Human Mutation

Hegde, Madhuri; Munnich, Arnold; Béroud, Christophe

doi: 10.1002/humu.23142pmid: N/A

doi: 10.1002/humu.22896pmid: N/A

Hegde, Madhuri; Munnich, Arnold; Béroud, Christophe

doi: 10.1002/humu.23134pmid: N/A

Niemiec, Emilia; Borry, Pascal; Pinxten, Wim; Howard, Heidi Carmen

doi: 10.1002/humu.23122pmid: 27647801

Whole exome sequencing (WES) and whole genome sequencing (WGS) have become increasingly available in the research and clinical settings and are now also being offered by direct‐to‐consumer (DTC) genetic testing (GT) companies. This offer can be perceived as amplifying the already identified concerns regarding adequacy of informed consent (IC) for both WES/WGS and the DTC GT context. We performed a qualitative content analysis of Websites of four companies offering WES/WGS DTC regarding the following elements of IC: pre‐test counseling, benefits and risks, and incidental findings (IFs). The analysis revealed concerns, including the potential lack of pre‐test counseling in three of the companies studied, missing relevant information in the risks and benefits sections, and potentially misleading information for consumers. Regarding IFs, only one company, which provides opportunistic screening, provides basic information about their management. In conclusion, some of the information (and related practices) present on the companies’ Web pages salient to the consent process are not adequate in reference to recommendations for IC for WGS or WES in the clinical context. Requisite resources should be allocated to ensure that commercial companies are offering high‐throughput sequencing under responsible conditions, including an adequate consent process.

Wouters, Roel H.P.; Bijlsma, Rhodé M.; Ausems, Margreet G.E.M.; Delden, Johannes J.M.; Voest, Emile E.; Bredenoord, Annelien L.

doi: 10.1002/humu.23118pmid: 27647774

Ever since genetic testing is possible for specific mutations, ethical debate has sparked on the question of whether professionals have a duty to warn not only patients but also their relatives that might be at risk for hereditary diseases. As next‐generation sequencing (NGS) swiftly finds its way into clinical practice, the question who is responsible for conveying unsolicited findings to family members becomes increasingly urgent. Traditionally, there is a strong emphasis on the duties of the professional in this debate. But what is the role of the patient and her family? In this article, we discuss the question of whose duty it is to convey relevant genetic risk information concerning hereditary diseases that can be cured or prevented to the relatives of patients undergoing NGS. We argue in favor of a shared responsibility for professionals and patients and present a strategy that reconciles these roles: a moral accountability nudge. Incorporated into informed consent and counseling services such as letters and online tools, this nudge aims to create awareness on specific patient responsibilities. Commitment of all parties is needed to ensure adequate dissemination of results in the NGS era.

Laurie, Steve; Fernandez‐Callejo, Marcos; Marco‐Sola, Santiago; Trotta, Jean‐Remi; Camps, Jordi; Chacón, Alejandro; Espinosa, Antonio; Gut, Marta; Gut, Ivo; Heath, Simon; Beltran, Sergi

doi: 10.1002/humu.23114pmid: 27604516

As whole genome sequencing becomes cheaper and faster, it will progressively substitute targeted next‐generation sequencing as standard practice in research and diagnostics. However, computing cost–performance ratio is not advancing at an equivalent rate. Therefore, it is essential to evaluate the robustness of the variant detection process taking into account the computing resources required. We have benchmarked six combinations of state‐of‐the‐art read aligners (BWA‐MEM and GEM3) and variant callers (FreeBayes, GATK HaplotypeCaller, SAMtools) on whole genome and whole exome sequencing data from the NA12878 human sample. Results have been compared between them and against the NIST Genome in a Bottle (GIAB) variants reference dataset. We report differences in speed of up to 20 times in some steps of the process and have observed that SNV, and to a lesser extent InDel, detection is highly consistent in 70% of the genome. SNV, and especially InDel, detection is less reliable in 20% of the genome, and almost unfeasible in the remaining 10%. These findings will aid in choosing the appropriate tools bearing in mind objectives, workload, and computing infrastructure available.

Salgado, David; Bellgard, Matthew I.; Desvignes, Jean‐Pierre; Béroud, Christophe

doi: 10.1002/humu.23110pmid: 27599893

High‐throughput sequencing technologies have become fundamental for the identification of disease‐causing mutations in human genetic diseases both in research and clinical testing contexts. The cumulative number of genes linked to rare diseases is now close to 3,500 with more than 1,000 genes identified between 2010 and 2014 because of the early adoption of Exome Sequencing technologies. However, despite these encouraging figures, the success rate of clinical exome diagnosis remains low due to several factors including wrong variant annotation and nonoptimal filtration practices, which may lead to misinterpretation of disease‐causing mutations. In this review, we describe the critical steps of variant annotation and filtration processes to highlight a handful of potential disease‐causing mutations for downstream analysis. We report the key annotation elements to gather at multiple levels for each mutation, and which systems are designed to help in collecting this mandatory information. We describe the filtration options, their efficiency, and limits and provide a generic filtration workflow and highlight potential pitfalls through a use case.

Veneziano, Dario; Di Bella, Sebastiano; Nigita, Giovanni; Laganà, Alessandro; Ferro, Afredo; Croce, Carlo M.

doi: 10.1002/humu.23066pmid: 27516218

One of the most significant biological discoveries of the last decade is represented by the reality that the vast majority of the transcribed genomic output comprises diverse classes of noncoding RNAs (ncRNAs) that may play key roles and/or be affected by many biochemical cellular processes (i.e., RNA editing), with implications in human health and disease. With 90% of the human genome being transcribed and novel classes of ncRNA emerging (tRNA‐derived small RNAs and circular RNAs among others), the great majority of the human transcriptome suggests that many important ncRNA functions/processes are yet to be discovered. An approach to filling such vast void of knowledge has been recently provided by the increasing application of next‐generation sequencing (NGS), offering the unprecedented opportunity to obtain a more accurate profiling with higher resolution, increased throughput, sequencing depth, and low experimental complexity, concurrently posing an increasing challenge in terms of efficiency, accuracy, and usability of data analysis software. This review provides an overview of ncRNAs, NGS technology, and the most recent/popular computational approaches and the challenges they attempt to solve, which are essential to a more sensitive and comprehensive ncRNA annotation capable of furthering our understanding of this still vastly uncharted genomic territory.

Pinard, Amélie; Miltgen, Morgane; Blanchard, Arnaud; Mathieu, Hélène; Desvignes, Jean‐Pierre; Salgado, David; Fabre, Aurélie; Arnaud, Pauline; Barré, Laura; Krahn, Martin; Grandval, Philippe; Olschwang, Sylviane; Zaffran, Stéphane; Boileau, Catherine; Béroud, Christophe;

Pinard, Amélie; Salgado, David; Desvignes, Jean‐Pierre; Rai, Ghadi; Hanna, Nadine; Arnaud, Pauline; Guien, Céline; Martinez, Maria; Faivre, Laurence; Jondeau, Guillaume; Boileau, Catherine; Zaffran, Stéphane; Béroud, Christophe; Collod‐Béroud, Gwenaëlle