title: Mutations in ZIC3 and ACVR2B are a common cause of heterotaxy and associated cardiovascular anomalies.
abstract: BACKGROUND
  Heterotaxy syndrome is caused by left-right asymmetry disturbances and is associated with abnormal lateralisation of the abdominal and thoracic organs. The heart is frequently involved and the severity of the abnormality usually determines the outcome.
  
  
  METHODS
  We performed a direct sequence analysis of the coding sequence of genes including Zinc Finger Protein of the Cerebellum 3, Left-Right Determination Factor 2, Activin A Receptor Type IIB, and Cryptic in 47 patients with laterality defects and congenital cardiac disease.
  
  
  RESULTS
  Of the 47 patients, 31 (66%) had atrioventricular septal defects, 34 (72%) had abnormal systemic venous return, 25 (53%) had transposed or malposed great arteries, and 20 (43%) had pulmonary venous abnormalities. We identified two novel genetic changes in Zinc Finger Protein of the Cerebellum 3, and these variants were not present in 100 ethnically matched control samples. One previously reported missense mutation in Activin A Receptor Type IIB was identified in two unrelated subjects. The genetic changes identified in this study are all located in conserved regions and are predicted to affect protein function in left-right axis formation and cardiovascular development.
  
  
  CONCLUSIONS
  Mutations in Zinc Finger Protein of the Cerebellum 3 and Activin A Receptor Type IIB were identified in 4 of the 47 patients with heterotaxy syndrome for a yield of approximately 8.5%. Our results expand the mutation spectrum of monogenic heterotaxy syndrome with associated cardiac anomalies and suggest that there are other causes of heterotaxy yet to be identified.
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, United States of America.
authors.forename: Lijiang
authors.initials: L
authors.lastname: Ma
authors.forename: Elif Seda
authors.initials: ES
authors.lastname: Selamet Tierney
authors.forename: Teresa
authors.initials: T
authors.lastname: Lee
authors.forename: Patricia
authors.initials: P
authors.lastname: Lanzano
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics*; D018376:Cardiovascular Abnormalities / Q000150:complications / Q000453:epidemiology* / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D005333:Fetus / Q000002:abnormalities; D005838:Genotype; D059446:Heterotaxy Syndrome / Q000150:complications / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D055458:Left-Right Determination Factors / Q000235:genetics; D008297:Male; D009154:Mutation; D009519:New York City / Q000453:epidemiology; D011247:Pregnancy; D017421:Sequence Analysis; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C491268:CFC1 protein, human; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D055458:Left-Right Determination Factors; D014157:Transcription Factors; C491595:ZIC3 protein, human; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B