Working up autism: the practical role of medical genetics

The autism spectrum disorders (ASD) comprise a group of neurobehavioral phenotypes of heterogeneous etiology. In spite of a worldwide extensive research effort to unravel the genetic mystery of autism, medical geneticists are still facing an embarrassing lack of knowledge in dealing with the diagnosis, and consequently prognosis, of a child with autism. However, some lessons can be learned from accumulating experience in the clinical and molecular genetic evaluation of children with this condition. Patient evaluation, indications for molecular testing and counseling are the three aspects that will be discussed in this review.     

Parental attitudes toward genetic testing for pediatric deafness

Recent molecular genetic advances have resulted in genetic testing becoming an option for deaf individuals and their families. However, there is little information about the interest in such testing. To investigate this issue, parents with normal hearing who have one or more deaf children were surveyed about their attitudes toward diagnostic, carrier, and prenatal genetic testing for deafness. This population was chosen because it represents the majority of individuals who are encountered in clinical practice, given that 90%-95% of deaf individuals are born to persons with normal hearing. Of 328 surveys distributed, 96 were completed and returned. Of the respondents, 96% recorded a positive attitude toward genetic testing for deafness, including prenatal testing, although none would use this information to terminate an affected pregnancy. All respondents had a poor understanding of genetics, with 98% both incorrectly estimating the recurrence risk of deafness and misunderstanding the concept of inheritance. Notably, these findings were similar in the group who had had genetic testing for their children and in the group who had not, suggesting either that the parents who received genetic testing did not receive genetic counseling or that the counseling was not effective. On the basis of these results, it was concluded that this population is interested in the use of genetic testing and that testing should not be done without first providing formal genetic counseling. Appropriate counseling can help parents to understand the risks, benefits, and limitations of genetic testing.     

Application of Molecular Biology and Genetics in Endocrinology

ObjectiveTo review the growing impact of molecular biology and genetics on clinical endocrinology.MethodsMedical literature, databases, and Web sites describing genetics and genomic medicine with relevance for clinical endocrinology were reviewed.ResultsMany monogenic disorders can now be explained at the molecular level and the diagnosis can be established through mutational analysis. The ability to establish a molecular diagnosis is relevant for carrier detection and genetic counseling. In contrast to the significant advances in monogenic disorders, the current knowledge about the genetic components contributing to the pathogenesis of complex disorders is still relatively modest and is a major focus of current research efforts. Molecular biology already has an important impact on therapy in endocrine disorders. A broad spectrum of recombinant peptides and proteins are used in daily practice, eg, insulin and insulin analogues. Moreover, the increasingly detailed understanding of the molecular pathogenesis of cancer is leading to the development of novel and more specific inhibitors. While genetic testing has many advantages, it is important that physicians and patients are aware of potential limitations. They include, among others, technical limitations and allelic and nonallelic heterogeneity. These limitations need to be discussed in detail with patients and relatives, and it is often useful to involve a genetic counselor before obtaining informed consent by the individuals undergoing testing.ConclusionMolecular biology and genetics play an increasingly important role for the diagnosis and therapy of endocrine disorders. Challenges for the future include the elucidation of the genetic components contributing to complex disorders, eg, diabetes mellitus type 2, and the development of cheaper and comprehensive DNA sequencing technologies. Lastly, it is important that there is continuing attention directed towards the ethical, social, and legal aspects surrounding genetic medicine. (Endocr Pract, 2007;13: 534-541)     

Genetic tests obtainable through pharmacies: the good,the bad,and the ugly

Genomic medicine seeks to exploit an individual’s genomic information in the context of guiding the clinical decision-making process. In the post-genomic era, a range of novel molecular genetic testing methodologies have emerged, allowing the genetic testing industry to grow at a very rapid pace. As a consequence, a considerable number of different private diagnostic testing laboratories now provide a wide variety of genetic testing services, often employing a direct-to-consumer (DTC) business model to identify mutations underlying (or associated with) common Mendelian disorders, to individualize drug response, to attempt to determine an individual’s risk of a multitude of complex (multifactorial) diseases, or even to determine a person’s identity. Recently, we have noted a novel trend in the provision of private molecular genetic testing services, namely saliva and buccal swab collection kits (for deoxyribonucleic acid (DNA) isolation) being offered for sale over the counter by pharmacies. This situation is somewhat different from the standard DTC genetic testing model, since pharmacists are healthcare professionals who are supposedly qualified to give appropriate advice to their clients. There are, however, a number of issues to be addressed in relation to the marketing of DNA collection kits for genetic testing through pharmacies, namely a requirement for regulatory clearance, the comparative lack of appropriate genetics education of the healthcare professionals involved, and most importantly, the lack of awareness on the part of both the patients and the general public with respect to the potential benefits or otherwise of the various types of genetic test offered, which may result in confusion as to which test could be beneficial in their own particular case. We believe that some form of genetic counseling should ideally be integrated into, and made inseparable from, the genetic testing process, while pharmacists should be obliged to receive some basic training about the genetic tests that they offer for sale.     

Contemplating choice: attitudes towards intervening in human reproduction in Sri Lanka

To date, relatively little is known about the ethical, legal and social responses to recent advances in reproductive and genetic technology outside Europe and North America. This article reports on a survey carried out among doctors (n=278) and medical students (n=1256) in Sri Lanka to find out more about their responses to novel interventions in human reproduction such as In-Vitro Fertilization, Pre-Implantation Genetic Diagnosis and genetic engineering. In the first part of the paper comparisons are drawn between this survey and a survey carried out in 1985 which also considered issues surrounding amniocentesis and therapeutic termination. The second part of the paper deals with more recent developments. The analysis reveals high levels of support for the use of new technologies in treating infertility and identifying genetic disorders. However, differences are apparent among the major religious communities represented in the sample and these are particularly in evidence in relation to prenatal genetic diagnosis. An important theme throughout both surveys is the continuing tension surrounding State policy and termination of pregnancy and the implications this has for the development of screening and counseling services where genetic disorders are concerned.     

Evaluation of genetic tests for susceptibility to common complex diseases: why, when and how?

Recent research into the human genome has generated a wealth of scientific knowledge and increased both public and professional interest in the concept of personalised medicine. Somewhat unexpectedly, in addition to increasing our understanding about the genetic basis for numerous diseases, these new discoveries have also spawned a burgeoning new industry of ‘consumer genetic testing’. In this paper, we present the principles learnt though the evaluation of tests for single gene disorders and suggest a comparable framework for the evaluation of genetic tests for susceptibility to common complex diseases. Both physicians and the general public will need to be able to assess the claims made by providers of genetic testing services, and ultimately policy-makers will need to decide if and when such tests should be offered through state funded healthcare systems.     

Contemplating choice: attitudes towards intervening in human reproduction in Sri Lanka

To date, relatively little is known about the ethical, legal and social responses to recent advances in reproductive and genetic technology outside of Europe and North America. This article reports on a survey carried out among doctors (n?=?278) and medical students (n?=?1256) in Sri Lanka to find out more about their responses to novel interventions in human reproduction such as In-Vitro Fertilization, Pre-Implantation Genetic Diagnosis and genetic engineering. In the first part of the paper comparisons are drawn between this survey and a survey carried out in 1985 which also considered issues surrounding amniocentesis and therapeutic termination. The second part of the paper deals with more recent developments. The analysis reveals high levels of support for the use of new technologies in treating infertility and identifying genetic disorders. However, differences are apparent among the major religious communities represented in the sample and these are particularly in evidence in relation to pre-natal genetic diagnosis. An important theme throughout both surveys is the continuing tension surrounding State policy on termination of pregnancy and the implications this has for the development of screening and counseling services where genetic disorders are concerned.     

Diagnostic efficacy and new variants in isolated and complex autism spectrum disorder using molecular karyotyping

Autism spectrum disorder (ASD) is a group of the neurodevelopment disorders presenting as an isolated ASD or more complex forms, where a broader clinical phenotype comprised of developmental delay and intellectual disability is present. Both the isolated and complex forms have a significant causal genetic component and submicroscopic genomic copy number variations (CNV) are the most common identifiable genetic factor in these patients. The data on microarray testing in ASD cohorts are still accumulating and novel loci are often identified; therefore, we aimed to evaluate the diagnostic efficacy of the method and the relevance of implementing it into routine genetic testing in ASD patients. A genome-wide CNV analysis using the Agilent microarrays was performed in a group of 150 individuals with an isolated or complex ASD. Altogether, 11 (7.3%) pathogenic CNVs and 15 (10.0%) variants of unknown significance (VOUS) were identified, with the highest proportion of pathogenic CNVs in the subgroup of the complex ASD patients (14.3%). An interesting case of previously unreported partial UPF3B gene deletion was identified among the pathogenic CNVs. Among the CNVs with unknown significance, four VOUS involved genes with possible correlation to ASD, namely genes SNTG2, PARK2, CADPS2 and NLGN4X. The diagnostic efficacy of aCGH in our cohort was comparable with those of the previously reported and identified an important proportion of genetic ASD cases. Despite the continuum of published studies on the CNV testing in ASD cohorts, a considerable number of VOUS CNVs is still being identified, namely 10.0% in our study.     

Telephone genetic counseling for high-risk women undergoing BRCA1 and BRCA2 testing: rationale and development of a randomized controlled trial

Genetic counseling and testing, particularly for adult onset conditions, has become increasingly available over the last decade, and it is expected that this trend will continue as additional genes are identified and as such testing diffuses into mainstream clinical care. To meet the increased demand for services, it will become necessary to explore alternative avenues to traditional face-to-face genetic counseling. One such modality is the use of telephone genetic counseling (TGC), which is easy to implement and still allows for comprehensive service delivery. Although TGC has been used with increased frequency, there is a paucity of data about its effectiveness and impact on important patient outcomes. This paper provides an overview of the evolution of telephone counseling in nongenetics and genetics settings. The rationale and aims of the largest randomized clinical trial to be performed with this mode of counseling in the context of cancer susceptibility testing for mutations in the BRCA1 and BRCA2 genes are also explained. In addition, procedural aspects of the genetic counseling intervention and the novel tools developed to facilitate this process and to ensure adequate counselor training and quality assurance are described.     

Close genetic relationships between a spousal pair with autism-affected children and high minor allele content in cases in autism-associated SNPs

Parents of children affected with autism spectrum disorders (ASD) often have mild forms of autistic-like characteristics. Past studies have focused on searching for individual genetic risk loci of ASD. Here we studied the overall properties of the genomes of ASD trios by using previously published genome-wide data for common SNPs. The pairwise genetic distance (PGD) between a spousal pair with ASD-affected children was found smaller than that of a random pair selected among the spouses in the ASD trios, and spousal relatedness correlated with severe forms of ASD. Furthermore, for a set of 970 ASD associated SNPs, cases showed higher homozygous minor allele content than parents. These results indicate new genetic elements in the broad phenotypes of parents with ASD-affected offspring and in ASD pathogenesis.     

Convergent synaptic and circuit substrates underlying autism genetic risks

There has been a surge of diagnosis of autism spectrum disorders （ASD） over the past decade. While large, high powered genome screening studies of children with ASD have identified numerous genetic risk factors, research efforts to understanding how each of these risk factors contributes to the development autism has met with limited success. Revealing the mechanisms by which these genetic risk factors affect brain development and predispose a child to autism requires mechanistic understanding of the neurobiological changes underlying this devastating group of developmental disorders at multifaceted molecular, cellular and system levels. It has been increasingly clear that the normal trajectory of neurodevelopment is compromised in autism, in multiple domains as much as aberrant neuronal production, growth, functional maturation, patterned connectivity, and balanced excitation and inhibition of brain networks. Many autism risk factors identified in humans have been now reconstituted in experimental mouse models to allow mechanistic interrogation of the biological role of the risk gene. Studies utilizing these mouse models have revealed that underlying the enormous heterogeneity of perturbed cellular events, mechanisms directing synaptic and circuit assembly may provide a unifying explanation for the pathophysiological changes and behavioral endophenotypes seen in autism, although synaptic perturbations are far from being the only alterations relevant for ASD. In this review, we discuss synaptic and circuit abnormalities obtained from several prevalent mouse models, particularly those reflecting syndromic forms of ASD that are caused by single gene perturbations. These compiled results reveal that ASD risk genes contribute to proper signaling of the developing gene networks that maintain synaptic and circuit homeostasis, which is fundamental to normal brain development.     

Factors determining dissemination of results and uptake of genetic testing in families with known BRCA1/2 mutations

BACKGROUND: Uptake of genetic testing remains low, even in families with known BRCA1 and BRCA2 (BRCA1/2) mutations, despite effective interventions to reduce risk. We report disclosure and uptake patterns by BRCA1/2-positive individuals to at-risk relatives, in the setting of no-cost genetic counseling and testing. METHODS: Relatives of BRCA1/2-positive individuals were offered cost-free and confidential genetic counseling and testing. If positive for a BRCA1/2 mutation, participants were eligible to complete a survey about their disclosure of mutation status and the subsequent uptake of genetic testing by at-risk family members. RESULTS: One hundred and fifteen of 142 eligible individuals responded to the survey (81%). Eighty-eight (77%) of those surveyed disclosed results to all at-risk relatives. Disclosure to first-degree relatives (FDRs) was higher than to second-degree relatives (SDRs) and third-degree relatives (TDR) (95% vs. 78%; p < 0.01). Disclosure rates to male versus female relatives were similar, but reported completion of genetic testing was higher among female versus male FDRs (73% vs. 49%; p < 0.01) and SDRs (68% vs. 43%; p < 0.01), and among members of maternal versus paternal lineages (63% vs. 0%; p < 0.01). Men were more likely than women to express general difficulty discussing positive BCRA1/2 results with at-risk family members (90% vs. 70%; p = 0.03), while women reported more emotional distress associated with disclosure than men (48% vs. 13%; p < 0.01). DISCUSSION: We report a very high rate of disclosure of genetic testing information to at-risk relatives. However, uptake of genetic testing among at-risk individuals was low despite cost-free testing services, particularly in men, SDRs, and members of paternal lineages. The complete lack of testing among paternally related at-risk individuals and the lower testing uptake among men signify a significant barrier to testing and a challenge for genetic counselors and physicians working with high-risk groups. Further research is necessary to ensure that family members understand their risk and the potential benefits of genetic counseling.     

Mitochondriale Erkrankungen

As outlined in other articles of this issue mitochondrial medicine is a complex area in clinical genetics. Due to the wide variability of clinical presentation in both pediatric and adult patients there are frequent constellations of symptoms that may suggest an underlying mitochondrial disorder. This is a challenge in genetic counseling because basically all patterns of inheritance have to be taken into account??including maternal transmission??but a straightforward genetic testing to confirm or exclude the suggested diagnosis is hampered by the immense genetic heterogeneity of the mitochondrial disease spectrum. This article focuses on a diagnostic strategy and specific aspects of genetic counseling in mitochondrial disorders.     

Socioeconomic Inequality in the Prevalence of Autism Spectrum Disorder: Evidence from a U.S. Cross-Sectional Study

Background

This study was designed to evaluate the hypothesis that the prevalence of autism spectrum disorder (ASD) among children in the United States is positively associated with socioeconomic status (SES).

Methods

A cross-sectional study was implemented with data from the Autism and Developmental Disabilities Monitoring Network, a multiple source surveillance system that incorporates data from educational and health care sources to determine the number of 8-year-old children with ASD among defined populations. For the years 2002 and 2004, there were 3,680 children with ASD among a population of 557 689 8-year-old children. Area-level census SES indicators were used to compute ASD prevalence by SES tertiles of the population.

Results

Prevalence increased with increasing SES in a dose-response manner, with prevalence ratios relative to medium SES of 0.70 (95% confidence interval [CI] 0.64, 0.76) for low SES, and of 1.25 (95% CI 1.16, 1.35) for high SES, (P<0.001). Significant SES gradients were observed for children with and without a pre-existing ASD diagnosis, and in analyses stratified by gender, race/ethnicity, and surveillance data source. The SES gradient was significantly stronger in children with a pre-existing diagnosis than in those meeting criteria for ASD but with no previous record of an ASD diagnosis (p<0.001), and was not present in children with co-occurring ASD and intellectual disability.

Conclusions

The stronger SES gradient in ASD prevalence in children with versus without a pre-existing ASD diagnosis points to potential ascertainment or diagnostic bias and to the possibility of SES disparity in access to services for children with autism. Further research is needed to confirm and understand the sources of this disparity so that policy implications can be drawn. Consideration should also be given to the possibility that there may be causal mechanisms or confounding factors associated with both high SES and vulnerability to ASD.     

Dealing with complex matters: the political regulation of genetic testing and genetic counseling in Austria,Germany and Japan

The three OECD countries Austria, Germany and Japan in the 1990s and 2000s had to react to the increased application of genetic testing. The paper describes and analyses the regulatory efforts of the three countries that at first sight look very different from each other, Austria featuring a law on genetic testing, Germany finally regulating the matter by law after a long series of failed attempts to do so and Japan being content with self-regulation by medical professionals. Yet upon closer inspection a number of similarities become visible between the three democracies’ efforts to come to terms with the challenges of dealing with a matter as knowledge-intensive and complex as genetic testing and counseling.     

Developing the Autism Model of Implementation for Autism spectrum disorder community providers: study protocol

ABSTRACT: BACKGROUND: Currently, 1 out of 88 children are diagnosed with an autism spectrum disorder (ASD), and the estimated cost for treatment services is $126 billion annually. Typically, ASD community providers (ASD-CPs) provide services to children with any severity of ASD symptoms using a combination of various treatment paradigms, some with an evidence-base and some without. When evidence-based practices (EBPs) are successfully implemented by ASD-CPs, they can result in positive outcomes. Despite this promise, EBPs are often implemented unsuccessfully and other treatments used by ASD-CPs lack supportive evidence, especially for school-age children with ASD. While it is not well understood why ASD-CPs are not implementing EBPs, organizational and individual characteristics likely play a role. As a response to this need and to improve the lives of children with ASD and their families, this study aims to develop and test the feasibility and acceptability of the Autism Model of Implementation (AMI) to support the implementation of EBPs by ASD-CPs. Methods/design An academic-community collaboration developed to partner with ASD-CPs will facilitate the development of the AMI, a process specifically for use by ASD community-based agencies. Using a mixed methods approach, the project will assess agency and individual factors likely to facilitate or hinder implementing EBPs in this context; develop the AMI to address identified barriers and facilitators; and pilot test the AMI to examine its feasibility and acceptability using a specific EBP to treat anxiety disorders in school-age children with ASD. DISCUSSION: The AMI will represent a data-informed approach to facilitate implementation of EBPs by ASD-CPs by providing an implementation model specifically developed for this context. This study is designed to address the real-world implications of EBP implementation in ASD community-based agencies. In doing so, the AMI will help to provide children with ASD the best and most effective services in their own community. Moreover, the proposed study will positively impact the field of implementation science by providing an empirically supported and tested model of implementation to facilitate the identification, adoption, and use of EBPs.     

Professional and personal attitudes about access and confidentiality in the genetic testing of children: a pilot study

The ability to perform predictive genetic testing of children raises ethical concerns regarding whether and when to test and the disclosure of results. Semi-structured interviews with a convenience sample of pediatricians (12) and geneticists (13) were conducted to see how they would react to parental requests for predictive genetic testing of their children, and their attitudes about testing their own children. We also asked about disclosure attitudes and practices for their patients' relatives and within their own families. Respondents would provide predictive genetic testing for most conditions, yet were less likely to seek this information about their own children. Respondents believed it was very important for patients to share some types of genetic information with relatives, and were directive in their counseling about intrafamilial disclosure, especially within their own families. Although respondents would almost never breach patient confidentiality, many would breach confidentiality within their own families. Health care professionals distinguish between their professional and personal roles with regard to issues of access and confidentiality in predictive testing of children. They are willing to provide greater access and more confidentiality for their patients than within their own families.     

Motivations and concerns of women considering genetic testing for breast cancer: a comparison between affected and at-risk probands

Since the discovery of the BRCA1 and BRCA2 genes, there has been an increasing demand for breast cancer risk assessment programs. In an effort to understand and serve the population such programs target better, several studies have identified factors influencing high-risk women to pursue breast cancer risk assessment and genetic testing services; none, however, has focused on how the motivations and concerns of at-risk women may differ from their previously affected counterparts, who are typically the initial members of their families to undergo genetic testing. The majority of both previously affected and unaffected women felt that preventative surgery decisions, surveillance practices, the assessment of children's risks, and increased breast cancer anxiety were "more important" or "very important" issues regarding their thoughts about genetic testing. Significantly more affected women deemed family members' opinions "more" or "very important" (p < 0.01). Opinions concerning insurance and employment discrimination did not vary significantly between groups; however, a larger percentage of affected women felt this issue was of importance. Although all issues above should be addressed with women seeking cancer risk assessment and genetic testing, this research may help health care providers to gain a greater understanding of how the motivators and concerns of high-risk women can differ with personal cancer status so that referral, counseling, and education can be executed optimally.     

Genetics and mitochondrial abnormalities in autism spectrum disorders: a review

We review the current status of the role and function of the mitochondrial DNA (mtDNA) in the etiology of autism spectrum disorders (ASD) and the interaction of nuclear and mitochondrial genes. High lactate levels reported in about one in five children with ASD may indicate involvement of the mitochondria in energy metabolism and brain development. Mitochondrial disturbances include depletion, decreased quantity or mutations of mtDNA producing defects in biochemical reactions within the mitochondria. A subset of individuals with ASD manifests copy number variation or small DNA deletions/duplications, but fewer than 20 percent are diagnosed with a single gene condition such as fragile X syndrome. The remaining individuals with ASD have chromosomal abnormalities (e.g., 15q11-q13 duplications), other genetic or multigenic causes or epigenetic defects. Next generation DNA sequencing techniques will enable better characterization of genetic and molecular anomalies in ASD, including defects in the mitochondrial genome particularly in younger children.     

Genetic architecture in autism spectrum disorder

Autism spectrum disorder (ASD) is characterized by impairments in reciprocal social interaction and communication, and by restricted and repetitive behaviors. Family studies indicate a significant genetic basis for ASD susceptibility, and genomic scanning is beginning to elucidate the underlying genetic architecture. Some 5-15% of individuals with ASD have an identifiable genetic etiology corresponding to known chromosomal rearrangements or single gene disorders. Rare (<1% frequency) de novo or inherited copy number variations (CNVs) (especially those that affect genes with synaptic function) are observed in 5-10% of idiopathic ASD cases. These findings, coupled with genome sequencing data suggest the existence of hundreds of ASD risk genes. Common variants, yet unidentified, exert only small effects on risk. Identification of ASD risk genes with high penetrance will broaden the targets amenable to genetic testing; while the biological pathways revealed by the deeper list of ASD genes should narrow the targets for therapeutic intervention.