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Gordon K.,St Georges, University of London | Schulte D.,Hubrecht Institute | Brice G.,SW Thames Regional Genetics Service | Simpson M.A.,Kings College London | And 10 more authors.
Circulation Research | Year: 2013

RATIONALE:: Mutations in vascular endothelial growth factor (VEGF) receptor-3 (VEGFR3 or FLT4) cause Milroy disease, an autosomal dominant condition that presents with congenital lymphedema. Mutations in VEGFR3 are identified in only 70% of patients with classic Milroy disease, suggesting genetic heterogeneity. OBJECTIVE:: To investigate the underlying cause in patients with clinical signs resembling Milroy disease in whom sequencing of the coding region of VEGFR3 did not reveal any pathogenic variation. METHODS AND RESULTS:: Exome sequencing of 5 such patients was performed, and a novel frameshift variant, c.571-572insTT in VEGFC, a ligand for VEGFR3, was identified in 1 proband. The variant cosegregated with the affected status in the family. An assay to assess the biological function of VEGFC activity in vivo, by expressing human VEGFC in the zebrafish floorplate was established. Forced expression of wild-type human VEGFC in the floorplate of zebrafish embryos leads to excessive sprouting in neighboring vessels. However, when overexpressing the human c.571-572insTT variant in the floorplate, no sprouting of vessels was observed, indicating that the base changes have a marked effect on the activity of VEGFC. CONCLUSIONS:: We propose that the mutation in VEGFC is causative for the Milroy disease-like phenotype seen in this family. This is the first time a mutation in one of the ligands of VEGFR3 has been reported to cause primary lymphedema. © 2013 American Heart Association, Inc.

Gordon K.,St Georges, University of London | Spiden S.L.,SW Thames Molecular Genetics Diagnostics Laboratory | Connell F.C.,Clinical Genetics | Brice G.,St Georges, University of London | And 7 more authors.
Human Mutation | Year: 2013

Milroy disease (MD) is an autosomal dominantly inherited primary lymphedema. In 1998, the gene locus for MD was mapped to 5q35.3 and variants in the VEGFR3 (FLT4) gene, encoding vascular endothelial growth factor receptor 3 (VEGFR3), were identified as being responsible for the majority of MD cases. Several reports have since been published detailing pathogenic FLT4 mutations. To date, a total of 58 different variants in FLT4, 20 of which are unpublished, have been observed in 95 families with MD. A review of published mutations is presented in this update. Furthermore, the unpublished variants are presented including clinical data. Comparison of clinical features in patients and their families with the same mutations reveals incomplete penetrance and variable expression, making genotype-phenotype correlations difficult. Most mutations are missense, but a few deletions and one splicing variant have also been reported. Several animal models have confirmed the role of VEGFR3 in lymphangiogenesis and studies show mutant VEGFR3 receptors are not phosphorylated. Here, an MD patient with the same p.Ile1053Phe change as seen in the Chy mouse is presented for the first time. This finding confirms that this mouse lineage is an excellent model for MD. All the data reviewed here has been submitted to a database based on the Leiden Open (source) Variation Database (LOVD) and is accessible online at www.lovd.nl/flt4. © 2012 Wiley Periodicals, Inc.

Connell F.,Clinical Genetics | Gordon K.,St Georges, University of London | Brice G.,St Georges, University of London | Keeley V.,Lymphoedema Clinic | And 4 more authors.
Clinical Genetics | Year: 2013

Historically, primary lymphoedema was classified into just three categories depending on the age of onset of swelling; congenital, praecox and tarda. Developments in clinical phenotyping and identification of the genetic cause of some of these conditions have demonstrated that primary lymphoedema is highly heterogenous. In 2010, we introduced a new classification and diagnostic pathway as a clinical and research tool. This algorithm has been used to delineate specific primary lymphoedema phenotypes, facilitating the discovery of new causative genes. This article reviews the latest molecular findings and provides an updated version of the classification and diagnostic pathway based on this new knowledge. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Naicker T.,Clinical Genetics | Aldous C.,University of KwaZulu - Natal
Fetal and Pediatric Pathology | Year: 2014

We report two cases of complete non-mosaic trisomy 22 who were born within 15 months of each other in KwaZulu Natal, South Africa. In an effort to consolidate diagnostic criteria to suspect trisomy 22 prior to chromosomal testing, we compare the clinical features of these infants with those of 23 other trisomy 22 live borns presented in the literature. We further compare the clinical phenotype of trisomy 22 with those of trisomies 13 and 18 to delineate a clinical picture to presume possible trisomy 22 soon after birth. Dysmorphic features which distinguish trisomy 22 from trisomy 13 and 18 include hypertelorism, long philtrum, long and thin upper lip, webbing of the neck, low set, wide spread nipples and an abnormal anus. Given the poor prognosis of this disorder and early mortality of most confirmed cases, non-aggressive versus aggressive treatment measures should be weighed up as soon after birth as possible. Copyright © Informa Healthcare USA, Inc.

Van Esch H.,University Hospitals Leuven | Rosser E.M.,Clinical Genetics | Janssens S.,Ghent University | Van Ingelghem I.,AZ Klina | And 2 more authors.
Journal of Medical Genetics | Year: 2010

Interstitial deletions of the long arm of chromosome 6 are rare, and most reported cases represent large, cytogenetically detectable deletions. The implementation of array comparative genome hybridisation in the diagnostic work-up of patients presenting with congenital disorders, including developmental delay, has enabled identification of many patients with smaller chromosomal imbalances. In this report, the cases are presented of four patients with a de novo interstitial deletion of chromosome 6q13-14, resulting in a common microdeletion of 3.7 Mb. All presented with developmental delay, mild dysmorphism and signs of lax connective tissue. Interestingly, the common deleted region harbours 16 genes, of which COL12A1 is a good candidate for the connective tissue pathology.

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