Limited Added Diagnostic Value of Whole Genome Sequencing in Genetic Testing of Inherited Retinal Diseases in a Swiss Patient Cohort

• Published in: International journal of molecular sciences 2024-06, Vol.25 (12), p.6540
• Main Authors: Maggi, Jordi, Koller, Samuel, Feil, Silke, Bachmann-Gagescu, Ruxandra, Gerth-Kahlert, Christina, Berger, Wolfgang
• Format: Article
• Language: English
• Subjects: added diagnostic value; Adolescent; Adult; Analysis; Child; Cohort Studies; Computational Biology - methods; diagnostic yield; Disease; DNA Copy Number Variations; DNA sequencing; Exome Sequencing - methods; Family medical history; Female; Genes; Genetic counseling; Genetic screening; Genetic testing; Genetic Testing - methods; Genomes; Genomics; Genotype & phenotype; Humans; Male; Medical tests; Middle Aged; molecular diagnostics; Nucleotide sequencing; Patients; Pedigree; Retinal diseases; Retinal Diseases - diagnosis; Retinal Diseases - genetics; Switzerland; whole exome sequencing (WES); whole genome sequencing (WGS); Whole Genome Sequencing - methods
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25126540

The purpose of this study was to assess the added diagnostic value of whole genome sequencing (WGS) for patients with inherited retinal diseases (IRDs) who remained undiagnosed after whole exome sequencing (WES). WGS was performed for index patients in 66 families. The datasets were analyzed according to GATK's guidelines. Additionally, DeepVariant was complemented by GATK's workflow, and a novel structural variant pipeline was developed. Overall, a molecular diagnosis was established in 19/66 (28.8%) index patients. Pathogenic deletions and one deep-intronic variant contributed to the diagnostic yield in 4/19 and 1/19 index patients, respectively. The remaining diagnoses (14/19) were attributed to exonic variants that were missed during WES analysis due to bioinformatic limitations, newly described loci, or unclear pathogenicity. The added diagnostic value of WGS equals 5/66 (9.6%) for our cohort, which is comparable to previous studies. This figure would decrease further to 1/66 (1.5%) with a standardized and reliable copy number variant workflow during WES analysis. Given the higher costs and limited added value, the implementation of WGS as a first-tier assay for inherited eye disorders in a diagnostic laboratory remains untimely. Instead, progress in bioinformatic tools and communication between diagnostic and clinical teams have the potential to ameliorate diagnostic yields.