The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing.

PURPOSE: Dilated cardiomyopathy is characterized by substantial locus, allelic, and clinical heterogeneity that necessitates testing of many genes across clinically overlapping diseases. Few studies have sequenced sufficient individuals; thus, the contributions of individual genes and the pathogenic variant spectrum are still poorly defined. We analyzed 766 dilated cardiomyopathy patients tested over 5 years in our molecular diagnostics laboratory. METHODS: Patients were tested using gene panels of increasing size from 5 to 46 genes, including 121 cases tested with a multiple-cardiomyopathy next-generation panel covering 46 genes. All variants were reassessed using our current clinical-grade scoring system to eliminate false-positive disease associations that afflict many older analyses. RESULTS: Up to 37% of dilated cardiomyopathy cases carry a clinically relevant variant in one of 20 genes, titin (TTN) being the largest contributor (up to 14%). Desmoplakin (DSP), an arrhythmogenic right ventricular cardiomyopathy gene, contributed 2.4%, illustrating the utility of multidisease testing. The clinical sensitivity increased from 10 to 37% as gene panel sizes increased. However, the number of inconclusive cases also increased from 4.6 to 51%. CONCLUSION: Our data illustrate the utility of broad gene panels for genetically and clinically heterogeneous diseases but also highlight challenges as molecular diagnostics moves toward genome-wide testing.

Teaching Parents Behavioral Strategies for Autism Spectrum Disorder (ASD): Effects on Stress, Strain, and Competence.

We report on parent outcomes from a randomized clinical trial of parent training (PT) versus psychoeducation (PEP) in 180 children with autism spectrum disorder (ASD) and disruptive behavior. We compare the impact of PT and PEP on parent outcomes: Parenting Stress Index (PSI), Parent Sense of Competence (PSOC), and Caregiver Strain Questionnaire (CGSQ). Mixed-effects linear models evaluated differences at weeks 12 and 24, controlling for baseline scores. Parents in PT reported greater improvement than PEP on the PSOC (ES = 0.34), CGSQ (ES = 0.50), and difficult child subdomain of the PSI (ES = 0.44). This is the largest trial assessing PT in ASD on parent outcomes. PT reduces disruptive behavior in children, and improves parental competence while reducing parental stress and parental strain.

Coilin, the signature protein of Cajal bodies, differentially modulates the interactions of plants with viruses in widely different taxa.

Cajal bodies (CBs) are distinct nuclear bodies physically and functionally associated with the nucleolus. In addition to their traditional function in coordinating maturation of certain nuclear RNAs, CBs participate in cell cycle regulation, development, and regulation of stress responses. A key "signature" component of CBs is coilin, the scaffolding protein essential for CB formation and function. Using an RNA silencing (loss-of-function) approach, we describe here new phenomena whereby coilin also affects, directly or indirectly, a variety of interactions between host plants and viruses that have RNA or DNA genomes. Moreover, the effects of coilin on these interactions are manifested differently: coilin contributes to plant defense against tobacco rattle virus (tobravirus), tomato black ring virus (nepovirus), barley stripe mosaic virus (hordeivirus), and tomato golden mosaic virus (begomovirus). In contrast, with potato virus Y (potyvirus) and turnip vein clearing virus (tobamovirus), coilin serves to increase virus pathogenicity. These findings show that interactions with coilin (or CBs) may involve diverse mechanisms with different viruses and that these mechanisms act at different phases of virus infection. Thus, coilin (CBs) has novel, unexpected natural functions that may be recruited or subverted by plant viruses for their own needs or, in contrast, are involved in plant defense mechanisms that suppress host susceptibility to the viruses.

Comprehensive diagnostic testing for stereocilin: an approach for analyzing medically important genes with high homology.

Next-generation sequencing (NGS) technologies have revolutionized genetic testing by enabling simultaneous analysis of unprecedented numbers of genes. However, genes with high-sequence homology pose challenges to current NGS technologies. Because diagnostic sequencing is moving toward exome analysis, knowledge of these homologous genes is essential to avoid false positive and negative results. An example is the STRC gene, one of >70 genes known to contribute to the genetic basis of hearing loss. STRC is 99.6% identical to a pseudogene (pSTRC) and therefore inaccessible to standard NGS methodologies. The STRC locus is also known to be a common site for large deletions. Comprehensive diagnostic testing for inherited hearing loss therefore necessitates a combination of several approaches to avoid pseudogene interference. We have developed a clinical test that combines standard NGS and NGS-based copy number assessment supplemented with a long-range PCR-based Sanger or MiSeq assay to eliminate pseudogene contamination. By using this combination of assays we could identify biallelic STRC variants in 14% (95% CI, 8%-24%) of individuals with isolated nonsyndromic hearing loss who had previously tested negative on our 70-gene hearing loss panel, corresponding to a detection rate of 11.2% (95% CI, 6%-19%) for previously untested patients. This approach has broad applicability because medically significant genes for many disease areas include genes with high-sequence homology.

A strong interactive link between sensory discriminations and intelligence.

Early psychologists, including Galton, Cattell, and Spearman, proposed that intelligence and simple sensory discriminations are constrained by common neural processes, predicting a close link between them. However, strong supporting evidence for this hypothesis remains elusive. Although people with higher intelligence quotients (IQs) are quicker at processing sensory stimuli, these broadly replicated findings explain a relatively modest proportion of variance in IQ. Processing speed alone is, arguably, a poor match for the information processing demands on the neural system. Our brains operate on overwhelming amounts of information, and thus their efficiency is fundamentally constrained by an ability to suppress irrelevant information. Here, we show that individual variability in a simple visual discrimination task that reflects both processing speed and perceptual suppression strongly correlates with IQ. High-IQ individuals, although quick at perceiving small moving objects, exhibit disproportionately large impairments in perceiving motion as stimulus size increases. These findings link intelligence with low-level sensory suppression of large moving patterns--background-like stimuli that are ecologically less relevant. We conjecture that the ability to suppress irrelevant and rapidly process relevant information fundamentally constrains both sensory discriminations and intelligence, providing an information-processing basis for the observed link.

Are executive control functions related to autism symptoms in high-functioning children?

BACKGROUND: Linking autism symptoms to cognitive abilities can expand phenotypic descriptions and facilitate investigations into the etiology and treatment of this multiplex disorder. Executive dysfunction is one of several potential cognitive phenotypes in autism. METHOD: Archival clinical data on 89 children diagnosed with Autism Spectrum Disorders and administered a large neuropsychological battery were evaluated for relationships between executive functioning and autism symptoms. RESULTS: Significant relationships between both laboratory tasks and behavior rating scales of executive functions and autism symptoms were identified. Multiple regression analyses revealed that measures of semantic fluency, divided auditory attention, and behavioral regulation were significantly correlated with autism symptoms, even after accounting for the variance from correlated "nuisance variables," such as vocabulary and age. CONCLUSIONS: Executive dysfunction is related to all three clusters of behavioral symptoms in Autism Spectrum Disorders.

Set-shifting in children with autism spectrum disorders: reversal shifting deficits on the Intradimensional/Extradimensional Shift Test correlate with repetitive behaviors.

Research examining set-shifting has revealed significant difficulties for adults with autism spectrum disorders (ASDs). However, research with high-functioning children with ASDs has yielded mixed results. The current study tested 6- to 13-year-old high-functioning children with ASD and typically developing controls matched on age, gender, and IQ using the Intradimensional/Extradimensional (ID/ED) Shift Test from the Cambridge Neuropsychological Test Automated Battery. Children with ASDs completed as many ED shifts and reversal ED shifts as controls; however, they made significantly more errors than controls while completing the ED reversal shifts. Analyses on a subset of cases revealed a significant positive correlation between ED reversal errors and the number of repetitive behavior symptoms in the ASD group. These findings suggest that high-functioning children with ASDs require additional feedback to shift successfully. In addition, the relationship between set-shifting and non-social symptoms suggests its utility as a potentially informative intermediate phenotype in ASDs.