ABSTRACT
Comparative analyses have identified genomic regions potentially involved in human evolution but do not directly assess function. Human accelerated regions (HARs) represent conserved genomic loci with elevated divergence in humans. If some HARs regulate human-specific social and behavioral traits, then mutations would likely impact cognitive and social disorders. Strikingly, rare biallelic point mutations-identified by whole-genome and targeted "HAR-ome" sequencing-showed a significant excess in individuals with ASD whose parents share common ancestry compared to familial controls, suggesting a contribution in 5% of consanguineous ASD cases. Using chromatin interaction sequencing, massively parallel reporter assays (MPRA), and transgenic mice, we identified disease-linked, biallelic HAR mutations in active enhancers for CUX1, PTBP2, GPC4, CDKL5, and other genes implicated in neural function, ASD, or both. Our data provide genetic evidence that specific HARs are essential for normal development, consistent with suggestions that their evolutionary changes may have altered social and/or cognitive behavior. PAPERCLIP.
Subject(s)
Autism Spectrum Disorder/genetics , Cognition , Genetic Predisposition to Disease , Neurogenesis/genetics , Point Mutation , Social Behavior , Alleles , Animals , Cerebral Cortex/metabolism , Gene Dosage , Genetic Variation , Genome, Human , Homeodomain Proteins/genetics , Humans , Introns , Mice , Mice, Transgenic , Nuclear Proteins/genetics , Quantitative Trait Loci , Regulatory Elements, Transcriptional , Repressor Proteins/genetics , Transcription FactorsABSTRACT
OBJECTIVES: To study the efficacy and safety of olanzapine for the treatment of children with autism associated with disruptive behavior problems. SUBJECTS AND METHODS: A prospective open-label trial was conducted on 40 male children (mean age 12.2 +/- 2.2 years, range 7-17 years) meeting Diagnostic Statistical Manual IV criteria for autism. After a washout period from previous medications (2-14 days), patients received olanzapine (5-10 mg/day) for a 13-week treatment period. The primary efficacy measures were Aberrant Behavior Checklist (ABC) and Clinical Global Impressions-Severity (CGI-S) done at baseline and end of treatment. At the beginning and end of treatment, patients underwent laboratory and physical investigations: ECG, chest X-ray, urinalysis, serum chemistry, blood glucose and lipid profile, hematology and hepatitis B serology. RESULTS: Paired comparison of baseline and 13-week endpoint scores showed significant reductions in ABC subscale scores for irritability (p < 0.0001), lethargy (p < 0.0001), stereotyped behavior (p < 0.005), hyperactivity (p < 0.0001) and inappropriate speech (p < 0.005). Of 40 patients, 12 (30%) were considered as 'improved' on CGI-S scores compared to baseline, a statistically significant difference (p < 0.05). No liver enzyme elevation or any other serum biochemical changes resulted from treatment, which was not associated with significant body weight changes or any other treatment-emergent side effects. CONCLUSIONS: The study shows that olanzapine treatment can be beneficial in alleviating some behavioral symptoms (irritability, hyperactivity/noncompliance and lethargy/withdrawal) associated with autism. The short period of this trial limits inferences about adverse effects such as body weight increase and tardive dyskinesia. Further long-term placebo-controlled studies of olanzapine are required.
Subject(s)
Antipsychotic Agents/therapeutic use , Autistic Disorder/complications , Autistic Disorder/drug therapy , Benzodiazepines/therapeutic use , Mental Disorders/drug therapy , Mental Disorders/etiology , Adolescent , Child , Humans , Kuwait , Male , Olanzapine , Prospective Studies , Psychological Tests , PsychometricsABSTRACT
Excess or deficiency of natural trace elements has been implicated in the etiology of autism. This study explores whether concentration levels of toxic metals in the hair of children with autism significantly differ from those of age- and sex-matched healthy controls. In-hair concentration levels of antimony, uranium, arsenic, beryllium, mercury, cadmium, lead and aluminum from 40 boys with autism and 40 healthy boys were determined by Perkin-Elmer mass spectrometry. The children with autism had significantly (p<0.001) higher in-hair concentration levels of lead, mercury and uranium. There was no significant difference between the two groups in the other five toxic elements. The ratio between nutritional elements and toxic metals among children with autism was within the normal range. The possible sources of the toxic metals are discussed. Such testing is informative but at present the practical implications in terms of diagnosis and clinical management are limited.
Subject(s)
Autistic Disorder/metabolism , Hair/metabolism , Trace Elements/metabolism , Child , Child, Preschool , Hair/chemistry , Humans , Kuwait , Male , Trace Elements/analysisABSTRACT
Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.
Subject(s)
Autistic Disorder/diagnosis , Autistic Disorder/genetics , Exome/genetics , Genome-Wide Association Study/methods , Adolescent , Animals , Cells, Cultured , Child , Child, Preschool , Cohort Studies , Female , Humans , Male , Pedigree , Rats , Sequence Analysis, DNA/methods , Young AdultABSTRACT
To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of "homozygosity mapping" in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.