We are performing whole-genome sequencing of families with autism spectrum disorder (ASD) to build a resource (MSSNG) for subcategorizing the phenotypes and underlying genetic factors involved. Here ...we report sequencing of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible on a cloud platform and through a controlled-access internet portal. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertions and deletions or copy number variations per ASD subject. We identified 18 new candidate ASD-risk genes and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (P = 6 × 10
). In 294 of 2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried copy number variations and/or chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD.
Autism spectrum disorder (ASD) en- compasses wide variation in symptom severity and functional impact. The core features of ASD include impairments in social communication, repetitive behaviours and ...restricted interests. Not all people with ASD identify their challenges as a disorder. Autism spectrum disorder affects more than 1% of the population,1 and a dramatic increase in its recognition is creating huge demands on health care systems for timely and accurate diagnosis. Health care professionals in many capacities encounter people and their families coping with ASD, and optimal care depends on a large net- work of providers, given the breadth of the associated medical issues. The Autism and Developmental Disabilities Monitoring Network of the US Centers for Dis- ease Control has surveyed ASD among eight- year-olds from up to 14 US centres every two years since 2000. The most recent analysis, which pertains to the 2008 surveillance year,1 estimates the overall prevalence to be 1 in 88 children - almost double the prevalence re- ported in the original cohort. These data cannot distin guish betwe en an increase cause d b y changes in ascertainment and a true increase in prevalence. Global prevalence, as reported in a comprehensive survey of epidemiological reports from 1966 to 2011,2 suggests that autism is still under-recognized, particularly in developing countries. In Canada, a population prevalence of 1% implies that about 67 000 children, aged 3- 20 years have ASD. Boys with ASD outnumber girls by as much as 4:1, but the underlying rea- sons for this difference remain elusive.3 The diagnostic assessment of ASD allows a physician to determine if a child meets the accepted ASD criteria (usually per Diagnostic and Statistical Manual of Mental Disorders DSM criteria), identify comorbid medical or genetic syndromes or psychopathology, and identify the patient's treatment needs. Figure 1 shows the typical paths to diagnosis, starting with concerns (including "red flags") raised by parents, teachers, childcare providers, early childhood educators, family physicians or pedia- tricians. Primary care providers then determine whether an assessment is needed for ASD or another developmental issue. A detailed develop- mental history is collected from the parents, and additional information is collected from teachers, early childhood educators and health profession- als. It is essential for the primary care provider to spend time with the child engaged in structured play activities that assess social-emotional relat- edness, the ability of the child to respond to and direct the attention of others, and his or her use of gestures, imitation, imagination and conversa- tion. Multiple prospective and retrospective stud- ies support the recommendations of comprehen- sive reviews and guidelines on diagnosis.18,19
Autism spectrum disorder (ASD) is often grouped with other brain-related phenotypes into a broader category of neurodevelopmental disorders (NDDs). In clinical practice, providers need to decide ...which genes to test in individuals with ASD phenotypes, which requires an understanding of the level of evidence for individual NDD genes that supports an association with ASD. Consensus is currently lacking about which NDD genes have sufficient evidence to support a relationship to ASD. Estimates of the number of genes relevant to ASD differ greatly among research groups and clinical sequencing panels, varying from a few to several hundred. This Roadmap discusses important considerations necessary to provide an evidence-based framework for the curation of NDD genes based on the level of information supporting a clinically relevant relationship between a given gene and ASD.
Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared ...etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in <0.1% of 10,851 population control samples. We found clinically relevant CNVs (broadly defined) in 284 (10.5%) of total subjects, including 22 (10.8%) among subjects with SCZ, 209 (11.4%) with ASD, 40 (9.4%) with ADHD, and 13 (5.6%) with OCD. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic disorder variants. We searched further for genes impacted by different CNVs in multiple disorders. Examples of NDD-associated genes linked across more than one disorder (listed in order of occurrence frequency) are
,
,
,
,
,
,
,
,
,
, and long non-coding RNAs:
and
. We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants.
...all known genetic predispositions will be available and, depending on the data sharing policy, accessible to a wide range of researchers and, possibly, the public at large--this, at a time when we ...are still seeking to understand the social, clinical, and personal implications of genetic information. More research and policy analysis on the issues associated with data release is clearly needed, including an analysis of the actual harms and benefits resulting from publicly accessible data; the implications for family members and relevant communities; the appropriate balance between public access and individual privacy interests; and considerations regarding compensation for research-related injury resulting from participation in personal genome research.
The National Institute of Diabetes and Digestive and Kidney Diseases convened a workshop on research gaps in gestational diabetes mellitus (GDM) with a focus on 1) early pregnancy diagnosis and ...treatment and 2) pharmacologic treatment strategies. This article summarizes the proceedings of the workshop. In early pregnancy, the appropriate diagnostic criteria for the diagnosis of GDM remain poorly defined, and an effect of early diagnosis and treatment on the risk of adverse outcomes has not been demonstrated. Despite many small randomized controlled trials of glucose-lowering medication treatment in GDM, our understanding of medication management of GDM is incomplete as evidenced by discrepancies among professional society treatment guidelines. The comparative effectiveness of insulin, metformin, and glyburide remains uncertain, particularly with respect to long-term outcomes. Additional topics in need of further research identified by workshop participants included phenotypic heterogeneity in GDM and novel and individualized treatment approaches. Further research on these topics is likely to improve our understanding of the pathophysiology and treatment of GDM to improve both short- and long-term outcomes for mothers and their children.
Two developments have sparked new directions in the genetics-to-genomics transition for research and medical applications: the advance of whole-genome assays by array or DNA sequencing technologies, ...and the discovery among human genomes of extensive submicroscopic genomic structural variation, including copy number variation. For health care to benefit from interpretation of genomic data, we need to know how these variants contribute to the phenotype of the individual. Research is revealing the spectrum, both in size and complexity, of structural genotypic variation, and its association with a broad range of human phenotypes. Genomic disorders associated with relatively large, recurrent contiguous variants have been recognized for some time, as have certain Mendelian traits associated with functional disruption of single genes by structural variation. More recent examples from phenotype- and genotype-driven studies demonstrate a greater level of complexity, with evidence of incremental dosage effects, gene interaction networks, buffering and modifiers, and position effects. Mechanisms underlying such variation are emerging to provide a handle on the bulk of human variation, which is associated with complex traits and adaptive potential. Interpreting genotypes for personalized health care and communicating knowledge to the individual will be significant challenges for genomics professionals.
A challenge in clinical genomics is to predict whether copy number variation (CNV) affecting a gene or multiple genes will manifest as disease. Increasing recognition of gene dosage effects in ...neurodevelopmental disorders prompted us to develop a computational approach based on critical-exon (highly expressed in brain, highly conserved) examination for potential etiologic effects. Using a large CNV dataset, our updated analyses revealed significant (P < 1.64 × 10(-15)) enrichment of critical-exons within rare CNVs in cases compared to controls. Separately, we used a weighted gene co-expression network analysis (WGCNA) to construct an unbiased protein module from prenatal and adult tissues and found it significantly enriched for critical exons in prenatal (P < 1.15 × 10(-50), OR = 2.11) and adult (P < 6.03 × 10(-18), OR = 1.55) tissues. WGCNA yielded 1,206 proteins for which we prioritized the corresponding genes as likely to have a role in neurodevelopmental disorders. We compared the gene lists obtained from critical-exon and WGCNA analysis and found 438 candidate genes associated with CNVs annotated as pathogenic, or as variants of uncertain significance (VOUS), from among 10,619 developmental delay cases. We identified genes containing CNVs previously considered to be VOUS to be new candidate genes for neurodevelopmental disorders (GIT1, MVB12B and PPP1R9A) demonstrating the utility of this strategy to index the clinical effects of CNVs.
Autism Spectrum Disorder (ASD) is a developmental condition of early childhood onset, which impacts socio-communicative functioning and is principally genetic in etiology. Currently, more than 50 ...genomic loci are deemed to be associated with susceptibility to ASD, showing
and inherited unbalanced copy number variants (CNVs) and smaller insertions and deletions (indels), more complex structural variants (SVs), as well as single nucleotide variants (SNVs) deemed of pathological significance. However, the phenotypes associated with many of these genes are variable, and penetrance is largely unelaborated in clinical descriptions. This case report describes a family harboring two CNV microdeletions, which affect regions of
and
- each well-established in association with risk of ASD and other neurodevelopmental disorders. Although each CNV would likely be categorized as pathologically significant, both genomic alterations are transmitted in this family from an unaffected father to the proband, and shared by an unaffected sibling. This family case illustrates the importance of recognizing that phenotype can vary among exon overlapping variants of the same gene, and the need to evaluate penetrance of such variants in order to properly inform on risks.
PDF
