title: A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease.
abstract: BACKGROUND
  Milroy and Milroy-like disease are rare disorders characterised by congenital lymphoedema caused by dysfunctional lymphatic vessel formation. Loss of extracellular response mediated by vascular endothelial growth factor receptor 3 (VEGFR-3) is associated with Milroy disease, and VEGFR-3 gene is mutated in around 70% of the cases diagnosed. The only genetic alteration known to be associated with Milroy-like disease was recently identified in a family with a frameshift mutation in vascular endothelial growth factor C (VEGFC) gene, which encodes a VEGFR3 ligand.
  
  
  RESULTS
  We report a newborn patient with an external phenotype consistent with Milroy disease and a truncating mutation (p.R210X) in the VEGFC gene detected by exome sequence analysis. Subsequent analysis, by lymphoscintigraphic scan, performed for research purposes, allowed us to correct the diagnosis, confirming patient's disease as Milroy-like. The mutation segregates with the phenotype in the family according to a dominant model with full penetrance.
  
  
  CONCLUSIONS
  The clinical presentation, similar to Milroy disease, indicates an overlapping of the external phenotype of both diseases, suggesting that genetic analysis of VEGFC would be useful in diagnosing patients that present with Milroy features but have no mutation in VEGFR-3. Establishing a well-defined genetic pattern would help with differential diagnosis.
authors.affiliation: Fundación Pública Galega de Medicina Xenómica, SERGAS, Santiago de Compostela, Spain.
authors.forename: Emilia
authors.initials: E
authors.lastname: Balboa-Beltran
authors.affiliation: Servicio de Neonatología, Departamento de Pediatría, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Fernández-Seara
authors.affiliation: Servicio de Neonatología, Departamento de Pediatría, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Pérez-Muñuzuri
authors.affiliation: Fundación Pública Galega de Medicina Xenómica, SERGAS, Santiago de Compostela, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Lago
authors.affiliation: Servicio de Neonatología, Departamento de Pediatría, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: García-Magán
authors.affiliation: Servicio de Neonatología, Departamento de Pediatría, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: Couce
authors.affiliation: Grupo de Medicina Xenómica-USC, CIBERER, Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Sobrino
authors.affiliation: Grupo de Medicina Xenómica-USC, CIBERER, Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Amigo
authors.affiliation: Fundación Pública Galega de Medicina Xenómica, SERGAS, Santiago de Compostela, Spain Grupo de Medicina Xenómica-USC, CIBERER, Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain King Abdulaziz University, Center of Excellence in Genomic Medicine Research, Jeddah, Saudi Arabia.
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.affiliation: Fundación Pública Galega de Medicina Xenómica, SERGAS, Santiago de Compostela, Spain Grupo de Medicina Xenómica-USC, CIBERER, Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Barros
mesh_terms: D018388:Codon, Terminator; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008209:Lymphedema / Q000175:diagnosis* / Q000235:genetics; D010375:Pedigree; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics*
chemical_list: D018388:Codon, Terminator; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C
keywords: Clinical Genetics; Diagnostics; Genetic Screening/Counselling