The complexities of ocular genetics

The cliché 'a picture is worth a thousand words' is a testament to the power of the visual system in helping us deal with our physical environment. Rarely do perturbations to the visual system, even minor ones, go unnoticed. Major defects in eye development may occur in the absence of systemic problems which threaten health. Ocular anomalies offer a window into many developmental events which would otherwise be difficult to study.     

Psychiatric genetics researchers' views on offering return of results to individual participants

In the middle of growing consensus that genomics researchers should offer to return clinically valid, medically relevant, and medically actionable findings identified in the course of research, psychiatric genetics researchers face new challenges. As they uncover the genetic architecture of psychiatric disorders through genome‐wide association studies and integrate whole genome and whole exome sequencing to their research, there is a pressing need for examining these researchers' views regarding the return of results (RoR) and the unique challenges for offering RoR from psychiatric genetics research. Based on qualitative interviews with 39 psychiatric genetics researchers from different countries operating at the forefront of their field, we provide an insider's view of researchers' practices regarding RoR and the most contentious issues in psychiatry researchers' decision‐making around RoR, including what are the strongest ethical, scientific, and practical arguments for and against offering RoR from this research. Notably, findings suggest that psychiatric genetics researchers (85%) overwhelmingly favor offering RoR of at least some findings, but only 22% of researchers are returning results. Researchers identified a number of scientific and practical concerns about RoR, and about how to return results in a responsible way to patients diagnosed with a severe psychiatric disorder. Furthermore, findings help highlight areas for further discussion and resolution of conflicts in the practice of RoR in psychiatric genetics research. As the pace of discovery in psychiatric genetics continues to surge, resolution of these uncertainties gains greater urgency to avoid ethical pitfalls and to maximize the positive impact of RoR.     

Bioinformatics for human genetics: promises and challenges

Recent developments, including next-generation sequencing (NGS), bio-ontologies and the Semantic Web, and the growing role of hospital information technology (IT) systems and electronic health records, amass ever-increasing amounts of data before human genetics scientists and clinicians. However, they have ever-improving tools to analyze those data for research and clinical care. Correspondingly, the field of bioinformatics is turning to research questions in the field of human genetics, and the field of human genetics is making greater use of bioinformatic algorithms and tools. The choice of "Bioinformatics and Human Genetics" as the topic of this special issue of Human Mutation reflects this new importance of bioinformatics and medical informatics in human genetics. Experts from among the attendees of the Paris 2010 Human Variome Project symposium provide a survey of some of the "hot" computational topics over the next decade. These experts identify the promise-what human geneticists who are not themselves bioinformaticians stand to gain-as well as the challenges and unmet needs that are likely to represent fruitful areas of research.     

Psychiatric genetic counseling: A mapping exercise

Psychiatric genetic counseling (PGC) is gradually developing globally, with countries in various stages of development. In some, PGC is established as a service or as part of research projects while in others, it is just emerging as a concept. In this article, we describe the current global landscape of this genetic counseling specialty and this field's professional development. Drawing on information provided by expert representatives from 16 countries, we highlight the following: (a) current understanding of PGC; (b) availability of services for patients; (c) availability of training; (d) healthcare system disparities and cultural differences impacting practice; and (e) anticipated challenges going forward.     

Breast carcinoma with basal differentiation: a proposal for pathology definition based on basal cytokeratin expression

AIM: To assess the expression and coexpression of a range of different biomarkers that have been used to define breast carcinomas with a basal phenotype (BP) and their relationship with prognosis in an attempt to refine the definition of BP and to evaluate the reliability of using a single biomarker to identify these tumours. METHODS AND RESULTS: The expression pattern of basal cytokeratins (CK5/6 and CK14), oestrogen, progesterone and androgen receptors, epidermal growth factor receptor, HER2, BRCA1, P-cadherin and myoepithelial markers (smooth muscle actin and p63) were studied in a well-characterized series of invasive breast carcinoma (1872 cases) with long-term follow-up using immunohistochemistry and tissue microarray. Although the additional markers were associated with basal CK expression, they did not serve to improve recognition of cases with differing outcome when compared with basal CKs alone and, if used to define cases, reduced considerably the proportion of cases allocated to this poor prognostic type of breast cancer. CONCLUSION: BP can be defined based on the expression of basal CKs regardless of the expression of other markers.     

Psychiatric genetics in silico: databases and tools for psychiatric geneticists

Bioinformatics can significantly impact the laboratory genetics process from the study design phase to conclusive identification of a disease gene. The present review will highlight key databases to enhance psychiatric genetic study design, based on full use of genomics data and the golden path sequence. It will address methods to ensure comprehensive genetic data mining, using the best available genomic and genetic databases such as the University of California Santa Cruz human genome browser, Ensembl, Mapview, dbSNP and GDB, and locus-specific databases such as Online Mendelian Inheritance In Man. Using the golden path sequence as a template, with the necessary quality checks, it is possible to design detailed genetic studies from sequence information alone. Drawing together this diverse information, it is possible to characterize a locus or gene in silico to a very detailed level. This in turn can have real cost and efficiency benefits by assisting in the identification of markers that are most likely to be informative, or by highlighting the best candidate genes for study.     

Developmental imaging genetics: challenges and promises for translational research

Advances in molecular biology, neuroimaging, genetic epidemiology, and developmental psychopathology have provided a unique opportunity to explore the interplay of genes, brain, and behavior within a translational research framework. Herein, we begin by outlining an experimental strategy by which genetic effects on brain function can be explored using neuroimaging, namely, imaging genetics. We next describe some major findings in imaging genetics to highlight the effectiveness of this strategy for delineating biological pathways and mechanisms by which individual differences in brain function emerge and potentially bias behavior and risk for psychiatric illness. We then discuss the importance of applying imaging genetics to the study of psychopathology within a developmental framework. By beginning to move toward a systems-level approach to understanding pathways to behavioral outcomes as they are expressed across development, it is anticipated that we will move closer to understanding the complexities of the specific mechanisms involved in the etiology of psychiatric disease. Despite the numerous challenges that lie ahead, we believe that developmental imaging genetics has potential to yield highly informative results that will ultimately translate into public health benefits. We attempt to set out guidelines and provide exemplars that may help in designing fruitful translational research applications that incorporate a developmental imaging genetics strategy.     

Costimulatory pathways in transplantation: challenges and new developments

Summary:  T cells are central to graft rejection, and therefore preventing T cells from recognizing and destroying allografts remains an important area of transplant research. However, T cells are also required for transplant tolerance; a subset can enforce a state of tolerance by functioning as regulatory cells. As both rejection and regulation directed against alloantigens require T-cell activation, costimulatory molecules undoubtedly play an important role in regulating both processes and ultimately the fate of the allograft. However, costimulation involves an incredibly complex array of interactions that may act contemporaneously or at different times; these interactions can have additive or opposing effects on T-cell activation or differentiation. While some costimulatory molecules mediate activation of naive T cells or generation of memory T cells, others inhibit T-cell activation and promote anergy or apoptosis. Moreover, a given pathway can have diametrically different effects on T-effector cells and regulatory T cells (Tregs). Such a complexity presents both challenges and opportunities in targeting T-cell costimulatory pathways to promote transplant tolerance. In this review article, we provide a summary of recent advances in our understanding of T-cell costimulatory pathways in regulating different phases of the T-cell response in transplant models. We focus specifically on costimulatory molecules in the immunoglobulin (Ig) superfamily, tumor necrosis factor (TNF)/TNF receptor superfamily, and in the emerging T-cell Ig domain and mucin domain family (TIM), highlighting their unique and redundant roles in regulating the T-effector and Treg responses after transplantation. Finally, we summarize emerging approaches toward inducing tolerance by tipping the balance between cytopathic T-effector cells and protective Tregs by selectively targeting specific T-cell costimulatory pathways that are critically involved.     

Current perspectives in zebrafish reverse genetics: moving forward.

Use of the zebrafish as a model of vertebrate development and disease has expanded dramatically over the past decade. While many articles have discussed the strengths of zebrafish forward genetics (the phenotype-driven approach), there has been less emphasis on equally important and frequently used reverse genetics (the candidate gene-driven approach). Here we review both current and prospective reverse genetic techniques that are applicable to the zebrafish model. We include discussion of pharmacological approaches, popular gain-of-function and knockdown approaches, and gene targeting strategies. We consider the need for temporal and spatial control over gain/loss of gene function, and discuss available and developing techniques to achieve this end. Our goal is both to reveal the current technical advantages of the zebrafish and to highlight those areas where work is still required to allow this system to be exploited to full advantage.     

临床遗传学的又一灰色地带——染色体22q11.2区微重复

染色体22q11.2区微重复应具有与该区域微缺失相似的频率。对国内外22q11.2区微重复报道不多的原因进行了分析,提示在22q11.2区微重复的发现过程中,常规诊断技术对其缺乏足够的敏感性。另一方面,携带者所具有的极端可变的表型亦造成了临床诊断上的困难。22q11.2区微重复相关的遗传学以及临床问题生动地反映了现阶段在解读基因型-表型相关性上所面临的挑战,提示临床遗传学研究中存在着又一灰色地带。     

Effects of Psychological Distress on Perceptions of Physical Health and Use of Medical and Psychiatric Facilities

Psychological distress not only contributes to bodily symptoms but also affects the way people perceive their physical health status and their use of medical care. Reporting on a program of research, this paper reviews evidence that psychological distress is an important component of illness behavior and response and must be taken into account in the appropriate organization of medical services.     

The genetics of osteoporosis: 'complexities and difficulties'

Osteoporosis is characterized by a decrease in bone mass as well as a deterioration of the bone architecture resulting in an increased risk of fracture. Although the disease is multifactorial, twin studies have shown that genetic factors account for up to 80% of the variance in bone mineral density, the best known predictor of the risk of osteoporosis. Some loci, such as the vitamin D and estrogen receptor genes, as well as the collagen type Ialpha1 locus, are promising genetic determinants of bone mass, and possibly other bone phenotypes, but this is controversial and the molecular basis of osteoporosis remains largely undefined. Considering that the effect of each candidate gene is expected to be modest, discrepancies between allelic association studies may have arisen because different populations carry different genetic backgrounds and exposure to environmental factors. Also, we realize the importance of gene-gene as well as gene-environment interactions as significant determinants of bone density and risk of osteoporosis. The use of new tools such as small nucleotide polymorphism maps now allows the possibility to perform allelic association studies in the context of whole-genome search. However, specific study design strategies in large epidemiological studies as well as the best statistical approach will need to be established. We may expect the development of population-specific at-risk profiles for osteoporosis that would include genetic and environmental factors, as well as their interactions. This should eventually lead to better prevention strategies and more adapted therapies against osteoporosis.     

Polydactyly: phenotypes,genetics and classification

Polydactyly is one of the most common hereditary limb malformations featuring additional digits in hands and/or feet. It constituted the highest proportion among the congenital limb defects in various epidemiological surveys. Polydactyly, primarily presenting as an additional pre‐axial or post‐axial digit of autopod, is a highly heterogeneous condition and depicts broad inter‐ and intra‐familial clinical variability. There is a plethora of polydactyly classification methods reported in the medical literature which approach the heterogeneity in polydactyly in various ways. In this communication, well‐characterized, non‐syndromic polydactylies in humans are reviewed. The cardinal features, phenotypic variability and molecular advances of each type have been presented. Polydactyly at cellular and developmental levels is mainly a failure in the control of digit number. Interestingly, GLI3 and SHH (ZRS/SHH enhancer), two antagonistic factors known to modulate digit number and identity during development, have also been implicated in polydactyly. Mutations in GLI3 and ZRS/SHH cause overlapping polydactyly phenotypes highlighting shared molecular cascades in the etiology of additional digits, and thus suggesting the lumping of at least six distinct polydactyly entities. However, owing to the extreme phenotypic and clinical heterogeneity witnessed in polydactyly a substantial genetic heterogeneity is expected across different populations and ethnic groups.     

Research in human genetics: the tension between doing no harm and personal autonomy

The physician-patient relationship was governed for centuries by the ethical principle of beneficence and the physician's dedication to the principle of doing no harm. This structure shifted, however, to the principle of personal autonomy as medical and surgical knowledge expanded and patients, rather than physicians, became the locus of decision-making authority. In biomedical research in the United States, however, beneficence of the research professional remained dominant until a spectrum of doubtful research practices was made public in the 1970s and thereafter. Over the past three decades, state and federal governments have instituted regulations that provide increased protections for human research subjects, although research results are rarely shared with subjects because of the provisional nature of unconfirmed laboratory results. Now, however, genetics researchers and others suggest that subjects may well have an interest in present and future results, even though provisional. These issues are presently under discussion and may eventually open new possibilities for sharing research information with subjects who wish to be informed.     

Molecular genetics of Turner syndrome: correlation with clinical phenotype and response to growth hormone therapy

To correlate the origin of the retained X in Turner syndrome with phenotype, pre-treatment height and response to recombinant human growth hormone (rhGH) therapy, systematic clinical assessment and molecular studies were carried out in 33 Greek children with Turner syndrome and their parents including 18 children with 45,X and 15 with X-mosaicism. Microsatellite markers on X chromosomes (DXS101 and DXS337) revealed that the intact X was paternal (Xp) in 15/30 and maternal (Xm) in 15/30 children, while 3/33 families were non-informative. No significant relationship was found between parental origin of the retained X and birth weight/length/gestational age, blepharoptosis, pterygium colli, webbed neck, low hairline, abnormal ears, lymphoedema, short 4th metacarpal, shield chest, widely spaced nipples, cubitus valgus, pigmented naevi, streak gonads, and cardiovascular/renal anomalies. With regard to the children's pre-treatment height, there was a significant correlation with maternal height and target height in both Xm and Xp groups. No differences were found between Xm and Xp groups and the improvement of growth velocity (GV) during the first and second year of rhGH administration, while for both groups GV significantly improved with rhGH by the end of the first and the second year. To our knowledge, this is the first attempt to correlate the parental origin of Turner syndrome with the response to rhGH therapy.     

Assessing the molecular genetics of the development of executive attention in children: focus on genetic pathways related to the anterior cingulate cortex and dopamine

It is well known that children show gradual and protracted improvement in an array of behaviors involved in the conscious control of thought and emotion. Non-invasive neuroimaging in developing populations has revealed many neural correlates of behavior, particularly in the developing cingulate cortex and frontostriatal circuits. These brain regions, themselves, undergo protracted molecular and cellular change in the first two decades of human development and, as such, are ideal regions of interest for cognitive- and imaging-genetic studies that seek to link processes at the biochemical and synaptic levels to brain activity and behavior. We review our research to date that employs both adult and child-friendly versions of the attention network task (ANT) in an effort to begin to describe the role of specific genes in the assembly of a functional attention system. Presently, we constrain our predictions for genetic association studies by focusing on the role of the anterior cingulate cortex (ACC) and of dopamine in the development of executive attention.