a1 Department of Pediatrics, Columbia University Medical Center, New York, United States of America
a2 Department of Pediatrics, Stanford University, Stanford, California, United States of America
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.
(Received December 04 2010)
(Accepted July 02 2011)
(Online publication August 25 2011)
c1 Correspondence to: W. Chung, MD PhD, Herbert Irving Assistant Professor of Pediatrics and Medicine, Director of Clinical Genetics, 1150 St. Nicholas Avenue, Room 620, New York, New York, United States of America. Tel:+10032 212 851 5313; Fax:+212 851 5306; E-mail: [email protected]