Investigation and Management of Apparently Sporadic Central Nervous System Haemangioblastoma for Evidence of Von Hippel-Lindau Disease.

Haemangioblastomas are rare, highly vascularised tumours that typically occur in the cerebellum, brain stem and spinal cord. Up to a third of individuals with a haemangioblastoma will have von Hippel-Lindau (VHL) disease. Individuals with haemangioblastoma and underlying VHL disease present, on average, at a younger age and frequently have a personal or family history of VHL disease-related tumours (e.g., retinal or central nervous system (CNS) haemangioblastomas, renal cell carcinoma, phaeochromocytoma). However, a subset present an apparently sporadic haemangioblastoma without other features of VHL disease. To detect such individuals, it has been recommended that genetic testing and clinical/radiological assessment for VHL disease should be offered to patients with a haemangioblastoma. To assess "real-world" clinical practice, we undertook a national survey of clinical genetics centres. All participating centres responded that they would offer genetic testing and a comprehensive assessment (ophthalmological examination and CNS and abdominal imaging) to a patient presenting with a CNS haemangioblastoma. However, for individuals who tested negative, there was variability in practice with regard to the need for continued follow-up. We then reviewed the results of follow-up surveillance in 91 such individuals seen at four centres. The risk of developing a potential VHL-related tumour (haemangioblastoma or RCC) was estimated at 10.8% at 10 years follow-up. The risks of developing a recurrent haemangioblastoma were higher in those who presented <40 years of age. In the light of these and previous findings, we propose an age-stratified protocol for surveillance of VHL-related tumours in individuals with apparently isolated haemangioblastoma.

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

The original article to which this Erratum refers was published in Human Mutation 36(6):593­598(DOI:10.1002/humu22795).The authors realized that a co-author, Nuria C. Bramswig, was left off of the title page of this article at the time of submission. This erratum serves to correct this error by including Dr. Bramswig and Dr. Bramswig's institution in the title page information.The authors regret the error.

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.

DOCK6 mutations are responsible for a distinct autosomal-recessive variant of Adams-Oliver syndrome associated with brain and eye anomalies.

Adams-Oliver syndrome (AOS) is characterized by the association of aplasia cutis congenita with terminal transverse limb defects, often accompanied by additional cardiovascular or neurological features. Both autosomal-dominant and autosomal-recessive disease transmission have been observed, with recent gene discoveries indicating extensive genetic heterogeneity. Mutations of the DOCK6 gene were first described in autosomal-recessive cases of AOS and only five DOCK6-related families have been reported to date. Recently, a second type of autosomal-recessive AOS has been attributed to EOGT mutations in three consanguineous families. Here, we describe the identification of 13 DOCK6 mutations, the majority of which are novel, across 10 unrelated individuals from a large cohort comprising 47 sporadic cases and 31 AOS pedigrees suggestive of autosomal-recessive inheritance. DOCK6 mutations were strongly associated with structural brain abnormalities, ocular anomalies, and intellectual disability, thus suggesting that DOCK6-linked disease represents a variant of AOS with a particularly poor prognosis.

Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension.

Heterozygous germline mutations of BMPR2 contribute to familial clustering of pulmonary arterial hypertension (PAH). To further explore the genetic basis of PAH in isolated cases, we undertook a candidate gene analysis to identify potentially deleterious variation. Members of the bone morphogenetic protein (BMP) pathway, namely SMAD1, SMAD4, SMAD5, and SMAD9, were screened by direct sequencing for gene defects. Four variants were identified in SMADs 1, 4, and 9 among a cohort of 324 PAH cases, each not detected in a substantial control population. Of three amino acid substitutions identified, two demonstrated reduced signaling activity in vitro. A putative splice site mutation in SMAD4 resulted in moderate transcript loss due to compromised splicing efficiency. These results demonstrate the role of BMPR2 mutation in the pathogenesis of PAH and indicate that variation within the SMAD family represents an infrequent cause of the disease.

Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies.

Regulation of cell proliferation and motility is essential for normal development. The Rho family of GTPases plays a critical role in the control of cell polarity and migration by effecting the cytoskeleton, membrane trafficking, and cell adhesion. We investigated a recognized developmental disorder, Adams-Oliver syndrome (AOS), characterized by the combination of aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD). Through a genome-wide linkage analysis, we detected a locus for autosomal-dominant ACC-TTLD on 3q generating a maximum LOD score of 4.93 at marker rs1464311. Candidate-gene- and exome-based sequencing led to the identification of independent premature truncating mutations in the terminal exon of the Rho GTPase-activating protein 31 gene, ARHGAP31, which encodes a Cdc42/Rac1 regulatory protein. Mutant transcripts are stable and increase ARHGAP31 activity in vitro through a gain-of-function mechanism. Constitutively active ARHGAP31 mutations result in a loss of available active Cdc42 and consequently disrupt actin cytoskeletal structures. Arhgap31 expression in the mouse is substantially restricted to the terminal limb buds and craniofacial processes during early development; these locations closely mirror the sites of impaired organogenesis that characterize this syndrome. These data identify the requirement for regulated Cdc42 and/or Rac1 signaling processes during early human development.

The spectra of clinical phenotypes in aplasia cutis congenita and terminal transverse limb defects.

The combination of aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD) is often referred to as the eponymous Adams-Oliver syndrome (AOS). The molecular basis of this disorder remains unknown, although the common occurrence of cardiac and vascular anomalies suggests a primary defect of vasculogenesis. Through the description of three previously unreported affected individuals, ascertained through the Adams-Oliver Syndrome European Consortium, we illustrate the phenotypic variability characteristically observed within extended families with AOS. Taken in combination with a detailed review of the available literature, we provide evidence for distinct clinical entities within the ACC/TTLD spectrum, which may reflect genetic heterogeneity within this spectrum of disorders.

Long-term survival in a child with severe congenital contractural arachnodactyly, autism and severe intellectual disability.

The severe form of congenital contractural arachnodactyly is usually associated with early mortality due to multisystem complications. Here, we report a 9-year-old male child with severe skeletal manifestations of congenital contractural arachnodactyly. He had none of the cardiovascular or gastrointestinal features that have been described in severe congenital contractural arachnodactyly. He had profound intellectual disability with autism. All exons of FBN2, the gene associated with congenital contractural arachnodactyly, were sequenced and no disease-causing mutation was found. When severe congenital contractural arachnodactyly is diagnosed in the newborn period, parents need to be aware that long-term survival is possible, particularly if no significant extraskeletal complications are present, and that significant neurodevelopmental delay may occur.