Investigation of second genetic hits at the BMPR2 locus as a modulator of disease progression in familial pulmonary arterial hypertension

BACKGROUND: Primary pulmonary arterial hypertension (PAH) is a potentially devastating condition resulting from occlusion of the pulmonary arterioles by the formation of vascular lesions. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type II (BMPR2) have been identified in both familial (FPAH) and idiopathic PAH. Mutant alleles are typically of low penetrance, indicating that other factors are required for the onset of PAH. Previous reports have suggested that the characteristic plexiform lesions in affected lungs are akin to neoplasia, showing monoclonal expansion and microsatellite instability. We hypothesized that in patients with germline mutations, BMPR2 might behave as a classic tumor suppressor gene, with somatic loss of the wild-type allele contributing to disease progression. METHODS AND RESULTS: To test this hypothesis, plexiform and concentric vascular lesions were serially microdissected from lung explant tissue derived from 7 FPAH cases. DNA was analyzed for loss of heterozygosity at BMPR2 and for microsatellite instability (MSI) at 5 loci. MSI was detected in 1 of 37 lesions at a single locus, BAT-26, whereas heterozygosity at BMPR2 was retained at all informative loci. We also describe a FPAH patient carrying biallelic constitutional missense mutations of BMPR2 who manifested disease at a stage and manner similar to heterozygous patients. CONCLUSIONS: Taken together, these data demonstrate that MSI is uncommon in FPAH and suggest that somatic loss of the remaining wild-type BMPR2 allele in heterozygous mutation carriers likely does not play a significant role in modulating the onset or progression of FPAH

Familial Infiltrative Fibromatosis (Desmoid Tumours) (MIM135290) Caused by a Recurrent 3′ APC Gene Mutation

Desmoid tumours are generally very rare but occur about 100 times more frequently in the colorectal cancer predisposition syndrome familial adenomatous polyposis (MIM 175100), being represented in about 10% of patients. In addition to desmoid disease occurring in familial adenomatous polyposis (FAP) there exist familial infiltrative fibromatosis (MIM 135290) kindreds where there is no evidence of FAP. Previously we have described a kindred with familial infiltrative fibromatosis (FIF) in which desmoid tumours were associated with nonpolyposis colorectal cancer. FAP is caused by mutations in the APC gene and various genotype-phenotype relationships have been defined including reports that colorectal polyposis is less severe with mutations 5′ to codon 157 and that the risk of desmoid tumours is high in FAP patients with APC gene mutations between codons 1444 and 1598. There is relatively little information on the phenotype of APC gene mutations 3′ to codon 1598; however, one large family has been reported with a mutation at codon 1987 which presents with a highly variable phenotype which includes desmoid disease. We screened our original FIF kindred and three further families with a similar phenotype for mutations in the APC gene. A 4 bp frameshift deletion in codon 1962 was identified in the original FIF kindred and two further apparently unrelated families. Haplotype analysis suggests a common origin for the APC mutation in all three families. Affected individuals had no evidence of congenital hypertrophy of the retinal pigment epithelium. Colorectal polyposis was variable, and most affected patients had either none or a few late onset polyps. These findings demonstrate (i) that FAP and FIF are allelic, and (ii) that APC gene mutations which truncate the APC protein distal to the beta-catenin binding domain are associated with desmoid tumours, absent CHRPE and variable but attenuated polyposis expressio

DOCK6 Mutations Are Responsible for a Distinct Autosomal-Recessive Variant of Adams-Oliver Syndrome Associated with Brain and Eye Anomalies

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Overcoming data scarcity of Twitter: using tweets as bootstrap with application to autism-related topic content analysis

Notwithstanding recent work which has demonstrated the potential of using Twitter messages for content-specific data mining and analysis, the depth of such analysis is inherently limited by the scarcity of data imposed by the 140 character tweet limit. In this paper we describe a novel approach for targeted knowledge exploration which uses tweet content analysis as a preliminary step. This step is used to bootstrap more sophisticated data collection from directly related but much richer content sources. In particular we demonstrate that valuable information can be collected by following URLs included in tweets. We automatically extract content from the corresponding web pages and treating each web page as a document linked to the original tweet show how a temporal topic model based on a hierarchical Dirichlet process can be used to track the evolution of a complex topic structure of a Twitter community. Using autism-related tweets we demonstrate that our method is capable of capturing a much more meaningful picture of information exchange than user-chosen hashtags.Comment: IEEE/ACM International Conference on Advances in Social Networks Analysis and Mining, 201

Haploinsufficiency of the NOTCH1 Receptor as a Cause of Adams-Oliver Syndrome With Variable Cardiac Anomalies.

BACKGROUND: Adams-Oliver syndrome (AOS) is a rare disorder characterized by congenital limb defects and scalp cutis aplasia. In a proportion of cases, notable cardiac involvement is also apparent. Despite recent advances in the understanding of the genetic basis of AOS, for the majority of affected subjects, the underlying molecular defect remains unresolved. This study aimed to identify novel genetic determinants of AOS. METHODS AND RESULTS: Whole-exome sequencing was performed for 12 probands, each with a clinical diagnosis of AOS. Analyses led to the identification of novel heterozygous truncating NOTCH1 mutations (c.1649dupA and c.6049_6050delTC) in 2 kindreds in which AOS was segregating as an autosomal dominant trait. Screening a cohort of 52 unrelated AOS subjects, we detected 8 additional unique NOTCH1 mutations, including 3 de novo amino acid substitutions, all within the ligand-binding domain. Congenital heart anomalies were noted in 47% (8/17) of NOTCH1-positive probands and affected family members. In leukocyte-derived RNA from subjects harboring NOTCH1 extracellular domain mutations, we observed significant reduction of NOTCH1 expression, suggesting instability and degradation of mutant mRNA transcripts by the cellular machinery. Transient transfection of mutagenized NOTCH1 missense constructs also revealed significant reduction in gene expression. Mutant NOTCH1 expression was associated with downregulation of the Notch target genes HEY1 and HES1, indicating that NOTCH1-related AOS arises through dysregulation of the Notch signaling pathway. CONCLUSIONS: These findings highlight a key role for NOTCH1 across a range of developmental anomalies that include cardiac defects and implicate NOTCH1 haploinsufficiency as a likely molecular mechanism for this group of disorders

Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus.

Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability