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Hum Mutat [journal]
- The Genome Clinic: A Multidisciplinary Approach to Assessing the Opportunities and Challenges of Integrating Genomic Analysis Into Clinical Care. [JOURNAL ARTICLE]
- Hum Mutat 2014 Mar 5.
Our increasing knowledge of how genomic variants affect human health and the falling costs of whole genome sequencing are driving the development of individualized genetic medicine. This new clinical paradigm uses knowledge of an individual's genomic variants to guide health care decisions throughout life, in order to anticipate, diagnose and manage disease. While individualized genetic medicine offers the promise of transformative change in health care, it forces us to reconsider existing ethical, scientific and clinical paradigms. The potential benefits of presymptomatic identification of at risk individuals, improved diagnostics, individualized therapy, accurate prognosis, and avoidance of adverse drug reactions co-exist with the potential risks of uninterpretable results, psychological harm, outmoded counselling models and increased health care costs. Here we review the challenges of integrating genomic analysis into clinical practice and describe a prototype for implementing genetic medicine. Our multidisciplinary team of bioinformaticians, health economists, ethicists, geneticists, genetic counsellors, and clinicians has designed a "Genome Clinic" research project that addresses multiple challenges in genomic medicine - ranging from development of bioinformatics tools for the clinical assessment of genomic variants and the discovery of disease genes to health policy inquiries, assessment of clinical care models, patient preference and the ethics of consent. This article is protected by copyright. All rights reserved.
- Elucidating Common Structural Features of Human Pathogenic Variations Using Large-Scale Atomic-Resolution Protein Networks. [JOURNAL ARTICLE]
- Hum Mutat 2014 Mar 5.
With the rapid growth of structural genomics, numerous protein crystal structures have become available. However, the parallel increase in knowledge of the functional principles underlying biological processes, and more specifically the underlying molecular mechanisms of disease, has been less dramatic. This notwithstanding, the study of complex cellular networks has made possible the inference of protein functions on a large scale. Here, we combine the scale of network systems biology with the resolution of traditional structural biology to generate a large-scale atomic-resolution interactome-network comprising 3,398 interactions between 2,890 proteins with a well-defined interaction interface and interface residues for each interaction. Within the framework of this atomic-resolution network, we have explored the structural principles underlying variations causing human inherited disease. We find that in-frame pathogenic variations are enriched at both the interface and in the interacting domain, suggesting that variations not only at interface "hot-spots", but in the entire interacting domain can result in alterations of interactions. Further, the sites of pathogenic variations are closely related to the biophysical strength of the interactions they perturb. Finally, we show that biochemical alterations consequent to these variations are considerably more disruptive than evolutionary changes, with the most significant alterations at the protein interaction interface. This article is protected by copyright. All rights reserved.
- The UMD-APC database, a model of nation-wide knowledge base: update with data from 3,581 variations. [JOURNAL ARTICLE]
- Hum Mutat 2014 Mar 5.
Familial adenomatous polyposis (FAP) is a rare autosomal inherited disease that highly predisposes to colorectal cancer, characterized by a diffuse duodenal and colorectal polyposis associated with various extradigestive tumors and linked to germline mutations within the APC gene. A French consortium of laboratories involved in APC mutation screening has progressively improved the description of the variation spectrum, inferred functional significance of non-truncating variations and delineated phenotypic characteristics of the disease. The current version of the UMD-APC database is here described. The total number of variations has risen to 5,453 representing 1,473 distinct variations. The published records initially registered into the database were extended with 3,581 germline variations found through genetic testing performed by the eight licensed laboratories belonging to the French APC network. Sixty-six of 149 variations of previously unknown significance have now been classified as (likely) causal or neutral. The database is available on the Internet (http://www.umd.be/APC/) and updated twice per year according to the consensus rules of the network. The UMD-APC database is thus expected to facilitate functional classification of rare synonymous, non-synonymous and intronic mutations and consequently improve genetic counseling and medical care in FAP families. This article is protected by copyright. All rights reserved.
- Mutations in the Human UBR1 Gene and the Associated Phenotypic Spectrum. [JOURNAL ARTICLE]
- Hum Mutat 2014 Mar 5.
Johanson-Blizzard syndrome (JBS) is a rare, autosomal recessive disorder characterised by exocrine pancreatic insufficiency, typical facial features, dental anomalies, hypothyroidism, sensorineural hearing loss, scalp defects, urogenital and anorectal anomalies, short stature, and cognitive impairment of variable degree. This syndrome is caused by a defect of the E3 ubiquitin ligase UBR1, which is part of the proteolytic N-end rule pathway. Herein we review previously reported (n = 29) and a total of 31 novel UBR1 mutations in relation to the associated phenotype in patients from 50 unrelated families. Mutation types include nonsense, frameshift, splice site, missense and small in-frame deletions consistent with the hypothesis that loss of UBR1 protein function is the molecular basis of JBS. There is an association of missense mutations and small in-frame deletions with milder physical abnormalities and a normal intellectual capacity, thus suggesting that at least some of these may represent hypomorphic UBR1 alleles. The review of clinical data of a large number of molecularly confirmed JBS cases allows us to define minimal clinical criteria for the diagnosis of JBS. For all previously reported and novel UBR1 mutations together with their clinical data, a mutation database has been established at LOVD. This article is protected by copyright. All rights reserved.
- An Evaluation of Copy Number Variation Detection Tools from Whole-Exome Sequencing Data. [JOURNAL ARTICLE]
- Hum Mutat 2014 Mar 5.
Copy number variation (CNV) has been found to play an important role in human disease. Next generation sequencing technology, including whole-genome sequencing (WGS) and whole-exome sequencing (WES), has become a primary strategy for studying the genetic basis of human disease. Several CNV calling tools have recently been developed on the basis of WES data. However, the comparative performance of these tools using real data remains unclear. An objective evaluation study of these tools in practical research situations would be beneficial. Here, we evaluated four well-known WES-based CNV detection tools (XHMM, CoNIFER, ExomeDepth, and CONTRA) using real data generated in house. After evaluation using six metrics, we found that the sensitive and accurate detection of CNVs in WES data remains challenging despite the many algorithms available. Each algorithm has its own strengths and weaknesses. None of the exome-based CNV calling methods performed well in all situations; in particular, compared with CNVs identified from high coverage WGS data from the same samples, all tools suffered from limited power. Our evaluation provides a comprehensive and objective comparison of several well-known detection tools designed for WES data, which will assist researchers in choosing the most suitable tools for their research needs. This article is protected by copyright. All rights reserved.
- Disease-causing Enhancer Variants: A Question of Penetrance. [Journal Article]
- Hum Mutat 2014 Mar; 35(3):v.
- Contents. [Journal Article]
- Hum Mutat 2014 Mar; 35(3):i-iii.
- Genomics into Healthcare: the 5(th) Pan Arab Human Genetics Conference and 2013 Golden Helix Symposium. [JOURNAL ARTICLE]
- Hum Mutat 2014 Feb 13.
The joint 5(th) Pan Arab Human Genetics conference and 2013 Golden Helix Symposium, "Genomics into Healthcare" was co-organized by the Center for Arab Genomic Studies (CAGS - http://www.cags.org.ae) in collaboration with the Golden Helix Foundation (http://www.goldenhelix.org) in Dubai, United Arab Emirates from 17-19 November, 2013. The meeting was attended by over 900 participants, doctors and biomedical students from over 50 countries and was organized into a series of nine themed sessions that covered cancer genomics and epigenetics, genomic and epigenetic studies, genomics of blood and metabolic disorders, cytogenetic diagnosis and molecular profiling, next generation sequencing, consanguinity and hereditary diseases, clinical genomics, clinical applications of pharmacogenomics and genomics in public health. This article is protected by copyright. All rights reserved.
- TBC1D7 Mutations are Associated with Intellectual Disability, Macrocrania, Patellar Dislocation and Celiac Disease. [JOURNAL ARTICLE]
- Hum Mutat 2014 Feb 11.
TBC1D7 forms a complex with TSC1 and TSC2 that inhibits mTORC1 signaling and limits cell growth. Mutations in TBC1D7 were reported in a family with intellectual disability and macrocrania. Using exome sequencing we identified two sisters homozygote for the novel c.17_20delAGAG, p.R7TfsX21 TBC1D7 truncating mutation. In addition to the already described macrocephaly and mild intellectual disability, they share osteo-articular defects, patella dislocation, behavioral abnormalities, psychosis, learning difficulties, celiac disease, prognathism, myopia and astigmatism. Consistent with a loss-of-function of TBC1D7 the patient's cell lines show an increase in the phosphorylation of 4EBP1, a direct downstream target of mTORC1 and a delay in the initiation of the autophagy process. This second family allows enlarging the phenotypic spectrum associated with TBC1D7 mutations and defining a TBC1D7 syndrome. Our work reinforces the involvement of TBC1D7 in the regulation of mTORC1 pathways and suggests an altered control of autophagy as possible cause of this disease. This article is protected by copyright. All rights reserved.
- Integrating Massively Parallel Sequencing into Diagnostic Workflows and Managing the Annotation and Clinical Interpretation Challenge. [JOURNAL ARTICLE]
- Hum Mutat 2014 Feb 7.
Massively parallel sequencing has become a powerful tool for the clinical management of patients with applications in diagnosis, guidance of treatment, prediction of drug response, and carrier screening. A considerable challenge for the clinical implementation of these technologies is the management of the vast amount of sequence data generated, in particular the annotation and clinical interpretation of genomic variants. Here, we describe annotation steps that can be automated and common strategies employed for variant prioritization. The definition of best practice standards for variant annotation and prioritization is still ongoing; at present, there is limited consensus regarding an optimal clinical sequencing pipeline. We provide considerations to help define these. For the first time, clinical genetics and genomics is not limited by our ability to sequence, but our ability to clinically interpret and use genomic information in health management. We argue that the development of standardized variant annotation and interpretation approaches and software tools implementing these warrants further support. As we gain a better understanding of the significance of genomic variation through research, patients will be able to benefit from the full scope that these technologies offer.