Large-scale discovery of novel genetic causes of developmental disorders.

Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders

Developmental disorders

Introduction: Connectionist models have recently provided a concrete computational platform from which to explore how different initial constraints in the cognitive system can interact with an environment to generate the behaviors we find in normal development (Elman et al., 1996; Mareschal & Thomas, 2000). In this sense, networks embody several principles inherent to Piagetian theory, the major developmental theory of the twentieth century. By extension, these models provide the opportunity to explore how shifts in these initial constraints (or boundary conditions) can result in the emergence of the abnormal behaviors we find in atypical development. Although this field is very new, connectionist models have already been put forward to explain disordered language development in Specific Language Impairment (Hoeffner & McClelland, 1993), Williams Syndrome (Thomas & Karmiloff-Smith, 1999), and developmental dyslexia (Seidenberg and colleagues, see e.g. Harm & Seidenberg, in press); to explain unusual characteristics of perceptual discrimination in autism (Cohen, 1994; Gustafsson, 1997); and to explore the emergence of disordered cortical feature maps using a neurobiologically constrained model (Oliver, Johnson, Karmiloff-Smith, & Pennington, in press). In this entry, we will examine the types of initial constraints that connectionist modelers typically build in to their models, and how variations in these constraints have been proposed as possible accounts of the causes of particular developmental disorders. In particular, we will examine the claim that these constraints are candidates for what will constitute innate knowledge. First, however, we need to consider a current debate concerning whether developmental disorders are a useful tool to explore the (possibly innate) structure of the normal cognitive system. We will find that connectionist approaches are much more consistent with one side of this debate than the other

Developmental disorders of vision

This review of developmental disorders of vision focuses on a few of the many disorders that disrupt visual development. Given the enormity of the human visual system in the primate brain and complexity of visual development, however, there are likely hundreds or thousands of potential types of disorders affecting high-level vision. The rapid progress seen in developmental dyslexia and Williams syndrome demonstrates the possibilities and difficulties inherent in researching such disorders, and the authors hope that similar progress will be made for congenital prosopagnosia and other disorders in the near future

Screening, intervention and outcome in autism and other developmental disorders: the role of randomized controlled trials

We draw attention to a number of important considerations in the arguments about screening and outcome of intervention in children with autism and other developmental disorders. Autism screening in itself never provides a final clinical diagnosis, but may well identify developmental deviations indicative of autism—or of other developmental disorders—that should lead to referral for further clinical assessment. Decisions regarding population or clinic screening cannot be allowed to be based on the fact that prospective longitudinal RCT designs over decades could never be performed in complex developmental disorders. We propose an alternative approach. Early screening for autism and other developmental disorders is likely to be of high societal importance and should be promoted and rigorously evaluated

Models of atypical development must also be models of normal development

Functional magnetic resonance imaging studies of developmental disorders and normal cognition that include children are becoming increasingly common and represent part of a newly expanding field of developmental cognitive neuroscience. These studies have illustrated the importance of the process of development in understanding brain mechanisms underlying cognition and including children ill the study of the etiology of developmental disorders

Hyperacusis in children: a preliminary study on the effects of hypersensitivity to sound on speech and language

There is a growing awareness that children may experience hyperacusis, a condition that is often associated with behavioral and developmental disorders. This preliminary study was aimed to investigate the effects of hyperacusis alone on various components of speech and language in children without developmental disorders. This study was conducted on 109 children aged between 4 and 7 years attending kindergarten and primary school. Hyperacusis was assessed through behavioral observation of children and questionnaires for parents. Different components of speech and language were assessed through specific tests. Hyperacusis was diagnosed in fifteen children (13.8%); ten (66.7%) were attending primary school and five (33.3%) kindergarten. A significant difference between children with and without hyperacusis was found for tests evaluating the average number of words in a sentence and phonemic fluency; older children appeared to have more difficulties. Several differences in education profiles were found: parents of children with hyperacusis spent less time with their children compared to parents of children without hyperacusis. Our preliminary results suggest some difficulties in lexical access and the use of shorter sentences by children with hypersensitivity to sound; however, the small size of our sample and the largely unknown interactions between hyperacusis and developmental disorders suggest caution when interpreting these results. Further studies on larger samples are necessary to gain additional knowledge on the effects of hyperacusis on speech and language in children without developmental disorders

Working memory in children with developmental disorders

The aim of the present study was to directly compare working memory skills across students with different developmental disorders to investigate whether the uniqueness of their diagnosis would impact memory skills. The authors report findings confirming differential memory profiles on the basis of the following developmental disorders: Specific Language Impairment, Developmental Coordination Disorder (DCD), Attention-Deficit/Hyperactivity Disorder, and Asperger syndrome(AS). Specifically, language impairments were associated with selective deficits in verbal short-term and working memory, whereas motor impairments (DCD) were associated with selective deficits in visuospatial short-term and working memory. Children with attention problems were impaired in working memory in both verbal and visuospatial domains, whereas the children with AS had deficits in verbal short-term memory but not in any other memory component. The implications of these findings are discussed in light of support for learning

Evidence for 28 genetic disorders discovered by combining healthcare and research data

De novo mutations in protein-coding genes are a well-established cause of developmental disorders. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent–offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders

Attention to facial emotion expressions in children with autism

High-functioning children in the autism spectrum are frequently noted for their impaired attention to facial expressions of emotions. In this study, we examined whether attention to emotion cues in others could be enhanced in children with autism, by varying the relevance of children's attention to emotion expressions. Twenty-eight high-functioning boys with autism and 31 boys from a control group were asked to sort photos depicting smiling or frowning faces of adults. As found in earlier studies, in neutral conditions children with autism were less attentive to emotion expressions than children from a control group. This difference disappeared when children were explicitly asked to make a socially relevant decision. These findings suggest that the attention of children with autism to emotion expressions in others is influenced by situational factors. Theoretical implications of these findings are discussed. © 2006 SAGE Publications and The National Autistic Society