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SMAD2 is a downstream effector in the TGF-β signaling pathway, which is important for pattern formation and tissue differentiation. Pathogenic variants in SMAD2 have been reported in association with arterial aneurysms and dissections and in large cohorts of subjects with complex congenital heart disease (CHD). We used whole exome sequencing (WES) to investigate the molecular cause of CHD and other congenital anomalies in three probands and of an arterial aneurysm in an additional patient. Patients 1 and 2 presented with complex CHD, developmental delay, seizures, dysmorphic features, short stature, and poor weight gain. Patient 3 was a fetus with complex CHD and heterotaxy. The fourth patient is an adult female with aortic root aneurysm and physical features suggestive of a connective tissue disorder. WES identified pathogenic truncating variants, a splice variant, and a predicted deleterious missense variant in SMAD2. We compare the phenotypes and genotypes in our patients with previously reported cases. Our data suggest two distinct phenotypes associated with pathogenic variants in SMAD2: complex CHD with or without laterality defects and other congenital anomalies, and a late-onset vascular phenotype characterized by arterial aneurysms with connective tissue abnormalities., (© 2018 Wiley Periodicals, Inc.)

Heart defects caused by loss-of-function mutations in CHD7 are a frequent cause of morbidity and mortality in CHARGE syndrome. Here we review the clinical and molecular aspects of CHD7 that are related to the cardiovascular manifestations of the syndrome. The types of heart defects found in patients with CHD7 mutations are variable, with an overrepresentation of atrioventricular septal defect and outflow tract defect including aortic arch anomalies compared to nonsyndromic heart defects. Chd7 haploinsufficiency in mouse is a good model for studying the heart effects seen in CHARGE syndrome, and mouse models reveal a role for Chd7 in multiple lineages during heart development. Formation of the great vessels requires Chd7 expression in the pharyngeal surface ectoderm, and this expression likely has an non-autonomous effect on neural crest cells. In the cardiogenic mesoderm, Chd7 is required for atrioventricular cushion development and septation of the outflow tract. Emerging knowledge about the function of CHD7 in the heart indicates that it may act in concert with transcription factors such as TBX1 and SMADs to regulate genes such as p53 and the cardiac transcription factor NKX2.5., (© 2017 Wiley Periodicals, Inc.)

Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)