55 research outputs found
The Role of Parental Cognitive, Behavioral, and Motor Profiles in Clinical Variability in Individuals with Chromosome 16p11.2 Deletions
Importance Most disorders caused by copy number variants (CNVs) display significant clinical variability, often referred to as incomplete penetrance and variable expressivity. Genetic and environmental sources of this variability are not well understood.
Objectives To investigate the contributors to phenotypic variability in probands with CNVs involving the same genomic region; to measure the effect size for de novo mutation events; and to explore the contribution of familial background to resulting cognitive, behavioral, and motor performance outcomes in probands with de novo CNVs.
Design, Setting, and Participants Family-based study design with a volunteer sample of 56 individuals with de novo 16p11.2 deletions and their noncarrier parents and siblings from the Simons Variation in Individuals Project.
Main Outcomes and Measures We used linear mixed-model analysis to measure effect size and intraclass correlation to determine the influence of family background for a de novo CNV on quantitative traits representing the following 3 neurodevelopmental domains: cognitive ability (Full-Scale IQ), social behavior (Social Responsiveness Scale), and neuromotor performance (Purdue Pegboard Test). We included an anthropometric trait, body mass index, for comparison.
Results A significant deleterious effect of the 16p11.2 deletion was demonstrated across all domains. Relative to the biparental mean, the effect sizes were −1.7 SD for cognitive ability, 2.2 SD for social behavior, and −1.3 SD for neuromotor performance (P \u3c .001). Despite large deleterious effects, significant positive correlations between parents and probands were preserved for the Full-Scale IQ (0.42 [P = .03]), the verbal IQ (0.53 [P = .004]), and the Social Responsiveness Scale (0.52 [P = .009]) scores. We also observed a 1-SD increase in the body mass index of probands compared with siblings, with an intraclass correlation of 0.40 (P = .07).
Conclusions and Relevance Analysis of families with de novo CNVs provides the least confounded estimate of the effect size of the 16p11.2 deletion on heritable, quantitative traits and demonstrates a 1- to 2-SD effect across all neurodevelopmental dimensions. Significant parent-proband correlations indicate that family background contributes to the phenotypic variability seen in this and perhaps other CNV disorders and may have implications for counseling families regarding their children’s developmental and psychiatric prognoses. Use of biparental mean scores rather than general population mean scores may be more relevant to examine the effect of a mutation or any other cause of trait variation on a neurodevelopmental outcome and possibly on systems of diagnosis and trait ascertainment for developmental disorders
Existence of a lens-shaped cluster of surfaces self-shrinking by mean curvature
We rigorously show the existence of a rotationally and centrally symmetric
"lens-shaped" cluster of three surfaces, meeting at a smooth common circle,
forming equal angles of 120 degrees, self-shrinking under the motion by mean
curvature.Comment: 22 pages, 2 figure
DLG4-related synaptopathy: a new rare brain disorder
PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing.RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies.CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.Genetics of disease, diagnosis and treatmen
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The MATRICS consensus cognitive battery for the assessment of cognitive impairment in schizotypal personality disorder
Cognitive deficits are a core impairment across the range of schizophrenia (SZ) spectrum disorders, including schizotypal personality disorder (SPD). The MATRICS Consensus Cognitive Battery (MCCB) was developed to be a robust, specific, and valid cognitive assessment battery to assess cognition in clinical trials for treating cognitive impairments in SZ. Despite the similarity of cognitive impairments shown in SPD and SZ and the clear relevance of uniform assessment across a diagnostic spectrum, the MCCB has yet to be validated in SPD. As such, this is the first study to evaluate the sensitivity of the MCCB for the assessment of cognitive function in individuals with SPD. Participants were 30 individuals with SPD and 54 healthy controls (HC) assessed with the MCCB and supplemental neurocognitive assessments (Trails B, DOT test, Paced Auditory Serial Addition Test (PASAT), AX Continuous Performance Task (AX-CPT), and N-back). Individuals with SPD performed worse than HC participants on all MCCB subtests, as well as on converging supplemental tasks including Trails B, DOT test, PASAT, AX-CPT, and N-back. These results indicate that the MCCB was sensitive to cognitive impairment in SPD compared to controls. SPD participants demonstrate impairments similar to data of SZ participants within the literature, although to a slightly lesser degree of severity. Taken together, these results highlight the generalizability of using the MCCB across SZ spectrum diagnostic groups to assess cognition. Such findings allow for further comparison across disorders, greater understanding of the cognitive characteristics in the spectrum, and use of uniform assessment within cognitive intervention research
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