Using mouse models to explore genotype-phenotype relationship in Down syndrome

Down Syndrome (DS) caused by trisomy 21 is characterized by a variety of phenotypes and involves multiple organs. Sequencing of human chromosome 21 (HSA21) and subsequently of its orthologues on mouse chromosome 16 have created an unprecedented opportunity to explore the complex relationship between various DS phenotypes and the extra copy of approximately 300 genes on HSA21. Advances in genetics together with the ability to generate genetically well-defined mouse models have been instrumental in understanding the relationships between genotype and phenotype in DS. Indeed, elucidation of these relationships will play an important role in understanding the pathophysiological basis of this disorder and helping to develop therapeutic interventions. A successful example of using such a strategy is our recent studies exploring the relationship between failed nerve growth factor (NGF) transport and amyloid precursor protein (App) overexpression. We found that increased dosage of the gene for App is linked to failed NGF signaling and cholinergic neurodegeneration in a mouse model of DS. Herein, we discuss several mouse models of DS and explore the emergence of exciting new insights into genotype-phenotype relationships, particularly those related to nervous system abnormalities. An important conclusion is that uncovering these relationships is enhanced by working from carefully defined phenotypes to the genes responsible.     

Epidemiology of Down syndrome

Down syndrome (DS) is the most commonly identified genetic form of mental retardation and the leading cause of specific birth defects and medical conditions. Traditional epidemiological studies to determine the prevalence, cause, and clinical significance of the syndrome have been conducted over the last 100 years. DS has been estimated to occur in approximately 1 in 732 infants in the United States, although there is some evidence that variability in prevalence of estimates exist among racial/ethnic groups. Progress has been made in characterizing the specific types of chromosome errors that lead to DS and in identifying associated factors that increase the risk of chromosome 21 malsegregation, i.e., advanced maternal age and recombination. Studies to examine the variability of the presence of specific DS-associated birth defects and medical conditions provide evidence for genetic and environmental modifiers. Here, we provide a brief survey of studies that address the current state of the field and suggest gaps in research that can soon be filled with new multidisciplinary approaches and technological advances.     

Down syndrome: cognitive phenotype

Down syndrome is the most prevalent cause of intellectual impairment associated with a genetic anomaly, in this case, trisomy of chromosome 21. It affects both physical and cognitive development and produces a characteristic phenotype, although affected individuals vary considerably with respect to severity of specific impairments. Studies focusing on the cognitive characteristics of Down syndrome were reviewed, and while performance in most areas could be predicted based upon overall intellectual disability, relative weaknesses were consistently found to be associated with expressive language, syntactic/morphosyntactic processing, and verbal working memory. This profile of uneven deficits could result from a failure to develop typically automatic processing for speech perception and production, and this possibility is discussed along with its implications for intervention.     

Preservation of long-term memory and synaptic plasticity despite short-term impairments in the Tc1 mouse model of Down syndrome

Down syndrome (DS) is a genetic disorder arising from the presence of a third copy of the human chromosome 21 (Hsa21). Recently, O’Doherty and colleagues in an earlier study generated a new genetic mouse model of DS (Tc1) that carries an almost complete Hsa21. Since DS is the most common genetic cause of mental retardation, we have undertaken a detailed analysis of cognitive function and synaptic plasticity in Tc1 mice. Here we show that Tc1 mice have impaired spatial working memory (WM) but spared long-term spatial reference memory (RM) in the Morris watermaze. Similarly, Tc1 mice are selectively impaired in short-term memory (STM) but have intact long-term memory (LTM) in the novel object recognition task. The pattern of impaired STM and normal LTM is paralleled by a corresponding phenotype in long-term potentiation (LTP). Freely-moving Tc1 mice exhibit reduced LTP 1 h after induction but normal maintenance over days in the dentate gyrus of the hippocampal formation. Biochemical analysis revealed a reduction in membrane surface expression of the AMPAR (α-amino-3-hydroxy-5-methyl-4-propionic acid receptor) subunit GluR1 in the hippocampus of Tc1 mice, suggesting a potential mechanism for the impairment in early LTP. Our observations also provide further evidence that STM and LTM for hippocampus-dependent tasks are subserved by parallel processing streams.     

Mosaic trisomy 20 and mitigation in capital crimes sentencing: A review and case report

Trisomy 20 is a genetic abnormality in which individuals have an extra copy of chromosome 20. Complete trisomy 20 is rare and believed to be incompatible with life. A mosaic form of trisomy 20, in which only some cells or tissues contain the extra chromosome, is a relatively commonly encountered chromosomal abnormality found during prenatal testing, and c. 90% result in a normal phenotype. However, despite the absence of a consistent phenotype, certain findings have been reported across multiple cases of mosaic trisomy 20. These include an array of morphological findings, developmental delays, and learning disabilities. Beyond physical manifestations, a wide range of developmental and learning delays have also been reported. In this work, we provide an overview of the trisomy 20 literature and a case report of a young adult male with mosaic trisomy 20 who committed homicide. His developmental and life history, eventual diagnosis of mosaic trisomy 20, similarities and differences in his condition compared with prior research findings, and potentially new phenotypic findings associated with trisomy 20 that he manifested (childhood visual hallucinations, self‐injury, polydactyly) are presented. Additionally, the potential role of this genetic diagnosis in his neuropsychiatric history and its successful application as a mitigating factor at his capital sentencing trial are described. We did not identify other similar cases during our search of major scientific and legal databases. As a backdrop, the use of genetics in criminal trials is on the rise, and courts are increasingly likely to accept behavioral genetics evidence; therefore, it is crucial that the legal system is well acquainted with the opportunities and limitations of these approaches.     

Searching for genetic influences on normal cognitive ageing

Differences in non-pathological cognitive ageing provide a useful case study for the opportunities and challenges facing cognitive science as it embraces advances in genetics. One replicated contributor to these differences is variability in the gene for apolipoprotein E. Genetic variations that influence neurodegenerative diseases, learning and memory, cardiovascular disease, and oxidative stress are among the candidates for influence on cognitive ageing differences. The area suffers the same problems as other domains in which quantitative trait loci are sought: uncertainty regarding the genetic architecture, unreliable strategies for candidate gene selection, lack of power leading to unreplicated findings, and poor characterisation of the phenotype. However, current progress in genetic knowledge, technology and informatics will contribute to progress in this important area.     

Genetic linkage in bipolar disorder

Bipolar disorder is an etiologically complex syndrome that is clearly heritable. Multiple genes, working singly or in concert, are likely to cause susceptibility to bipolar disorder. Bipolar disorder genetics has progressed rapidly in the last few decades. However, specific causal genetic mutations for bipolar disorder have not been identified. Both candidate gene studies and complete genome screens have been conducted. They have provided compelling evidence for several potential bipolar disorder susceptibility loci in several regions of the genome. The strongest evidence suggests that bipolar disorder susceptibility loci may lie in one or more genomic regions on chromosomes 18, 4, and 21. Other regions of interest, including those on chromosomes 5 and 8, are also under investigation. New approaches, such as the use of genetically isolated populations and the use of endophenotypes for bipolar disorder, hold promise for continued advancement in the search to identify specific bipolar disorder genes.     

多巴胺相关基因甲基化、家庭环境与创造力的关系

“遗传与环境”的争论一直是创造力研究的核心问题, 但目前对于环境以及遗传与环境交互作用对创造力影响的分子生物机制还未有研究涉及。近年来, 随着表观遗传学的兴起, 揭示影响心理行为的表观遗传机制现已成为心理学研究的热点。作为环境与基因组之间的纽带, 表观遗传学研究为揭示环境以及遗传与环境交互作用对创造力影响的分子生物机制提供了机遇。本研究以多巴胺相关基因、家庭环境以及两者对于创造力的交互作用为切入点, 对影响创造力的表观遗传机制进行考察, 并在此基础之上, 对环境以及遗传与环境交互作用对创造力影响的分子生物机制进行探索。具体研究内容包括：(1)通过对多巴胺相关基因甲基化模式与创造力关系的系统考察, 筛选出甲基化模式与创造力有关的基因; (2)对筛选出的基因, 进一步考察其甲基化模式在家庭环境及其遗传多态性与家庭环境交互作用对创造力影响中的中介作用。本研究有助于揭示创造力的表观遗传机制, 深化关于遗传与环境对创造力影响的作用机制的理解。     

Mitochondrial defects in neurodegenerative disease

Over the past 12 years, a wide variety of neurodegenerative diseases has been linked to mutations in mitochondrial genes located in either the mitochondrial DNA (mtDNA) or the nuclear DNA (nDNA). These disorders encompass an array of unorthodox inheritance patterns and a plethora of symptoms ranging from lethal neonatal multi-symptom disorders to later onset myopathies, cardiomyopathies, movement disorders, and dementias. The bases for the genetic and phenotypic variability of mitochondrial diseases lie in the multiplicity of the mitochondria genes dispersed across the human genome and the variety of cellular pathways and functions in which the mitochondria play a central role.     

Advances in research on the fragile X syndrome

Fragile X syndrome is a neurodevelopmental disorder that results from a single gene mutation on the X chromosome. The purpose of this review is to summarize key advances made in understanding the fragile X premutation gene seen in carriers and the full mutation gene seen in persons with the syndrome. DNA testing has replaced cytogenetic testing as the primary method for identification of fragile X, although the efficacy of protein level screening is being explored. The premutation is associated with no effects, although there is evidence of physical effects-primarily premature menopause and mild outward features of the fragile X syndrome-among premutation carriers. There is much controversy regarding premutation effects on psychological development. The few experimental studies carried out to date do not suggest noticeable or significant effects. One challenge in addressing this controversy is the sometimes ambiguous differentiation between premutation and full mutation genes. There is a well-established yet highly variable phenotype of the full mutation. Research from this decade has helped to address specific aspects of this phenotype, including the early course of its development in males, the influence of home and family environments, the nature of social difficulties and autistic features seen in boys and girls with fragile X, and the potential role of hyperarousal or hyper-reactivity. Studies in these areas, and on the role of FMR protein, will contribute towards ongoing advances in our understanding of fragile X syndrome and its mechanisms. The variability in physical, social, and cognitive features, as described in this review, is one that prohibits clear-cut screening guidelines designed to avoid high rates of both false positives and false negatives. Results from recent studies indicate the need to consider behavioral features in selecting candidates for fragile X screening. MRDD Research Reviews 2000;6:96-106.     

The Early Presentation of Dementia in People with Down Syndrome: a Systematic Review of Longitudinal Studies

Adults with Down syndrome (DS) are at a very high risk of developing early onset Alzheimer’s disease (AD) due to trisomy of chromosome 21. AD is preceded by a prolonged prodromal “pre-clinical” phase presenting with clinical features that do not fulfil the diagnostic criteria for AD. It is important to clinically characterise this prodromal stage to help early detection of the disease as neuropathology of AD is almost universal by the fifth decade in DS. There is a lack of knowledge of the trajectory of decline associated with the onset of dementia in this population and early signs may be overlooked or misdiagnosed, negatively affecting the quality of life of those affected and the use of early pharmacological or psychosocial interventions. The objective of this systematic review is to evaluate the published literature on longitudinal data in order to identify the cognitive and behavioural changes occurring during the prodromal and early stages of AD in this population. Fifteen peer-reviewed articles met the inclusion criteria, including a total number of 831 participants, with the duration between baseline and follow up varying from 1 year to 47 years. Results suggest that, compared to the general population for which short-term (episodic) memory loss is the most common indicator associated with the onset of AD, in people with DS, executive dysfunction and Behavioural and Psychological Symptoms of Dementia (BPSD) are commonly observed during pre-clinical and early stages and may precede memory loss. The review highlights the importance of using a broad spectrum of assessments in the context of heterogeneity of symptoms. Theoretical and practical implications are discussed, as well as the need for further research.     

Unintended Diagnosis of Von Hippel Lindau Syndrome Using Array Comparative Genomic Hybridization (CGH): Counseling Challenges Arising from Unexpected Information

Array Comparative Genomic Hybridization (array CGH) is a powerful tool for identifying genomic imbalances and providing a diagnosis in individuals with a normal karyotype. It has been particularly useful in the investigation of individuals with developmental delay +/?, dysmorphic features and/or multiple congenital abnormalities. However, this non-targeted method of scanning the whole genome can reveal unexpected information. We present a case where array CGH identified the cause of a proband’s moderate mental retardation by discovery of a de novo deletion of chromosome 3p25.3. This deletion was shown to contain at least 25 genes including the VHL gene, the deletion or mutation of which leads to Von Hippel Lindau (VHL) syndrome. Presymptomatic testing for VHL is usually offered after appropriate genetic counseling about the implications of this condition. Therefore, scanning the genome by array CGH presents a number of challenges for the genetic counselor. We suggest that further understanding of the psychosocial effects of array CGH is needed in order for appropriate pre- and post-test counseling to be provided.     

Genetic approaches to understanding brain development: holoprosencephaly as a model

Holoprosencephaly (HPE) is the most common major developmental defect of the forebrain in humans. Clinical expression is variable, ranging from a small brain with a single cerebral ventricle and cyclopia to clinically unaffected carriers in familial HPE. Significant etiologic heterogeneity exists in HPE and includes both genetic and environmental causes. Defects in the cell signaling pathway involving the Sonic Hedgehog (SHH) gene, as well as defects in the cholesterol biosynthesis have been shown to cause HPE in humans. More recently, HPE genes from additional signaling pathways have been identified. These discoveries and current genetic approaches serve as a paradigm for studying normal and abnormal brain morphogenesis. MRDD Research Reviews 6:15-21, 2000.     

Turner syndrome: a review of genetic and hormonal influences on neuropsychological functioning.

Turner syndrome (TS) is a genetic disorder affecting mainly females that arises from a loss of X chromosome material, most usually one of the two X chromosomes. TS is associated with a number of characteristic physical features such as short stature and absent ovaries as well as a set of common neuropsychological deficits and social and behavioral features. This paper will serve to review the cognitive, social, and psychoeducational abilities of individuals with TS as well as neuroimaging findings. Several putative genetic mechanisms contributing to their particular neurocognitive deficits will also be described including candidate genes. In addition, the available evidence on how hormones affect specific abilities in TS will be reviewed. It will be concluded that the TS neurobehavioral profile arises from an atypical cerebral organization caused by the complex interplay of insufficient expression of certain (unknown) genes on the X chromosome and by abnormal hormonal levels; however, it is still not clear exactly how the specific genes affect broader cognitive abilities. Future research needs to identify the elemental processes that are disturbed in TS and map these both to events in early brain development and subsequent brain function and to specific gene and hormonal contributions.     

Behavioural phenotyping of transgenic mice

This paper reviews the current work on mouse genetics, brain, and behaviour in my laboratory. It starts with an historical account of our research and shows how certain research themes, such as olfaction, learning, social behaviour, and environmental effects in rodents have led to our current research on behavioural phenotyping of inbred, mutant, knockout, and transgenic mice. We are concerned with finding neural and behavioural sequelae to genetic manipulations in mice and use a battery of tests to detect behaviours that are altered in genetically modified mice. In this way we are working to dissociate neural and behavioural effects of different gene manipulations in mouse models of neurodegenerative diseases. Sensory, motor, cognitive, affective, and social behaviours may all be affected by gene manipulation, thus careful behavioural techniques, with attention to the mice themselves, the apparatus, and procedure, experimenter variables, and environmental effects are necessary in order to determine a reliable and valid mouse behavioural phenotype. As both the genome and the environment have significant effects on the behavioural phenotype, our future research will utilize an epigenetic approach to examine how environmental cues modulate gene expression in the behavioural phenotyping of transgenic mice.     

Genetics of neuronal migration in the cerebral cortex

The development of the cerebral cortex requires large-scale movement of neurons from areas of proliferation to areas of differentiation and adult function in the cortex proper, and the patterns of this neuronal migration are surprisingly complex. The migration of neurons is affected by several naturally occurring genetic defects in humans and mice; identification of the genes responsible for some of these conditions has recently yielded new insights into the mechanisms that regulate migration. Other key genes have been identified via the creation of induced mutations that can also cause dramatic disorders of neuronal migration. However, our understanding of the physiological and biochemical links between these genes is still relatively spotty. A number of molecules have also been studied in mice (Reelin, mDab1, and the VLDL and ApoE2 receptors) that appear to represent part of a coherent signaling pathway that regulates migration, because multiple genes cause an indistinguishable phenotype when mutated. On the other hand, two human genes that cause lissencephaly (LIS1, DCX) encode proteins that have recently been implicated as regulators or microtubule dynamics. This article reviews some of the mutant phenotypes in light of the mechanisms of neuronal migration. MRDD Research Reviews 6:34-40, 2000.     

Points to Consider in the Clinical Use of NGS Panels for Mitochondrial Disease: An Analysis of Gene Inclusion and Consent Forms

Mitochondrial next generation sequencing (NGS) panels offer single-step analysis of the numerous nuclear genes involved in the structure, function, and maintenance of mitochondria. However, the complexities of mitochondrial biology and genetics raise points for consideration in clinical use of these tests. To understand the current status of mitochondrial genetic testing, we assessed the gene offerings and consent forms of mitochondrial NGS panels available from seven US-based clinical laboratories. The NGS panels varied markedly in number of genes (101–1204 genes), and the proportion of genes causing “classic” mitochondrial diseases and their phenocopies ranged widely between labs (18 %–94 % of panel contents). All panels included genes not associated with classic mitochondrial diseases (6 %–28 % of panel contents), including genes causing adult-onset neurodegenerative disorders, cancer predisposition, and other genetic syndromes or inborn errors of metabolism. Five of the panels included genes that are not listed in OMIM to be associated with a disease phenotype (5 %–49 % of panel contents). None of the consent documents reviewed had options for patient preference regarding receipt of incidental findings. These findings raise points of discussion applicable to mitochondrial diagnostics, but also to the larger arenas of exome and genome sequencing, including the need to consider the boundaries between clinical and research testing, the necessity of appropriate informed consent, and the responsibilities of clinical laboratories and clinicians. Based on these findings, we recommend careful evaluation by laboratories of the genes offered on NGS panels, clear communication of the predicted phenotypes, and revised consent forms to allow patients to make choices about receiving incidental findings. We hope that our analysis and recommendations will help to maximize the considerable clinical utility of NGS panels for the diagnosis of mitochondrial disease.     

Is there a unique moral status of human DNA that prevents patenting?

The gene patenting debate, which proved to be a focal point for divergent moral concerns about recent developments in genome research and biotechnology, has revealed that the moral status of DNA is not clear. One of the arguments used to stop undesirable developments was that DNA possesses a unique status, which renders it unfit for patenting. This paper investigates the allegedly unique (moral) status of genetic material and the information it holds from different perspectives. Several properties of DNA prove to be unique. We examine the relevance of these for patentability of genes and conclude that only the unique symbolic meaning of DNA is a relevant factor, which should be taken into account but weighed against other interests involved.     

Demographic and Experiential Correlates of Public Attitudes Towards Cell-Free Fetal DNA Screening

This study seeks to inform clinical application of cell-free fetal DNA (cffDNA) screening as a novel method for prenatal trisomy detection by investigating public attitudes towards this technology and demographic and experiential characteristics related to these attitudes. Two versions of a 25-item survey assessing interest in cffDNA and existing first-trimester combined screening for either trisomy 13 and 18 or trisomy 21 were distributed among 3,164 members of the United States public. Logistic regression was performed to determine variables predictive of interest in screening options. Approximately 47 % of respondents expressed an interest in cffDNA screening for trisomy 13, 18, and 21, with a majority interested in cffDNA screening as a stand-alone technique. A significantly greater percent would consider termination of pregnancy following a diagnosis of trisomy 13 or 18 (52 %) over one of trisomy 21 (44 %). Willingness to consider abortion of an affected pregnancy was the strongest correlate to interest in both cffDNA and first-trimester combined screening, although markedly more respondents expressed an interest in some form of screening (69 % and 71 %, respectively) than would consider termination. Greater educational attainment, higher income, and insurance coverage predicted interest in cffDNA screening; stronger religious identification also corresponded to decreased interest. Prior experience with disability and genetic testing was associated with increased interest in cffDNA screening. Several of these factors, in addition to advanced age and Asian race, were, in turn, predictive of respondents’ increased willingness to consider post-diagnosis termination of pregnancy. In conclusion, divergent attitudes towards cffDNA screening—and prenatal options more generally – appear correlated with individual socioeconomic and religious backgrounds and experiences with disability and genetic testing. Clinical implementation and counseling for novel prenatal technologies should take these diverse stakeholder values into consideration.