Showing papers by "John W. Belmont published in 2010"

Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size

Abstract: Deletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay. We identified 27 deletions and 18 duplications of 16p11.2 in 0.6% of all samples submitted for clinical array-CGH analysis. The most common clinical manifestations in 17 deletion and ten duplication subjects were speech/language delay and cognitive impairment. Other phenotypes in the deletion patients included motor delay (50%), seizures (~40%), behavioral problems (~40%), congenital anomalies (~30%), and autism (~20%). The phenotypes among duplication patients included motor delay (6/10), behavioral problems (especially ADHD) (6/10), congenital anomalies (5/10), and seizures (3/10). Patients with the 16p11.2 deletion had statistically significant macrocephaly (p< 0.0017) and six of the ten patients with the duplication had microcephaly. One subject with the deletion was asymptomatic and another with the duplication had a normal cognitive and behavioral phenotype. Genomic analyses revealed additional complexity to the 16p11.2 region with mechanistic implications. The chromosomal rearrangement was de novo in all but two of the ten deletion cases in which parental studies were available. Additionally, two de novo cases were apparently mosaic for the deletion in the analyzed blood sample. Three de novo and two inherited cases were observed in the 5 of 10 duplication patients where data were available. The autism and macrocephaly observed with deletion and ADHD and microcephaly seen in duplication patients support a diametric model of autism-spectrum and psychotic-spectrum behavioral phenotypes in genomic sister disorders.

Rare copy number variants disrupt genes regulating vascular smooth muscle cell adhesion and contractility in sporadic thoracic aortic aneurysms and dissections.

Abstract: Thoracic aortic aneurysms and dissections (TAAD) cause significant morbidity and mortality, but the genetic origins of TAAD remain largely unknown. In a genome-wide analysis of 418 sporadic TAAD cases, we identified 47 copy number variant (CNV) regions that were enriched in or unique to TAAD patients compared to population controls. Gene ontology, expression profiling, and network analysis showed that genes within TAAD CNVs regulate smooth muscle cell adhesion or contractility and interact with the smooth muscle-specific isoforms of α-actin and β-myosin, which are known to cause familial TAAD when altered. Enrichment of these gene functions in rare CNVs was replicated in independent cohorts with sporadic TAAD (STAAD, n = 387) and inherited TAAD (FTAAD, n = 88). The overall prevalence of rare CNVs (23%) was significantly increased in FTAAD compared with STAAD patients (Fisher's exact test, p = 0.03). Our findings suggest that rare CNVs disrupting smooth muscle adhesion or contraction contribute to both sporadic and familial disease.

FBN1 mutations in patients with descending thoracic aortic dissections

Abstract: Aortic aneurysm and dissection cause significant morbidity and mortality There are several known single gene disorders that predispose to isolated aortic disease and eventually aneurysm and dissection FBN1 mutations are associated with multiple clinical phenotypes, including Marfan syndrome (MFS), MASS phenotype, and familial ectopia lentis, but rarely with isolated aortic aneurysm and dissection In this report, we describe three patients who presented with primary descending thoracic aortic dissection and who were found to have an FBN1 mutation None of the patients fulfilled clinical criteria for the diagnosis of MFS, and all had few or none of the skeletal features typical of the condition Two patients had a history of long-term hypertension, and such a history was suspected in the third patient These observations suggest that some individuals with FBN1 mutations have significant aortic disease involvement of other systems that is typical of FBN1 mutation-related syndromes Superimposed risk factors, such as hypertension, may weaken the aortic wall and eventually lead to aortic dissection Given that the cost continues to decrease, we suggest that diagnostic DNA sequencing for FBN1 mutations in patients with thoracic aortic aneurysms and dissection may be a practical clinical step in evaluating such patients and at-risk family members

Novel cardiac findings in periventricular nodular heterotopia.

Abstract: Periventricular nodular heterotopia (PNH) is a set of neuronal migration disorders that occur during fetal development. Neurons in the brain fail to migrate from the lining of the lateral ventricles to the cortex of the brain. When the neurons fail to migrate, ectopic neuronal nodules form. Epilepsy is a common symptom of PNH. The majority of PNH cases appear to be due to mutations in filamin A, an X-linked gene. Most of the affected individuals are female because affected males typically die in utero. Filamin A anchors integral membrane proteins to the cytoskeleton by binding actin filaments in the cytoplasm. Both animal and human studies indicate that filamin A also plays a role in blood vessel development. In this report, we describe novel cardiac findings in an 18-month-old girl with PNH associated with a nonsense mutation in FLNA, including a dysplastic pulmonary valve and clefting of the mitral valve. These findings broaden the range of cardiac anomalies associated with filamin A mutations to include abnormality of the pulmonary valve and clefting of the mitral valve, consistent with a role for filamin A in valve leaflet development.

PTPN11 mutation associated with aortic dilation and hypertrophic cardiomyopathy in a pediatric patient with Noonan syndrome.

Abstract: Noonan syndrome is an autosomal dominant disease that manifests a wide variety of clinical characteristics. The syndrome is also associated with some cardiac defects. Half of all Noonan syndrome cases are caused by mutations in the PTPN11 gene, but only limited data are available regarding aortic involvement in these cases. No reports exist regarding PTPN11 mutations in association with both aortic dilation and hypertrophic cardiomyopathy. We describe an 8-year-old girl who had Noonan syndrome involving a PTPN11 mutation, hypertrophic cardiomyopathy, main pulmonary artery dilation, and aortic root dilation. To our knowledge, this is the first case in which all three of these cardiovascular features have been observed in a single patient with Noonan syndrome.

Large deletions and uniparental disomy detected by SNP arrays in adults with thoracic aortic aneurysms and dissections

Abstract: Large Deletions and Uniparental Disomy Detected by SNP Arrays in Adults With Thoracic Aortic Aneurysms and Dissections Siddharth Prakash, Scott A. LeMaire, Molly Bray, Dianna M. Milewicz, and John W. Belmont* Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas Texas Heart Institute at St. Luke’s Episcopal Hospital, Houston, Texas Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas