Search

Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder with multisystem involvement and cancer predisposition, caused by mutations in the A-T mutated (ATM) gene. To study genotype-phenotype correlations, we evaluated the clinical and laboratory data of 51 genetically proven A-T patients, and additionally measured ATM protein expression and kinase activity. Patients without ATM kinase activity showed the classical phenotype. The presence of ATM protein, correlated with slightly better immunological function. Residual kinase activity correlated with a milder and essentially different neurological phenotype, absence of telangiectasia, normal endocrine and pulmonary function, normal immunoglobulins, significantly lower X-ray hypersensitivity in lymphocytes, and extended lifespan. In these patients, cancer occurred later in life and generally consisted of solid instead of lymphoid malignancies. The genotypes of severely affected patients generally included truncating mutations resulting in total absence of ATM kinase activity, while patients with milder phenotypes harbored at least one missense or splice site mutation resulting in expression of ATM with some kinase activity. Overall, the phenotypic manifestations in A-T show a continuous spectrum from severe classical childhood-onset A-T to a relatively mild adult-onset disorder, depending on the presence of ATM protein and kinase activity. Each patient is left with a tremendously increased cancer risk. Hum Mutat 33:561-571, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Purpose: To validate two prognostic models for childhood-onset epilepsy designed to predict a terminal remission of <6 months at 2 years after diagnosis in children referred to the hospital. Methods: A hospital-based cohort of children with newly diagnosed epilepsy was recruited and followed up for 2 years to validate previously developed models. One model was based on variables collected at intake, and the other was based on intake variables plus variables collected during the first 6 months of follow-up. The accuracy of both models was estimated by measuring the area under the receiver-operant-characteristic curves (ROC area). Results: The ROC area of the model developed with intake variables was 0.69 [95% confidence interval (CI), 0.64–0.74] for the original cohort and 0.62 (95% CI, 0.55–0.69) for the validation cohort. The best combination of sensitivity and specificity for the original cohort was 61.6% and 69.1%, whereas it was 60.0% and 61.4% for the validation cohort. For the model with intake and 6-month variables combined, the ROC area was 0.78 (95% CI, 0.73–0.82) for the original cohort and 0.71 (95% CI, 0.64–0.78) for the validation cohort. The sensitivity and specificity were 72.6% and 73.1%, respectively, for the original cohort and 67.4% and 60.2%, respectively, for the validation cohort. Conclusions: Although both models predict outcome better than chance, they are insufficiently accurate to be of practical value. Both models performed marginally less well with the validation cohort than with the original cohort, but in both instances, the model based on intake and 6-month variables was more accurate. [ABSTRACT FROM AUTHOR]

We identified de novo truncating mutations in ARID1B in three individuals with Coffin-Siris syndrome (CSS) by exome sequencing. Array-based copy-number variation (CNV) analysis in 2,000 individuals with intellectual disability revealed deletions encompassing ARID1B in 3 subjects with phenotypes partially overlapping that of CSS. Taken together with published data, these results indicate that haploinsufficiency of the ARID1B gene, which encodes an epigenetic modifier of chromatin structure, is an important cause of CSS and is potentially a common cause of intellectual disability and speech impairment. [ABSTRACT FROM AUTHOR]