title: Genetic heterogeneity in a large cohort of Indian type 3 von Willebrand disease patients.
abstract: BACKGROUND
  Though von Willebrand disease (VWD) is a common coagulation disorder, due to the complexity of the molecular analysis of von Willebrand factor gene (VWF), not many reports are available from this country. Large size of the gene, heterogeneous nature of mutations and presence of a highly homologous pseudogene region are the major impediments in the genetic diagnosis of VWD. The study is aimed at unravelling the molecular pathology in a large series of VWD patients from India using an effective strategy.
  
  
  METHODS
  We evaluated 85 unrelated Indian type 3 VWD families to identify the molecular defects using a combination of techniques i.e. PCR-RFLP, direct DNA sequencing and multiple ligation probe amplification (MLPA).
  
  
  RESULTS
  Mutations could be characterized in 77 unrelated index cases (ICs). 59 different mutations i.e. nonsense 20 (33.9%), missense 13 (22%), splice site 4 (6.8%), gene conversions 6 (10.2%), insertions 2 (3.4%), duplication 1 (1.7%), small deletions 10 (17%) and large deletions 3 (5.1%) were identified, of which 34 were novel. Two common mutations i.e. p.R1779* and p.L970del were identified in our population with founder effect. Development of alloantibodies to VWF was seen in two patients, one with nonsense mutation (p.R2434*) and the other had a large deletion spanning exons 16-52.
  
  
  CONCLUSIONS
  The molecular pathology of a large cohort of Indian VWD patients could be identified using a combination of techniques. A wide heterogeneity was observed in the nature of mutations in Indian VWD patients.
authors.affiliation: Department of Haemostasis and Thrombosis, National Institute of Immunohaematology (ICMR), KEM Hospital, Parel, Mumbai, India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Kasatkar
authors.affiliation: Department of Haemostasis and Thrombosis, National Institute of Immunohaematology (ICMR), KEM Hospital, Parel, Mumbai, India.
authors.forename: Shrimati
authors.initials: S
authors.lastname: Shetty
authors.affiliation: Department of Haemostasis and Thrombosis, National Institute of Immunohaematology (ICMR), KEM Hospital, Parel, Mumbai, India.
authors.forename: Kanjaksha
authors.initials: K
authors.lastname: Ghosh
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D015331:Cohort Studies; D005091:Exons; D005260:Female; D005785:Gene Conversion; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D006239:Haplotypes; D006470:Hemorrhage; D006801:Humans; D007194:India; D007518:Isoantibodies / Q000276:immunology; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D017384:Sequence Deletion; D012720:Severity of Illness Index; D055815:Young Adult; D056729:von Willebrand Disease, Type 3 / Q000150:complications / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D014841:von Willebrand Factor / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; D007518:Isoantibodies; D014841:von Willebrand Factor