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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.

Cowden disease, also known as multiple hamartoma syndrome, is an autosomal dominant cancer syndrome with a high risk of breast and thyroid cancer. The gene involved has been localized to chromosome 10q22-23. Recently, the tumour suppressor gene PTEN/MMAC1, encoding a putative protein tyrosine or dual-specificity phosphatase, was cloned from that region and three mutations were detected in patients with Cowden disease. We confirmed that the PTEN/MMAC1 gene is indeed the gene for Cowden disease by a refined localization of the gene to the interval between D10S1761 and D10S541, which contains the PTEN/MMAC1 gene and, by mutation analysis in eight unrelated familial and 11 sporadic patients with Cowden disease. Eight different mutations were detected in various regions of the PTEN/MMAC1 gene. One mutation was detected twice. All detected changes in the gene can be predicted to have a very deleterious effect on the putative protein. Five of the nine patients have a mutation in exon 5 coding for the putative active site and flanking amino acids. Evaluation of the clinical data of the patients in which a mutation could be detected gives no clear indications for a correlation between the genotype and phenotype. In 10 patients no mutation could be detected so far. In support of the linkage data, no evidence has emerged from the phenotype of these patients suggestive for genetic heterogeneity.

SUMMARYPurpose: To study the course and outcome of childhoodonset epilepsy during 15-year follow-up (FU). Methods: We extended FU in 413 of 494 children with new-onset epilepsy recruited in a previously described prospective hospital-based study by questionnaire. Results: Mean FU was 14.8 years (range 11.6-17.5 years). Five-year terminal remission (TR) was reached by 71% of the cohort. Course during FU was favorable in 50%, improving in 29%, and poor or deteriorating in 16%. Mean duration of seizure activity was 6.0 years (range 0-21.5 years), strongly depending on etiology and epilepsy type. Duration was <1 year in 25% of the cohort and exceeded 12 years in another 25%. Antiepileptic drugs (AEDs) were used by 86% during a mean of 7.4 years: one-third had their last seizure within 1 year of treatment, and onethird continued treatment at the end, although some had a 5-year TR. At last contact, 9% of the cohort was intractable. In multivariate analysis, predictors were nonidiopathic etiology, febrile seizures, no 3-month remission, and early intractability. Eighteen patients died; 17 had remote symptomatic etiology. Standardized mortality ratio for remote symptomatic etiology was 31.6 [95% confidence interval (CI) 18.4-50.6], versus 0.8 [95% CI 0.02-4.2] for idiopathic/cryptogenic etiology. Discussion: In most children with newly diagnosed epilepsy, the long-term prognosis of epilepsy is favorable, and in particular, patients with idiopathic etiology will eventually reach remission. In contrast, epilepsy remains active in 30% and becomes intractable in 10%. AEDs probably do not influence epilepsy course; they merely suppress seizures. Mortality is significantly higher only in those with remote symptomatic etiology.

Cowden disease (CD) is characterised by multiple hamartomas in a variety of tissues. The pathological hallmark is the presence of a number of trichilemmomas. Several neurological symptoms are also part of CD with megalencephaly and Lhermitte-Duclos disease (LDD) as the most important features. Early recognition of CD patients is important because of the increased risk of developing malignancies. Breast cancer is the most frequent malignancy, but also urogenital, digestive tract, and thyroid cancers are found with higher frequencies. CD was localised to chromosome 10q23 and the PTEN gene (also known as MMAC1 or TEP1) was shown to be involved. Germline mutations were identified in both familial and sporadic CD patients. We identified eight PTEN mutations, of which seven were novel, in 13 CD patients. Combined with previous data we have identified 17 independent CD mutations. Gross DNA alterations in CD patients were not detected. Genotype-phenotype relations are discussed. The only correlation suggested to exist is that missense mutations are not detected in LDD patients. However, larger numbers are needed to confirm this. Association of PTEN mutations and the occurrence of malignant breast disease found in an earlier study cannot be confirmed. Clinical features of five CD patients without a PTEN mutation in the coding sequence do not differ from CD patients with a PTEN mutation. Furthermore, it is likely that we have identified the majority of CD patients in the Netherlands. From this we estimate that CD has a prevalence of about 1 in 250 000 in the Dutch population with a low mutation frequency.