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Kristiana Gordon,
Sarah L Spiden, Fiona C Connell,
Glen Brice,
Sally Cottrell,
John Short,
Rohan Taylor,
Steve Jeffery,
Peter S Mortimer,
Sahar Mansour,
Pia Ostergaard
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ABSTRACT: 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 To date, a total of 58 different variants in FLT4, 20 of which are unpublished, have been observed in 95 families with MD.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 Furthermore, the unpublished variants are presented including clinical data.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.
Human Mutation 10/2012; · 5.69 Impact Factor
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Pia Ostergaard,
Michael A Simpson,
Antonella Mendola,
Pradeep Vasudevan, Fiona C Connell,
Andreas van Impel,
Anthony T Moore,
Bart L Loeys,
Arash Ghalamkarpour,
Alexandros Onoufriadis, [......],
Meriel McEntagart,
Oliver Quarrell,
Glen Brice,
Richard C Trembath,
Stefan Schulte-Merker,
Taija Makinen,
Miikka Vikkula,
Peter S Mortimer,
Sahar Mansour,
Steve Jeffery
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ABSTRACT: We have identified KIF11 mutations in individuals with syndromic autosomal-dominant microcephaly associated with lymphedema and/or chorioretinopathy. Initial whole-exome sequencing revealed heterozygous KIF11 mutations in three individuals with a combination of microcephaly and lymphedema from a microcephaly-lymphedema-chorioretinal-dysplasia cohort. Subsequent Sanger sequencing of KIF11 in a further 15 unrelated microcephalic probands with lymphedema and/or chorioretinopathy identified additional heterozygous mutations in 12 of them. KIF11 encodes EG5, a homotetramer kinesin motor. The variety of mutations we have found (two nonsense, two splice site, four missense, and six indels causing frameshifts) are all predicted to have an impact on protein function. EG5 has previously been shown to play a role in spindle assembly and function, and these findings highlight the critical role of proteins necessary for spindle formation in CNS development. Moreover, identification of KIF11 mutations in patients with chorioretinopathy and lymphedema suggests that EG5 is involved in the development and maintenance of retinal and lymphatic structures.
The American Journal of Human Genetics 02/2012; 90(2):356-62. · 10.60 Impact Factor
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Pia Ostergaard,
Michael A Simpson, Fiona C Connell,
Colin G Steward,
Glen Brice,
Wesley J Woollard,
Dimitra Dafou,
Tatjana Kilo,
Sarah Smithson,
Peter Lunt,
Victoria A Murday,
Shirley Hodgson,
Russell Keenan,
Daniela T Pilz,
Ines Martinez-Corral,
Taija Makinen,
Peter S Mortimer,
Steve Jeffery,
Richard C Trembath,
Sahar Mansour
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ABSTRACT: We report an allelic series of eight mutations in GATA2 underlying Emberger syndrome, an autosomal dominant primary lymphedema associated with a predisposition to acute myeloid leukemia. GATA2 is a transcription factor that plays an essential role in gene regulation during vascular development and hematopoietic differentiation. Our findings indicate that haploinsufficiency of GATA2 underlies primary lymphedema and predisposes to acute myeloid leukemia in this syndrome.
Nature Genetics 09/2011; 43(10):929-31. · 35.53 Impact Factor
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Emma M M Burkitt Wright,
Mohnish Suri,
Susan M White,
Nicole de Leeuw,
Anneke T Vulto-van Silfhout,
Fiona Stewart,
Shane McKee,
Sahar Mansour, Fiona C Connell,
Maya Chopra,
Edwin P Kirk,
Koen Devriendt,
Willie Reardon,
Han Brunner,
Dian Donnai
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ABSTRACT: Pierpont syndrome is a multiple congenital anomaly syndrome with learning disability first described in 1998. There are only three patients with Pierpont syndrome who have previously been published in the literature. Details of a series of patients with features of this condition were therefore obtained retrospectively to better characterize its key features. These patients were noted to have distinctive shared facial characteristics, in addition to plantar fat pads and other limb abnormalities. Further individuals with equally striking hand and foot findings were identified whose facies were less characteristic, and hence we considered them unlikely to be affected with the same condition. Despite several patients with possible Pierpont syndrome having had high-resolution array CGH or SNP array, the etiology of this phenotype remains unknown. Whilst it is as yet unclear whether it is a single entity, there appears to be a group of patients in whom Pierpont syndrome may be a recognizable condition, with typical facies, particularly when smiling, and characteristic hand and foot findings.
American Journal of Medical Genetics Part A 09/2011; 155A(9):2203-11. · 2.39 Impact Factor
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Pia Ostergaard,
Michael A Simpson,
Glen Brice,
Sahar Mansour, Fiona C Connell,
Alexandros Onoufriadis,
Anne H Child,
Jae Hwang,
Kamini Kalidas,
Peter S Mortimer,
Richard Trembath,
Steve Jeffery
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ABSTRACT: Primary lymphoedema describes a chronic, frequently progressive, failure of lymphatic drainage. This disorder is frequently genetic in origin, and a multigenerational family in which eight individuals developed postnatal lymphoedema of all four limbs was ascertained from the joint Lymphoedema/Genetic clinic at St George's Hospital.
Linkage analysis was used to determine a locus, and exome sequencing was employed to look for causative variants.
Linkage analysis revealed cosegregation of a 16.1 Mb haplotype on chromosome 1q42 that contained 173 known or predicted genes. Whole exome sequencing in a single affected individual was undertaken, and the search for the causative variant was focused to within the linkage interval. This approach revealed two novel non-synonymous single nucleotide substitutions within the chromosome 1 locus, in NVL and GJC2. NVL and GJC2 were sequenced in an additional cohort of individuals with a similar phenotype and non-synonymous variants were found in GJC2 in four additional families.
This report demonstrates the power of exome sequencing efficiently applied to a traditional positional cloning pipeline in disease gene discovery, and suggests that the phenotype produced by GJC2 mutations is predominantly one of 4 limb lymphoedema.
Journal of Medical Genetics 01/2011; 48(4):251-5. · 6.36 Impact Factor
