Pleuropulmonary blastoma (PPB) is a rare pediatric lung tumor that is often part of an inherited cancer syndrome. PPBs consist of mesenchymal cells that are susceptible to malignant transformation and cysts lined by epithelial cells. In a subset of patients, overgrowth of the cysts by mesenchymal cells leads to sarcoma formation. Here, we show that 11 multiplex PPB families harbor heterozygous germline mutations in DICER1, a gene encoding an endoribonuclease critical to the generation of small noncoding regulatory RNAs. Expression of DICER1 protein was undetectable in the epithelial component of PPB tumors but was retained in the malignant mesenchyme (sarcoma). We hypothesize that loss of DICER1 in the epithelium of the developing lung alters the regulation of diffusible factors that promote mesenchymal proliferation.

Epilepsy is one of the most common neurological disorders in humans with a prevalence of 1% and a lifetime incidence of 3%. Several genes have been identified in rare autosomal dominant and severe sporadic forms of epilepsy, but the genetic cause is unknown in the vast majority of cases. Copy number variants (CNVs) are known to play an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID), autism, and schizophrenia. Genome-wide studies of copy number variation in epilepsy have not been performed. We have applied whole-genome oligonucleotide array comparative genomic hybridization to a cohort of 517 individuals with various idiopathic, non-lesional epilepsies. We detected one or more rare genic CNVs in 8.9% of affected individuals that are not present in 2,493 controls; five individuals had two rare CNVs. We identified CNVs in genes previously implicated in other neurodevelopmental disorders, including two deletions in AUTS2 and one deletion in CNTNAP2. Therefore, our findings indicate that rare CNVs are likely to contribute to a broad range of generalized and focal epilepsies. In addition, we find that 2.9% of patients carry deletions at 15q11.2, 15q13.3, or 16p13.11, genomic hotspots previously associated with ID, autism, or schizophrenia. In summary, our findings suggest common etiological factors for seemingly diverse diseases such as ID, autism, schizophrenia, and epilepsy. Epilepsy, a common neurological disorder characterized by recurrent seizures, affects up to 3% of the population. In some cases, the epilepsy has a clear cause such as an abnormality in the brain or a head injury. However, in many cases there is no obvious cause. Numerous studies have shown that genetic factors are important in these types of epilepsy, but although several epilepsy genes are known, we can still only identify the genetic cause in a very small fraction of cases. In order to identify new genes that contribute to the genetic causes of epilepsy, we searched the human genome for deletions (missing copies) and duplications (extra copies) of genes in ∼500 patients with epilepsy that are not found in control individuals. Using this approach, we identified several large deletions that are important in at least 3% of epilepsy cases. Furthermore, we found new candidate genes, some of which are also thought to play a role in other related disorders such as autism and intellectual disability. These genes are candidates for further studies in patients with epilepsy.

Background:The nonoperative technique for the treatment of idiopathic congenital talipes equinovarus (clubfoot) described by Ponseti is a popular method, but it requires two to four years of orthotic management. The purpose of this study was to examine the patient characteristics and demographic fac

Although clubfoot is one of the most common congenital abnormalities affecting the lower limb, it remains a challenge not only to understand its genetic origins but also to provide effective long-term treatment. This review provides an update on the etiology of clubfoot as well as current treatment strategies. Understanding the exact genetic etiology of clubfoot may eventually be helpful in determining both prognosis and the selection of appropriate treatment methods in individual patients. The primary treatment goal is to provide long-term correction with a foot that is fully functional and pain-free. To achieve this, a combination of approaches that applies the strengths of several methods (Ponseti method and French method) may be needed. Avoidance of extensive soft-tissue release operations in the primary treatment should be a priority, and the use of surgery for clubfoot correction should be limited to an “a la carte” mode and only after failed conservative methods. Level of Evidence: Level V, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.