RESUMEN
Celiac disease is a multifactorial disorder caused by an unknown number of genetic factors interacting with an environmental factor. Hence, most patients are singletons and large families segregating with celiac disease are rare. We report on a three-generation family with six patients in which the inheritance pattern is consistent with an autosomal dominant model. To date, 27 loci explain up to 40% of the heritable disease risk. We hypothesized that part of the missing heritability is because of low frequency or rare variants. Such causal variants could be more prominent in multigeneration families where private mutations might co-segregate with the disease. They can be identified by linkage analysis combined with whole exome sequencing. We found three linkage regions on 4q32.3-4q33, 8q24.13-8q24.21 and 10q23.1-10q23.32 that segregate with celiac disease in this family. We performed exome sequencing on two affected individuals to investigate the positional candidate regions and the remaining exome for causal nonsense variants. We identified 12 nonsense mutations with a low frequency (minor allele frequency <10%) present in both individuals, but none mapped to the linkage regions. Two variants in the CSAG1 and KRT37 genes were present in all six affected individuals. Two nonsense variants in the MADD and GBGT1 genes were also present in 5 of 6 and 4 of 6 individuals, respectively; future studies should determine if any of these nonsense variants is causally related to celiac disease.
Asunto(s)
Enfermedad Celíaca/genética , Exones/genética , Genoma Humano/genética , Antígenos de Neoplasias/genética , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/genética , Femenino , Frecuencia de los Genes , Ligamiento Genético , Predisposición Genética a la Enfermedad , Factores de Intercambio de Guanina Nucleótido/genética , Humanos , Queratinas Específicas del Pelo/genética , Queratinas Tipo I/genética , Masculino , Proteínas de Neoplasias/genética , Linaje , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADNRESUMEN
Recent advances in the field of bioinformatics present a number of challenges in the secure and efficient management and analysis of biological data resources. Workflow technologies aim to assist scientists and domain experts in the design of complex, long running, data and computing intensive experiments that involve many data processing and analysis tasks with the objective of generating new knowledge or formulate new hypothesis. In this paper we present a bioinformatics workflow authoring and execution environment that intends to greatly facilitate the whole lifecycle of such experiments. Emphasis is given on the security and ethical requirements of these scenarios and the corresponding technological response. In addition we present our semantic framework used for supporting specific user-requirements related to the reasoning and inference capabilities of the environment.