BACKGROUND Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management. METHODS We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization. RESULTS Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P = 2.11×10−38). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; P<0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P<0.001), and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring (P = 0.02). CONCLUSIONS Multiple, large copy-number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy-number variants are preferentially transmitted from maternal carriers. (Funded by the Simons Foundation Autism Research Initiative and the National Institutes of Health.)

Heterogeneity within groups of psychiatric patients poses problems for theory, research, and treatment. The present study illustrates that the distinction between juvenile vs adult-onset MDD is important for understanding heterogeneity within depression.

Allan-Herndon-Dudley syndrome was among the first of the X-linked mental retardation syndromes to be described (in 1944) and among the first to be regionally mapped on the X chromosome (in 1990). Six large families with the syndrome have been identified, and linkage studies have placed the gene locus in Xq13.2. Mutations in the monocarboxylate transporter 8 gene (MCT8) have been found in each of the six families. One essential function of the protein encoded by this gene appears to be the transport of triiodothyronine into neurons. Abnormal transporter function is reflected in elevated free triiodothyronine and lowered free thyroxine levels in the blood. Infancy and childhood in the Allan-Herndon-Dudley syndrome are marked by hypotonia, weakness, reduced muscle mass, and delay of developmental milestones. Facial manifestations are not distinctive, but the face tends to be elongated with bifrontal narrowing, and the ears are often simply formed or cupped. Some patients have myopathic facies. Generalized weakness is manifested by excessive drooling, forward positioning of the head and neck, failure to ambulate independently, or ataxia in those who do ambulate. Speech is dysarthric or absent altogether. Hypotonia gives way in adult life to spasticity. The hands exhibit dystonic and athetoid posturing and fisting. Cognitive development is severely impaired. No major malformations occur, intrauterine growth is not impaired, and head circumference and genital development are usually normal. Behavior tends to be passive, with little evidence of aggressive or disruptive behavior. Although clinical signs of thyroid dysfunction are usually absent in affected males, the disturbances in blood levels of thyroid hormones suggest the possibility of systematic detection through screening of high-risk populations.

Background-Childhood factors have been associated with increased risk of developing posttraumatic stress disorder (PTSD). Previous studies assessed only a limited number of childhood factors retrospectively. We examined the association between childhood neurodevelopmental, temperamental, behavioral and family environmental characteristics assessed before age 11 years and the development of PTSD up to age 32 years in a birth cohort.

Ninety-three children in a primary school and 59 children in two first-year classes of a secondary school were asked individually to observe a paragraph of random letters arranged to resemble text, and to compare the perceptual effects on its clarity of coloured plastic sheets overlaid on the text. A total of 29 colours were compared using 10 coloured plastic sheets and 19 pairwise combinations of sheets, one superimposed on another. The resulting colours sampled CIE 1976 hue angle (huv) and saturation (suv) systematically and efficiently. All the children who reported beneficial perceptual effects (53 per cent) were given their preferred overlay or combination of overlays to use as and when they wished. When the children were examined three months later the children tended to choose a colour similar to one 531 * Requests for reprints. 532Rebecca Jeanes et al. they had chosen previously. Ten months later, 22 per cent of those offered the overlaps were still using them of their own volition. These children, but not those who had ceased to use their overlay(s), read randomly ordered simple words more quickly with their overlay than without. In a second independent group of children referred to the Norfolk Sensory Support Service, who used overlays routinely, the reading speed was similar with a grey or clear overlay; and slower than with the chosen co!oured overlay, suggesting that reduction of contrast was not the critical factor. In a third independent group of children in a primary school in Kent, the increase in reading speed with the chosen overlay predicted the children who continued to use their overlay during the ensuing eight weeks.