A deletion of FGFR2 creating a chimeric IIIb/IIIc exon in a child with Apert syndrome.

BACKGROUND: Signalling by fibroblast growth factor receptor type 2 (FGFR2) normally involves a tissue-specific alternative splice choice between two exons (IIIb and IIIc), which generates two receptor isoforms (FGFR2b and FGFR2c respectively) with differing repertoires of FGF-binding specificity. Here we describe a unique chimeric IIIb/c exon in a patient with Apert syndrome, generated by a non-allelic homologous recombination event. CASE PRESENTATION: We present a child with Apert syndrome in whom routine genetic testing had excluded the FGFR2 missense mutations commonly associated with this disorder. The patient was found to harbour a heterozygous 1372 bp deletion between FGFR2 exons IIIb and IIIc, apparently originating from recombination between 13 bp of identical DNA sequence present in both exons. The rearrangement was not present in the unaffected parents. CONCLUSIONS: Based on the known pathogenesis of Apert syndrome, the chimeric FGFR2 protein is predicted to act in a dominant gain-of-function manner. This is likely to result from its expression in mesenchymal tissues, where retention of most of the residues essential for FGFR2b binding activity would result in autocrine activation. This report adds to the repertoire of rare cases of Apert syndrome for which a pathogenesis based on atypical FGFR2 rearrangements can be demonstrated.

Clinical and molecular genetic features of Beckwith-Wiedemann syndrome associated with assisted reproductive technologies.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is a model imprinting disorder resulting from mutations or epigenetic events affecting imprinted genes at 11p15.5. Most BWS cases are sporadic and result from imprinting errors (epimutations) involving either of the two 11p15.5 imprinting control regions (IC1 and IC2). Previously, we and other reported an association between sporadic BWS and assisted reproductive technologies (ARTs). METHODS: In this study, we compared the clinical phenotype and molecular features of ART (IVF and ICSI) and non-ART children with sporadic BWS. A total of 25 patients with post-ART BWS were ascertained (12 after IVF and 13 after ICSI). RESULTS: Molecular genetic analysis revealed an IC2 epimutations (KvDMR1 loss of methylation) in 24 of the 25 children tested. Comparison of clinical features of children with post-ART BWS to those with non-ART BWS and IC2 defects revealed a lower frequency of exomphalos (43 versus 69%, P = 0.029) and a higher risk of neoplasia (two cases, P = 0.0014). As loss of methylation at imprinting control regions other than 11p15.5 might modify the phenotype of BWS patients with IC2 epimutations, we investigated differentially methylated regions (DMRs) at 6q24, 7q32 and 15q13 in post-ART and non-ART BWS IC2 cases (n = 55). Loss of maternal allele methylation at these DMRs occurred in 37.5% of ART and 6.4% of non-ART BWS IC2 defect cases. Thus, more generalized DMR hypomethylation is more frequent, but not exclusive to post-ART BWS. CONCLUSIONS: These findings provide further evidence that ART may be associated with disturbed normal genomic imprinting in a subset of children.

Multidisciplinary Aortopathy Clinics Should Now Be the Standard of Care in Canada.

Thoracic aortic aneurysm is often undiagnosed and has a very poor prognosis when presented with acute aortic dissection. Early diagnosis, expert medical management, and elective aortic surgery are the cornerstones of improvement of long-term survival in thoracic aortic disease (TAD). International guidelines now recommend the acute and long-term management of patients with TAD to occur within multidisciplinary aortopathy clinics under the care of professionals with specific training and experience. Multidisciplinary "heart teams" are recognized to be more focused on patient-centric care, to facilitate faster clinical decision times with increased adherence to guideline-directed therapy, and to improve knowledge translation and physician and patient satisfaction. The range of differential diagnoses for TAD has expanded rapidly over the past decade. Diagnosis of an index case with a syndromic or nonsyndromic familial TAD allows for preventative care. Effective family screening can save lives by allowing for elective management of thoracic aortic aneurysm rather than emergent care of acute aortic complications. Expert cardiac imaging with access to the full range of required imaging modalities is central to all clinical management decisions. Medical and surgical management of TAD is now provided as personalized care according to patient- and disease-specific factors. Special considerations apply to pregnancy management for women with TAD. Multidisciplinary aortopathy clinics should now be the standard of care for the management of TAD in Canada and we should implement best practice guidelines. With the already established and emerging clinics, the stage is now set to build a Canadian Aortopathy Clinics Trials network.

Genetic Testing in Thoracic Aortic Disease--When, Why, and How?

Advances in genetic technology over the past 10 years have revealed the polygenic basis of thoracic aortic aneurysm and thoracic aortic acute dissection (TAAD) in a subset of patients. There is mounting evidence to show that clinical risk stratification for aneurysmal dilatation and acute dissection can be based on genotype for some of the known genes, allowing individualized medical and surgical management with the aim of reducing morbidity and mortality. This evidence has led to a recommendation by the American College of Cardiology Foundation and the American Heart Association that the underlying genetic mutation should dictate the timing of aortic repair. Other benefits of identifying a specific genetic cause include prediction of multisystem involvement in syndromic forms of TAAD and cascade screening for other at-risk family members. Mutation analysis for genes associated with TAAD in a clinical setting is typically ordered by geneticists or cardiologists with an interest or expertise in cardiac genetics. We present an approach to assist cardiologists and vascular surgeons in recognizing which patients would benefit from genetic testing, provide justification for such testing, and outline a practical approach to ordering the tests.

The Expanding Clinical Spectrum of Extracardiovascular and Cardiovascular Manifestations of Heritable Thoracic Aortic Aneurysm and Dissection.

More than 30 heritable conditions are associated with thoracic aortic aneurysm and dissection (TAAD). Heritable syndromic conditions, such as Marfan syndrome, Loeys-Dietz syndrome, and vascular Ehlers-Danlos syndrome, have somewhat overlapping systemic features, but careful clinical assessment usually enables a diagnosis that can be validated with genetic testing. Nonsyndromic FTAAD can also occur and in 20%-25% of these probands mutations exist in genes that encode elements of the extracellular matrix, signalling pathways (especially involving transforming growth factor-ß), and vascular smooth muscle cytoskeletal and contractile processes. Affected individuals with either a syndromic presentation or isolated TAAD can have mutations in the same gene. In this review we focus on the genes currently known to have causal mutations for syndromic and isolated FTAAD and outline the range of associated extracardiovascular and cardiovascular manifestations with each.

Molecular subtypes and phenotypic expression of Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann Syndrome (BWS) results from mutations or epigenetic events involving imprinted genes at 11p15.5. Most BWS cases are sporadic and uniparental disomy (UPD) or putative imprinting errors predominate in this group. Sporadic cases with putative imprinting defects may be subdivided into (a) those with loss of imprinting (LOI) of IGF2 and H19 hypermethylation and silencing due to a defect in a distal 11p15.5 imprinting control element (IC1) and (b) those with loss of methylation at KvDMR1, LOI of KCNQ1OT1 (LIT1) and variable LOI of IGF2 in whom there is a defect at a more proximal imprinting control element (IC2). We investigated genotype/epigenotype-phenotype correlations in 200 cases with a confirmed molecular genetic diagnosis of BWS (16 with CDKN1C mutations, 116 with imprinting centre 2 defects, 14 with imprinting centre 1 defects and 54 with UPD). Hemihypertrophy was strongly associated with UPD (P<0.0001) and exomphalos was associated with an IC2 defect or CDKN1C mutation but not UPD or IC1 defect (P<0.0001). When comparing birth weight centile, IC1 defect cases were significantly heavier than the patients with CDKN1C mutations or IC2 defect (P=0.018). The risk of neoplasia was significantly higher in UPD and IC1 defect cases than in IC2 defect and CDKN1C mutation cases. Kaplan-Meier analysis revealed a risk of neoplasia for all patients of 9% at age 5 years, but 24% in the UPD subgroup. The risk of Wilms' tumour in the IC2 defect subgroup appears to be minimal and intensive screening for Wilms' tumour appears not to be indicated. In UPD patients, UPD extending to WT1 was associated with renal neoplasia (P=0.054). These findings demonstrate that BWS represents a spectrum of disorders. Identification of the molecular subtype allows more accurate prognostic predictions and enhances the management and surveillance of BWS children such that screening for Wilms' tumour and hepatoblastoma can be focused on those at highest risk.