title: A Novel Missense Mutation in FLT4 Causes Autosomal Recessive Hereditary Lymphedema.
abstract: BACKGROUND
  Primary lymphedema covers around 10% of all lymphedema cases. Most cases segregate as an autosomal dominant trait and rarely manifest autosomal recessive inheritance. Our research aimed to map and ultimately to hunt the mutation that causes hereditary lymphedema in an extended consanguineous Muslim family consisting of several affected individuals.
  
  
  RESULTS
  We attempted molecular diagnosis by applying homozygosity mapping and whole genome linkage analysis. A candidate locus of 2.3 Mb located on chromosome 5q35.3 was identified, yielding an overall LOD score of 3.18. This locus has been previously linked to congenital lymphedema, namely by the FLT4 gene. Mutations in FLT4 that were previously described in Muslim-Israeli families were discarded as culprit using sequence analysis. Sanger sequencing the gene revealed a novel missense variant in exon 28 (NM_182925.4: c.3704C>G; p.Ser1235Cys). This variant has perfect segregation within the extended family and was not previously reported in either common or pathogenic variants databases.
  
  
  CONCLUSIONS
  Our mutation is the first reported pathogenic variant located outside the tyrosine kinase domains of the VEGFR3 receptor, and the second to portray autosomal recessive inheritance. The homozygous substitution of serine by cysteine at position 1235 affects protein tyrosine kinase activity, possibly through a null effect mechanism rather than a negative dominant effect. Our variant is associated with a mild phenotype, possibly reflecting some residual receptor activity, most probably attributed to the variant's location beyond the TK domains.
authors.affiliation: 1 Institute of Human Genetics , Rambam Health Care Campus, Haifa, Israel .|2 The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology , Haifa, Israel .
authors.forename: Svetlana
authors.initials: S
authors.lastname: Melikhan-Revzin
authors.affiliation: 1 Institute of Human Genetics , Rambam Health Care Campus, Haifa, Israel .|2 The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology , Haifa, Israel .
authors.forename: Alina
authors.initials: A
authors.lastname: Kurolap
authors.affiliation: 3 Department of Nursing, Faculty of Social Welfare and Health Sciences, University of Haifa , Haifa, Israel .
authors.forename: Efrat
authors.initials: E
authors.lastname: Dagan
authors.affiliation: 1 Institute of Human Genetics , Rambam Health Care Campus, Haifa, Israel .
authors.forename: Adi
authors.initials: A
authors.lastname: Mory
authors.affiliation: 1 Institute of Human Genetics , Rambam Health Care Campus, Haifa, Israel .|2 The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology , Haifa, Israel .
authors.forename: Ruth
authors.initials: R
authors.lastname: Gershoni-Baruch
mesh_terms: D004252:DNA Mutational Analysis; D005260:Female; D023061:Gene Order; D005808:Genes, Recessive; D056726:Genetic Association Studies; D056426:Genetic Loci; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008209:Lymphedema / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D012326:RNA Splicing; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics*
chemical_list: D040321:Vascular Endothelial Growth Factor Receptor-3