately genotypes highly homologous genes, and applied it to resolve ten clinically relevant genes.<br /><br />The document provides detailed results for three genomic regions, including PMS2 (Lynch syndrome), SMN1 (spinal muscular atrophy), and the RCCX module (C4A/B, CYP21A2, TNXB). For example, Paraphase resolved haplotypes of PMS2 and its pseudogene PMS2CL, showing gene conversion patterns. In the case of SMN1, Paraphase identified haplotypes and determined copy numbers, enabling the identification of standard carriers and calling pathogenic variants. <br /><br />The authors also highlight that Paraphase can be used for other clinically important genes, such as STRC, IKBKG, NCF1, NEB, F8, and CFC1, and is being extended to a generalized genome-wide caller for paralogs.<br /><br />Additionally, the document discusses the identification of copy number variants and pathogenic variants resulting from gene conversion in the RCCX module. It also analyzes the frequency of CNVs and pathogenic variants in CYP21A2 across different populations.<br /><br />Overall, Paraphase provides a comprehensive framework for resolving highly homologous genes and has the potential to improve the accuracy and understanding of these challenging genomic regions.

Asset Subtitle

Presenting Author - Xiao Chen, PhD; Co-Author - Michael A. Eberle, PhD;

Meta Tag

Bioinformatics

Genetic Testing

Genome sequencing

Genomic Methodologies

Genomic Structure

Population Genetics

Sequencing

Co-Author Michael A. Eberle, PhD

Presenting Author Xiao Chen, PhD

Keywords

PacBio HiFi

homologous genes

Paraphase1

clinically relevant genes

PMS2

SMN1

RCCX module

haplotypes

copy numbers

pathogenic variants