Victor McKusick and his role in the founding of the European School of Genetic Medicine.

Between 1988 and 2007, during the courses of the European School of Genetic Medicine, many of us had the opportunity to appreciate the tolerant and open-minded personality of Victor McKusick. He was gifted with a unique foresight for the innovations introduced into medicine through the development of the Human Genome Project. The aim of our separate contributions in this article is to document how his insights had an important impact on the European medical training system.

Consent recommendations for research and international data sharing involving persons with dementia.

Consent is generally required for research and sharing rich individual-level data but presents additional ethical and legal challenges where participants have diminished decision-making capacity. We formed a multi-disciplinary team to develop best practices for consent in data-intensive dementia research. We recommend that consent processes for research and data sharing support decision-making by persons with dementia, protect them from exploitation, and promote the common good. Broad consent designed to endure beyond a loss of capacity and combined with ongoing oversight can best achieve these goals. Persons with dementia should be supported to make decisions and enabled to express their will and preferences about participation in advance of a loss of capacity. Regulatory frameworks should clarify who can act as a representative for research decisions. By promoting harmonization of consent practices across institutions, sectors, and countries, we hope to facilitate data sharing to accelerate progress in dementia research, care, and prevention.

A decision tool to guide the ethics review of a challenging breed of emerging genomic projects.

Recent projects conducted by the International Cancer Genome Consortium (ICGC) have raised the important issue of distinguishing quality assurance (QA) activities from research in the context of genomics. Research was historically defined as a systematic effort to expand a shared body of knowledge, whereas QA was defined as an effort to ascertain whether a specific project met desired standards. However, the two categories increasingly overlap due to advances in bioinformatics and the shift toward open science. As few ethics review policies take these changes into account, it is often difficult to determine the appropriate level of review. Mislabeling can result in unnecessary burdens for the investigators or, conversely, in underestimation of the risks to participants. Therefore, it is important to develop a consistent method of selecting the review process for genomics and bioinformatics projects. This paper begins by discussing two case studies from the ICGC, followed by a literature review on the distinction between QA and research and a comparative analysis of ethics review policies from Canada, the United States, the United Kingdom, and Australia. These results are synthesized into a novel two-step decision tool for researchers and policymakers, which uses traditional criteria to sort clearly defined activities while requiring the use of actual risk levels to decide more complex cases.

Data Safe Havens in health research and healthcare.

MOTIVATION: The data that put the 'evidence' into 'evidence-based medicine' are central to developments in public health, primary and hospital care. A fundamental challenge is to site such data in repositories that can easily be accessed under appropriate technical and governance controls which are effectively audited and are viewed as trustworthy by diverse stakeholders. This demands socio-technical solutions that may easily become enmeshed in protracted debate and controversy as they encounter the norms, values, expectations and concerns of diverse stakeholders. In this context, the development of what are called 'Data Safe Havens' has been crucial. Unfortunately, the origins and evolution of the term have led to a range of different definitions being assumed by different groups. There is, however, an intuitively meaningful interpretation that is often assumed by those who have not previously encountered the term: a repository in which useful but potentially sensitive data may be kept securely under governance and informatics systems that are fit-for-purpose and appropriately tailored to the nature of the data being maintained, and may be accessed and utilized by legitimate users undertaking work and research contributing to biomedicine, health and/or to ongoing development of healthcare systems. RESULTS: This review explores a fundamental question: 'what are the specific criteria that ought reasonably to be met by a data repository if it is to be seen as consistent with this interpretation and viewed as worthy of being accorded the status of 'Data Safe Haven' by key stakeholders'? We propose 12 such criteria. CONTACT: paul.burton@bristol.ac.uk.

Managing clinically significant findings in research: the UK10K example.

Recent advances in sequencing technology allow data on the human genome to be generated more quickly and in greater detail than ever before. Such detail includes findings that may be of significance to the health of the research participant involved. Although research studies generally do not feed back information on clinically significant findings (CSFs) to participants, this stance is increasingly being questioned. There may be difficulties and risks in feeding clinically significant information back to research participants, however, the UK10K consortium sought to address these by creating a detailed management pathway. This was not intended to create any obligation upon the researchers to feed back any CSFs they discovered. Instead, it provides a mechanism to ensure that any such findings can be passed on to the participant where appropriate. This paper describes this mechanism and the specific criteria, which must be fulfilled in order for a finding and participant to qualify for feedback. This mechanism could be used by future research consortia, and may also assist in the development of sound principles for dealing with CSFs.

International network of cancer genome projects.

The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.

Prepublication data sharing.

Rapid release of prepublication data has served the field of genomics well. Attendees at a workshop in Toronto recommend extending the practice to other biological data sets.

Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation.

Nonsense-mediated mRNA decay (NMD) is of universal biological significance. It has emerged as an important global RNA, DNA and translation regulatory pathway. By systematically sequencing 737 genes (annotated in the Vertebrate Genome Annotation database) on the human X chromosome in 250 families with X-linked mental retardation, we identified mutations in the UPF3 regulator of nonsense transcripts homolog B (yeast) (UPF3B) leading to protein truncations in three families: two with the Lujan-Fryns phenotype and one with the FG phenotype. We also identified a missense mutation in another family with nonsyndromic mental retardation. Three mutations lead to the introduction of a premature termination codon and subsequent NMD of mutant UPF3B mRNA. Protein blot analysis using lymphoblastoid cell lines from affected individuals showed an absence of the UPF3B protein in two families. The UPF3B protein is an important component of the NMD surveillance machinery. Our results directly implicate abnormalities of NMD in human disease and suggest at least partial redundancy of NMD pathways.

Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly.

In the course of systematic screening of the X-chromosome coding sequences in 250 families with nonsyndromic X-linked mental retardation (XLMR), two families were identified with truncating mutations in BRWD3, a gene encoding a bromodomain and WD-repeat domain-containing protein. In both families, the mutation segregates with the phenotype in affected males. Affected males have macrocephaly with a prominent forehead, large cupped ears, and mild-to-moderate intellectual disability. No truncating variants were found in 520 control X chromosomes. BRWD3 is therefore a new gene implicated in the etiology of XLMR associated with macrocephaly and may cause disease by altering intracellular signaling pathways affecting cellular proliferation.

Mutations in ZDHHC9, which encodes a palmitoyltransferase of NRAS and HRAS, cause X-linked mental retardation associated with a Marfanoid habitus.

We have identified one frameshift mutation, one splice-site mutation, and two missense mutations in highly conserved residues in ZDHHC9 at Xq26.1 in 4 of 250 families with X-linked mental retardation (XLMR). In three of the families, the mental retardation phenotype is associated with a Marfanoid habitus, although none of the affected individuals meets the Ghent criteria for Marfan syndrome. ZDHHC9 is a palmitoyltransferase that catalyzes the posttranslational modification of NRAS and HRAS. The degree of palmitoylation determines the temporal and spatial location of these proteins in the plasma membrane and Golgi complex. The finding of mutations in ZDHHC9 suggests that alterations in the concentrations and cellular distribution of target proteins are sufficient to cause disease. This is the first XLMR gene to be reported that encodes a posttranslational modification enzyme, palmitoyltransferase. Furthermore, now that the first palmitoyltransferase that causes mental retardation has been identified, defects in other palmitoylation transferases become good candidates for causing other mental retardation syndromes.

Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor.

We have identified three truncating, two splice-site, and three missense variants at conserved amino acids in the CUL4B gene on Xq24 in 8 of 250 families with X-linked mental retardation (XLMR). During affected subjects' adolescence, a syndrome emerged with delayed puberty, hypogonadism, relative macrocephaly, moderate short stature, central obesity, unprovoked aggressive outbursts, fine intention tremor, pes cavus, and abnormalities of the toes. This syndrome was first described by Cazebas et al., in a family that was included in our study and that carried a CUL4B missense variant. CUL4B is a ubiquitin E3 ligase subunit implicated in the regulation of several biological processes, and CUL4B is the first XLMR gene that encodes an E3 ubiquitin ligase. The relatively high frequency of CUL4B mutations in this series indicates that it is one of the most commonly mutated genes underlying XLMR and suggests that its introduction into clinical diagnostics should be a high priority.

Mutations in the gene encoding the Sigma 2 subunit of the adaptor protein 1 complex, AP1S2, cause X-linked mental retardation.

In a systematic sequencing screen of the coding exons of the X chromosome in 250 families with X-linked mental retardation (XLMR), we identified two nonsense mutations and one consensus splice-site mutation in the AP1S2 gene on Xp22 in three families. Affected individuals in these families showed mild-to-profound mental retardation. Other features included hypotonia early in life and delay in walking. AP1S2 encodes an adaptin protein that constitutes part of the adaptor protein complex found at the cytoplasmic face of coated vesicles located at the Golgi complex. The complex mediates the recruitment of clathrin to the vesicle membrane. Aberrant endocytic processing through disruption of adaptor protein complexes is likely to result from the AP1S2 mutations identified in the three XLMR-affected families, and such defects may plausibly cause abnormal synaptic development and function. AP1S2 is the first reported XLMR gene that encodes a protein directly involved in the assembly of endocytic vesicles.