From cytogenetics to cytogenomics whole genome sequencing as a comprehensive genetic test in rare disease diagnostics

• Published in: EUROPEAN JOURNAL OF HUMAN GENETICS Vol. 27; p. 1666
• Main Authors: Nilsson, D., Eisfeldt, J., Lundin, J., Pettersson, M., Kvarnung, M., Lieden, A., Sahlin, E., Lagerstedt, K., Martin, M., Ygberg, S., Bjerin, O., Stranneheim, H., Wedell, A., Nordenskjold, M., Soller, M. Johansson, Nordgren, A., Wirta, Valtteri, Lindstrand, A.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: 2019
• Subjects: Medicin och hälsovetenskap
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/s41431-019-0494-2

Rare genetic diseases are caused by different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements. Recent data indicates that whole genome sequencing (WGS) may be used as a comprehensive test to identify multiple types of pathologic genetic aberrations in a single analysis. We present FindSV, a bioinformatic pipeline for detection of balanced (inversions and translocations) and unbalanced (deletions and duplications) structural variants (SVs). First, FindSV was tested on 106 validated deletions and duplications with a median size of 850 kb (min: 511 bp, max: 155 Mb). All variants were detected. Second, we demonstrated the clinical utility in 138 monogenic WGS panels. SV analysis yielded 11 diagnostic findings (8%). Remarkably, a complex structural rearrangement involving two clustered deletions disrupting SCN1A , SCN2A , and SCN3A was identified in a three months old girl with epileptic encephalopathy. Finally, 100 consecutive samples referred for clinical microarray were also analyzed by WGS. The WGS data was screened for large (>2 kbp) SVs genome wide, processed for visualization in our clinical routine arrayCGH workflow with the newly developed tool vcf2cytosure, and for exonic SVs and SNVs in a panel of 700 genes linked to intellectual disability. We also applied short tandem repeat (STR) expansion detection and discovered one pathologic expansion in ATXN7 . The diagnostic rate (29%) was doubled compared to clinical microarray (12%). In conclusion, using WGS we have detected a wide range of structural variation with high accuracy, confirming it a powerful comprehensive genetic test in a clinical diagnostic laboratory setting.