2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Optimization of the Diagnostic Aid PhenoVar for the Interpretation of Rapid Whole Genome Sequencing Data in Newborns in Intensive Care

Optimization of the Diagnostic Aid PhenoVar for the Interpretation of Rapid Whole Genome Sequencing Data in Newborns in Intensive Care
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The study focuses on optimizing the diagnostic aid tool PhenoVar for the interpretation of rapid whole genome sequencing (rWGS) data in newborns in intensive care. Early diagnosis of rare genetic diseases in newborns is important for their management and quality of life. rWGS is a rapid technique that can detect various types of genetic variants, but the manual interpretation of these variants is challenging. PhenoVar is a phenotype-driven diagnostic aid that prioritizes genetic diseases based on the patient's phenotype and genotype. It has been validated for exome sequencing in patients with congenital anomalies. The optimization process of PhenoVar was performed on a cohort of 36 newborns diagnosed with trio whole genome sequencing. PhenoVar predictions were compared to known diagnoses, and if the known diagnosis was absent or not highly ranked, potential explanations were investigated to improve the algorithm. The results showed that PhenoVar was unable to rank nine diagnoses, including unanalyzed genetic alterations and no phenotypic matches in the patient's disease in the HPO database. Additionally, three diagnoses were not observed in the top three ranks due to prioritizing recessive diseases with single heterozygote pathogenic allele over autosomal dominant or X-linked diseases. To address these limitations, an improved version of PhenoVar called PhenoVar-dev was created. PhenoVar-dev considered disease onset as a phenotypic trait and improved the genotypic score calculations based on the heredity, combination of variations, and molecular mechanism. However, CNV and UPD remained reasons for diagnoses not found by PhenoVar-dev, and diagnoses caused by inherited variants in autosomal dominant diseases with incomplete penetrance were ranked lower. The study concluded that PhenoVar-dev outperformed the original version in neonates but further improvements, including CNV and UPD analysis, are needed. The validation of PhenoVar and PhenoVar-dev will be conducted on more than 750 rWGS trios through the PRAGMatIQ project.

Asset Subtitle

Presenting Author - Jonathan Cayouette, BSc; Co-Author - Philippe Thibault, MSc; Co-Author - Jacques L. Michaud, MD; Co-Author - Sebastien Levesque, MD, PhD;

Meta Tag

Bioinformatics

Genome sequencing

Co-Author Philippe Thibault, MSc

Co-Author Jacques L. Michaud, MD

Co-Author Sebastien Levesque, MD, PhD

Presenting Author Jonathan Cayouette, BSc

Keywords

diagnostic aid tool

PhenoVar

rapid whole genome sequencing

genetic diseases

early diagnosis

phenotype-driven diagnostic aid

exome sequencing

trio whole genome sequencing

known diagnoses

PhenoVar-dev