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.)

Purpose: Mutations in the MECP2 gene are associated with Rett syndrome, an X-linked mental retardation disorder in females. Mutations also cause variable neurodevelopmental phenotypes in rare affected males. Recent clinical testing for MECP2 gene rearrangements revealed that entire MECP2 gene duplication occurs in some males manifesting a progressive neurodevelopmental syndrome. Methods: Clinical testing through quantitative DNA methods and chromosomal microarray analysis in our laboratories identified seven male patients with increased MECP2 gene copy number.Results: Duplication of the entire MECP2 gene was found in six patients, and MECP2 triplication was found in one patient with the most severe phenotype. The Xq28 duplications observed in these males are unique and vary in size from approximately 200 kb to 2.2 Mb. Three of the mothers who were tested were asymptomatic duplication carriers with skewed X-inactivation. In silico analysis of the Xq28 flanking region showed numerous low-copy repeats with potential roles in recombination. Conclusions: These collective data suggest that increased MECP2 gene copy number is mainly responsible for the neurodevelopmental phenotypes in these males. These findings underscore the allelic and phenotypic heterogeneity associated with the MECP2 gene and highlight the value of molecular analysis for patient diagnosis, family members at risk, and genetic counseling. Genet Med 2006:8(12):784-792.

Background Cerebral arteriopathies, including an idiopathic focal cerebral arteriopathy of childhood (FCA), are common in children with arterial ischemic stroke (AIS) and strongly predictive of recurrence. To better understand these lesions, we measured predictors of arteriopathy within a large international series of children with AIS. Methods and Results Between 1/2003 and 7/2007, 30 centers within the International Pediatric Stroke Study (IPSS) enrolled 667 children (29 days-19 years of age) with AIS and abstracted clinical and radiographic data. Cerebral arteriopathy and its subtypes were defined using published definitions; FCA was defined as cerebral arterial stenosis not attributed to specific diagnoses such as moyamoya, arterial dissection, vasculitis, or post-varicella angiopathy. We used multivariate logistic regression techniques to determine predictors of arteriopathy and FCA among those subjects who received vascular imaging. The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written. Of 667 subjects, 525 had known vascular imaging results, and 53% of those (n=277) had an arteriopathy. The most common arteriopathies were FCA (n=69, 25%), moyamoya (n=61, 22%), and arterial dissection (n=56; 20%). Predictors of arteriopathy include early school age (5-9 years), recent upper respiratory infections (URI), and sickle cell disease, while prior cardiac disease and sepsis reduced the risk of arteriopathy. The only predictor of FCA was recent URI. Conclusions Arteriopathy is prevalent among children with AIS, particularly those presenting in early school age, and those with a history of sickle cell disease. Recent URI predicted cerebral arteriopathy, and FCA in particular, suggesting a possible role for infection in the pathogenesis of these lesions.

Introduction We quantified clinical and imaging characteristics associated with childhood arteriopathy subtypes to facilitate their diagnosis and classification in research and clinical settings. Methods The “Vascular effects of Infection in Pediatric Stroke” (VIPS) study prospectively enrolled 355 children with arterial ischemic stroke (AIS) (2010–2014). A central team of experts reviewed all data to diagnose childhood arteriopathy and classify subtypes, including arterial dissection, focal cerebral arteriopathy-inflammatory type (FCA-i, which includes transient cerebral arteriopathy, TCA), moyamoya, and diffuse/multifocal vasculitis. Only children whose stroke etiology could be conclusively diagnosed were included in these analyses. We constructed logistic regression models to identify characteristics associated with each arteriopathy subtype. Results Among 127 children with definite arteriopathy, the arteriopathy subtype could not be classified in 18 (14%). Moyamoya (n=34) occurred mostly in children <8 years old, FCA-i (n=25) in 8–15 year olds, and dissection (n=26) at all ages. Vertigo at stroke presentation was common in dissection. Dissection affected cervical arteries, while moyamoya involved supraclinoid internal carotid arteries. A banded appearance of the M1 segment of the middle cerebral artery was pathognomonic of FCA-i, but present in <25% of FCA-i cases; a small lenticulostriate distribution infarct was a more common predictor of FCA-i, present in 76%. It remained difficult to distinguish FCA-i from intracranial dissection of the anterior circulation (FCA-d). We observed only secondary forms of diffuse/multifocal vasculitis, mostly due to meningitis. Conclusions Childhood arteriopathy subtypes have some typical features that aid diagnosis. Better imaging methods, including vessel wall imaging, are needed for improved classification of FCA.