Medical genomics: The intricate path from genetic variant identification to clinical interpretation.
The field of medical genomics involves translating high throughput genetic methods to the clinic, in order to improve diagnostic efficiency and treatment decision making. Technical questions related to sample enrichment, sequencing methodologies and variant identification and calling algorithms, still need careful investigation in order to validate the analytical step of next generation sequencing techniques for clinical applications. However, the main foreseeable challenge will be interpreting the clinical significance of the variants observed in a given patient, as well as their significance for family members and for other patients. Every step in the variant interpretation process has limitations and difficulties, and its quote of contribution to false positive and false negative results. There is no single piece of evidence enough on its own to make firm conclusions on the pathogenicity and disease causality of a given variant. A plethora of automated analysis software tools is being developed that will enhance efficiency and accuracy. However a risk of misinterpretation could derive from biased biorepository content, facilitated by annotation of variant functional consequences using previous datasets stored in the same or linked repositories. In order to improve variant interpretation and avoid an exponential accumulation of confounding noise in the medical literature, the use of terms in a standard way should be sought and requested when reporting genetic variants and their consequences. Generally, stepwise and linear interpretation processes are likely to overrate some pieces of evidence while underscoring others. Algorithms are needed that allow a multidimensional, parallel analysis of diverse lines of evidence to be carried out by expert teams for specific genes, cellular pathways or disorders.
Fundación Pública Galega de Medicina Xenómica and Instituto de Investigación Sanitaria, SERGAS, Santiago de Compostela, Spain; Centro para Investigación Biomédica en red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Spain.
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Quintáns
Fundación Pública Galega de Medicina Xenómica and Instituto de Investigación Sanitaria, SERGAS, Santiago de Compostela, Spain; Universidade de Santiago de Compostela, Spain.
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Ordóñez-Ugalde
Fundación Pública Galega de Medicina Xenómica and Instituto de Investigación Sanitaria, SERGAS, Santiago de Compostela, Spain; Universidade de Santiago de Compostela, Spain.
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Cacheiro
Fundación Pública Galega de Medicina Xenómica and Instituto de Investigación Sanitaria, SERGAS, Santiago de Compostela, Spain; Centro para Investigación Biomédica en red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Spain; Universidade de Santiago de Compostela, Spain.
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Carracedo
Fundación Pública Galega de Medicina Xenómica and Instituto de Investigación Sanitaria, SERGAS, Santiago de Compostela, Spain; Centro para Investigación Biomédica en red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Spain.
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Sobrido
Clinical significance; Family co-segregation; Genetic variant; Informatics pipeline; Interpretation challenge; Pathogenicity assessment