ABSTRACT
Considering the growing interest towards next generation sequencing (NGS) and data analysis, and the substantial challenges associated to fully exploiting these technologies and data without the proper experience, an expert knowledge-based user-friendly analytical tool was developed to allow non-bioinformatics experts to process NGS genomic data, automatically prioritise genomic variants and make their own annotations. This tool was developed using a user-centred methodology, where an iterative process was followed until a useful product was developed. This tool allows the users to set-up the pre-processing pipeline, filter the obtained data, annotate it using external and local databases (DBs) and help on deciding which variants are more relevant for each study, taking advantage of its customised expert-based scoring system. The end users involved in the project concluded that CRIBOMICS was easy to learn, use and interact with, reducing the analysis time and possible errors of variant prioritisation for genetic diagnosis.
Subject(s)
Genetic Variation , Software , Computational Biology , Genetic Variation/genetics , Genomics , High-Throughput Nucleotide Sequencing , Knowledge BasesABSTRACT
El complejo esclerosis tuberosa (OMIM #191100 y #613254) es un trastorno multisistémico que presenta un patrón de herencia autosómico dominante y se caracteriza por la presencia de crecimiento de hamartomas en cerebro, ojos, piel, riñones, corazón y pulmón. Se debe a la mutación heterocigótica en uno de los dos genes supresores de tumor TSC1 (OMIM #605284) y TSC2 (OMIM #191092). Las proteínas codificadas de estos genes forman un complejo que controla el crecimiento celular a través de mecanismos que incluyen la inhibición de la vía de señalización de la diana de rapamicina en las células de mamífero. Es por ello, que la comprensión de la fisiopatología de la entidad ha llevado al desarrollo de opciones terapéuticas para sus diversas manifestaciones. Además, se requiere un equipo multidisciplinario familiarizado en la evaluación clínica, siguiendo las recomendaciones para optimizar y estandarizar los sistemas de vigilancia de los pacientes con el objeto de garantizar una mejor calidad de vida y poder brindar un oportuno asesoramiento genético.
Tuberous sclerosis complex (OMIM #191100 and #613254) is a multisystem disorder that presents an autosomal dominant pattern of inheritance and is characterized by the presence of hamartomas in brain, eyes, skin, kidneys, heart and lungs. It is due to a heterozygous mutation in one of the two tumor suppressor genes TSC1 (OMIM #605284) and TSC2 (OMIM #191092). The encoded proteins of these genes form a complex that controls cell growth by mechanisms that include inhibition of the signaling pathway of the rapamycin target of mammalian cells. It is for this reason that the understanding of the pathophysiology of this entity has led to the development of therapeutic options for its various manifestations. In addition, a multidisciplinary team familiarized with the clinical evaluation is required, following the recommendations to optimize and standardize surveillance systems for these patients in order to guarantee a better life quality and provide timely genetic counseling.
ABSTRACT
The effects of missense changes and small in-frame deletions and insertions on protein function are not easy to predict, and the identification of such variants in individuals at risk of a genetic disease can complicate genetic counselling. One option is to perform functional tests to assess whether the variants affect protein function. We have used this strategy to characterize variants identified in the TSC1 and TSC2 genes in individuals with, or suspected of having, Tuberous Sclerosis Complex (TSC). Here we present an overview of our functional studies on 45 TSC1 and 107 TSC2 variants. Using a standardized protocol we classified 16 TSC1 variants and 70 TSC2 variants as pathogenic. In addition we identified eight putative splice site mutations (five TSC1 and three TSC2). The remaining 24 TSC1 and 34 TSC2 variants were classified as probably neutral.
