Structural variation (copy number variation CNV including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder ...(ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in ∼7% and ∼2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the
SHANK3-
NLGN4-
NRXN1 postsynaptic density genes and also identify novel loci at
DPP6-DPP10-PCDH9 (synapse complex),
ANKRD11,
DPYD,
PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at ∼1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.
This article seeks to provide the practising clinician with guidance on the pharmacological management of tic disorders in children and adults. We performed a systematic review of the literature on ...the treatment of tic disorders. A multi-institutional group of 14 experts in psychiatry, child psychiatry, neurology, pediatrics, and psychology engaged in a consensus meeting. The evidence was presented and discussed, and nominal group techniques were employed to arrive at consensus on recommendations. A strong recommendation is made when the benefits of treatment clearly outweigh the risks and burdens, and can apply to most patients in most circumstances without reservation. With a weak recommendation, the benefits, risks, and burdens are more closely balanced, and the best action may differ depending on the circumstances. Based on these principles, weak recommendations were made for the use of pimozide, haloperidol, fluphenazine, metoclopramide (children only), risperidone, aripiprazole, olanzapine, quetiapine, ziprasidone, topiramate, baclofen (children only), botulinum toxin injections, tetrabenazine, and cannabinoids (adults only). Strong recommendations were made for the use of clonidine and guanfacine (children only). While the evidence supports the efficacy of many of the antipsychotics for the treatment of tics, the high rates of side effects associated with these medications resulted in only weak recommendations for these drugs. In situations where tics are not severe or disabling, the use of a medication with only a weak recommendation is not warranted. However, when tics are more distressing and interfering, the need for tic suppression to improve quality of life is stronger, and patients and clinicians may be more willing to accept the risks of pharmacotherapy.
The use of genome-wide tests to provide molecular diagnosis for individuals with autism spectrum disorder (ASD) requires more study.
To perform chromosomal microarray analysis (CMA) and whole-exome ...sequencing (WES) in a heterogeneous group of children with ASD to determine the molecular diagnostic yield of these tests in a sample typical of a developmental pediatric clinic.
The sample consisted of 258 consecutively ascertained unrelated children with ASD who underwent detailed assessments to define morphology scores based on the presence of major congenital abnormalities and minor physical anomalies. The children were recruited between 2008 and 2013 in Newfoundland and Labrador, Canada. The probands were stratified into 3 groups of increasing morphological severity: essential, equivocal, and complex (scores of 0-3, 4-5, and ≥6).
All probands underwent CMA, with WES performed for 95 proband-parent trios.
The overall molecular diagnostic yield for CMA and WES in a population-based ASD sample stratified in 3 phenotypic groups.
Of 258 probands, 24 (9.3%, 95%CI, 6.1%-13.5%) received a molecular diagnosis from CMA and 8 of 95 (8.4%, 95%CI, 3.7%-15.9%) from WES. The yields were statistically different between the morphological groups. Among the children who underwent both CMA and WES testing, the estimated proportion with an identifiable genetic etiology was 15.8% (95%CI, 9.1%-24.7%; 15/95 children). This included 2 children who received molecular diagnoses from both tests. The combined yield was significantly higher in the complex group when compared with the essential group (pairwise comparison, P = .002). table: see text.
Among a heterogeneous sample of children with ASD, the molecular diagnostic yields of CMA and WES were comparable, and the combined molecular diagnostic yield was higher in children with more complex morphological phenotypes in comparison with the children in the essential category. If replicated in additional populations, these findings may inform appropriate selection of molecular diagnostic testing for children affected by ASD.
Recurrent microdeletions and microduplications of approximately 555 kb at 16p11.2 confer susceptibility to autism spectrum disorder (ASD) in up to 1% of ASD patients. No physical or behavioural ...features have been identified that distinguish these individuals as having a distinct ASD subtype, but clinical data are limited.
We report five autistic probands identified by microarray analysis with copy number variation (CNV) of 16p11.2 (three deletions, two duplications). Each patient was assessed for ASD and dysmorphic features. We also describe a deletion positive 26-month-old female who has developmental delay (DD) and autistic features.
Proband 1 (female with ASD, de novo deletion) is not dysmorphic. Proband 2 (male with autism, de novo deletion) and proband 3 and his brother (males with autism, inherited deletions) are dysmorphic, but the two probands do not resemble one another. The mother of proband 3 has mild mental retardation (MR), minor dysmorphism and meets the criteria for ASD. Proband 4 (dysmorphic autistic male, de novo duplication) had a congenital diaphragmatic hernia. Proband 5 (non-dysmorphic ASD female with a duplication) has two apparently healthy duplication positive relatives. Probands 1 and 2 have deletion negative siblings with ASD and Asperger syndrome, respectively. Proband 6 (a female with DD and an inherited duplication) is dysmorphic, but has oligohydramnios sequence.
The phenotypic spectrum associated with CNV at 16p11.2 includes ASD, MR/DD and/or possibly other primary psychiatric disorders. Compared with the microduplications, the reciprocal microdeletions are more likely to be penetrant and to be associated with non-specific major or minor dysmorphism. There are deletion positive ASD probands with a less severe phenotype than deletion negative ASD siblings underscoring the significant phenotypic heterogeneity.
This clinical guideline provides recommendations for nonpharmacological treatments for tic disorders. We conducted a systematic literature search for clinical trials on the treatment of tics. One ...evidence-based review (including 30 studies) and 3 studies on behavioural interventions, 3 studies on deep brain stimulation (DBS), and 3 studies on transcranial magnetic stimulation (TMS) met our inclusion criteria. Based on this evidence, we have made strong recommendations for the use of habit reversal therapy and exposure and response prevention, preferably embedded within a supportive, psychoeducational program, and with the option to combine either of these approaches with pharmacotherapy. Although evidence exists for the effcacy of DBS, the quality of this evidence is poor and the risks and burdens of the procedure are fnely balanced with the perceived benefts. Our recommendation is that this intervention continues to be considered an experimental treatment for severe, medically refractory tics that have imposed severe limitations on quality of life. We recommend that the procedure should only be performed within the context of research studies and by physicians expert in DBS programming and in the management of tics. There is no evidence to support the use of TMS in the treatment of tics. However, the procedure is associated with a low rate of known complications and could continue to be evaluated within research protocols. The recommendations we provide are based on current knowledge, and further studies may result in their revision in future.
Adversity in early childhood may have a profound impact on physical and mental health as well as general well-being later in life. Despite increasing research evidence on the lifelong impact of ...adverse experiences, one of the key questions that motivated this research was how to translate this knowledge into preventive measures. This article presents data from an exploratory study aimed to explore strategies and effective practices to prevent adverse experiences in early childhood. An ecological framework organized participants' suggested actions, highlighting the importance of proactive, multifaceted approaches and interventions that connect the child to the background environment where adversity takes place.
Mutant alleles of TMPRSS3 are associated with nonsyndromic recessive deafness (DFNB8/B10). TMPRSS3 encodes a predicted secreted serine protease, although the deduced amino acid sequence has no signal ...peptide. In this study, we searched for mutant alleles of TMPRSS3 in families from Pakistan and Newfoundland with recessive deafness co-segregating with DFNB8/B10 linked haplotypes and also more thoroughly characterized the genomic structure of TMPRSS3.
We enrolled families segregating recessive hearing loss from Pakistan and Newfoundland. Microsatellite markers flanking the TMPRSS3 locus were used for linkage analysis. DNA samples from participating individuals were sequenced for TMPRSS3. The structure of TMPRSS3 was characterized bioinformatically and experimentally by sequencing novel cDNA clones of TMPRSS3.
We identified mutations in TMPRSS3 in four Pakistani families with recessive, nonsyndromic congenital deafness. We also identified two recessive mutations, one of which is novel, of TMPRSS3 segregating in a six-generation extended family from Newfoundland. The spectrum of TMPRSS3 mutations is reviewed in the context of a genotype-phenotype correlation. Our study also revealed a longer isoform of TMPRSS3 with a hitherto unidentified exon encoding a signal peptide, which is expressed in several tissues.
Mutations of TMPRSS3 contribute to hearing loss in many communities worldwide and account for 1.8% (8 of 449) of Pakistani families segregating congenital deafness as an autosomal recessive trait. The newly identified TMPRSS3 isoform e will be helpful in the functional characterization of the full length protein.
Structural variation (copy number variation CNV including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder ...(ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and reexamined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in ~7% and ~2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6- DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at ~1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup. PUBLICATION ABSTRACT
A mentally retarded male with dysmorphic features was found to have a de novo 46,XY,inv dup(8) (p.23.1-->12). Confirmation of the segments duplicated in the rearrangement was achieved by biochemical ...analysis of glutathione reductase, which maps to 8p21.1, and DNA studies using the chromosome specific probe y-19-1D (D85131), which maps to 8p21. Assay of cathepsin B, which has been localised to 8p22, did not differ from controls with normal chromosomal constitution. DNA studies using the Defensin 1 gene probe, which maps to 8p23, showed a previously undetected deletion of that segment. We propose that the inverted tandem duplication/deletion arose as a single U-type exchange within an inversion loop.
RNA-binding proteins (RBPs) act as posttranscriptional regulators controlling the fate of target mRNAs. Unraveling how RNAs are recognized by RBPs and in turn are assembled into neuronal RNA granules ...is therefore key to understanding the underlying mechanism. While RNA sequence elements have been extensively characterized, the functional impact of RNA secondary structures is only recently being explored. Here, we show that Staufen2 binds complex, long-ranged RNA hairpins in the 3'-untranslated region (UTR) of its targets. These structures are involved in the assembly of Staufen2 into RNA granules. Furthermore, we provide direct evidence that a defined
RNA duplex regulates Staufen2-dependent RNA localization to distal dendrites. Importantly, disrupting the RNA hairpin impairs the observed effects. Finally, we show that these secondary structures differently affect protein expression in neurons. In conclusion, our data reveal the importance of RNA secondary structure in regulating RNA granule assembly, localization and eventually translation. It is therefore tempting to speculate that secondary structures represent an important code for cells to control the intracellular fate of their mRNAs.
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