The role of clinical genomic testing in diagnosis and discovery of pathogenic mutations

Abstract

Next-generation sequencing in clinical practice allows for a critical review of the literature to evaluate disease relatedness of specific genes and pathogenicity of individual mutations, while providing an important discovery tool for new disease genes and disease-causing mutations. Data obtained from large panels, whole exome or whole genome sequencing, performed for constitutional or cancer cases, need to be managed in a transparent, yet powerful analytical framework. Assessment of reported pathogenic potential of a variant or disease association of a gene requires careful consideration of population allele frequency, variant data from parents, and precise, yet concise phenotypic description of the entire family and other individuals or families that have the same variant. The full potential for discovery can only be realized if there is data sharing between clinicians performing the interpretation worldwide and structural biologists, analytical chemists and cell biologists interested and knowledgeable of the structure and function of the genes involved.

Keywords:

• analytical pipeline
• animal models
• clinical testing
• constitutional disorders
• data sharing
• database design
• disease-causing mutation
• mass spectrometry
• molecular modeling
• next-generation sequencing
• somatic mutation
• structural prediction of disruptive potential

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.