German Demidov, Steven Laurie, Annalaura Torella, Giulio Piluso, Marcello Scala, Manuela Morleo, Vincenzo Nigro, Holm Graessner, Siddharth Banka, Solve-RD consortium, Katja Lohmann, Stephan Ossowski
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Structural variant calling and clinical interpretation in 6224 unsolved rare disease exomes
Structural variants (SVs), including large deletions, duplications, inversions, translocations, and more complex events have the potential to disrupt gene function resulting in rare disease. Nevertheless, current pipelines and clinical decision support systems for exome sequencing (ES) tend to focus on small alterations such as single nucleotide variants (SNVs) and insertions-deletions shorter than 50 base pairs (indels). Additionally, detection and interpretation of large copy-number variants (CNVs) are frequently performed. However, detection of other types of SVs in ES data is hampered by the difficulty of identifying breakpoints in off-target (intergenic or intronic) regions, which makes robust identification of SVs challenging. In this paper, we demonstrate the utility of SV calling in ES resulting in a diagnostic yield of 0.4% (23 out of 5825 probands) for a large cohort of unsolved patients collected by the Solve-RD consortium. Remarkably, 8 out of 23 pathogenic SV were not found by comprehensive read-depth-based CNV analysis, resulting in a 0.13% increased diagnostic value.
期刊介绍:
The European Journal of Human Genetics is the official journal of the European Society of Human Genetics, publishing high-quality, original research papers, short reports and reviews in the rapidly expanding field of human genetics and genomics. It covers molecular, clinical and cytogenetics, interfacing between advanced biomedical research and the clinician, and bridging the great diversity of facilities, resources and viewpoints in the genetics community.
Key areas include:
-Monogenic and multifactorial disorders
-Development and malformation
-Hereditary cancer
-Medical Genomics
-Gene mapping and functional studies
-Genotype-phenotype correlations
-Genetic variation and genome diversity
-Statistical and computational genetics
-Bioinformatics
-Advances in diagnostics
-Therapy and prevention
-Animal models
-Genetic services
-Community genetics