Importance of microdeletions of chromosomal region 22q11 as a cause of selected malformations of the ventricular outflow tracts and aortic arch: A three-year prospective study,☆☆,,★★

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Abstract

OBJECTIVES: To assess the incidence of microdeletions of chromosomal region 22q11 in a population of infants coming to a regional pediatric cardiac center with selected abnormalities of the ventricular outflow tracts and aortic arch and, further, to provide phenotypic/genetic correlations to determine whether patients with 22q11 deletions can be clinically recognized in infancy. BACKGROUND: DiGeorge syndrome and velocardiofacial syndrome are frequently associated with malformations of the ventricular outflow tracts and aortic arch. Both are usually caused by microdeletions of chromosomal region 22q11. The overall importance of such deletions as a cause of these cardiac malformations remains to be established. STUDY DESIGN: All infants with the candidate cardiac phenotypes during a 34-month period were studied. Dysmorphic features, type of cardiac defect, serum calcium concentration, and thymic status were recorded. Cytogenetic studies, including high-resolution karyotyping and fluorescence in situ hybridization using cosmids (cEO or cH748) from the DiGeorge critical region, were performed after clinical assessment. RESULTS: Fifty infants (including 36 with tetralogy of Fallot with or without pulmonary atresia) were seen during the study period. Twenty-six infants (52%) were dysmorphic, including 19 who were considered to have a phenotypic appearance consistent with 22q11 deletion. Genetic analysis confirmed hemizygosity for 22q11 in 8 of these 19 cases. Results of fluorescence in situ hybridization studies were normal in 22 infants without dysmorphic features and in 5 infants with dysmorphic features not suggestive of a 22q11 deletion. CONCLUSIONS: Microdeletions of chromosomal region 22q11 are an important cause of selected malformations of the ventricular outflow tracts and aortic arch and account for about 15% to 20% of cases. These deletions may be clinically recognized in early infancy and can be rapidly confirmed by fluorescence in situ hybridization. (J PEDIATR 1996;129:26-32)

Section snippets

METHODS

All patients who came to Wessex Cardiothoracic Centre from June 1992 to March 1995 were prospectively studied. This regional referral center provides pediatric cardiology and cardiothoracic surgical services to a population of approximately 3 million people. All patients with a new diagnosis of the following cardiac malformations were identified: tetralogy of Fallot with pulmonary stenosis or atresia (with or without systemic-to-pulmonary artery collateral vessels), including those with

Patient characteristics

Fifty children with the selected cardiac malformations came to the Wessex Cardiothoracic Unit during the 34-month period of study. Two cases were identified in fetal life with abnormal echocardiograms. The remaining 48 patients were seen from 1 day to 4 months of age, with all but four having been seen within the first month of life. Cardiac diagnoses were as follows: tetralogy of Fallot with pulmonary stenosis (24 cases), tetralogy of Fallot with pulmonary atresia (12), interrupted aortic arch

DISCUSSION

The pediatric cardiologist caring for an infant with newly diagnosed congenital heart disease is rarely able to offer parents an adequate explanation for the cause of the defect. Recurrence risks are generally provided on the basis of epidemiologic studies rather than of an understanding of the genetic or environmental contributions within an individual family. The recent application of the tools of molecular biology to the study of children with heart disease has provided insights into the

Acknowledgements

We are grateful to Dr. P. J. Scambler, Institute of Child Health, London, for supplying cosmids EO and H748 and primer sequences for the polymorphic marker D22S941 and to Dr. M. Budarf, Children's Hospital of Philadelphia, for supplying cosmid pH17.

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    From the Wessex Cardiothoracic Centre, Southampton General Hospital, Southampton, Wessex Regional Genetics Service, Princess Anne Hospital, Southampton, and Wessex Regional Genetics Laboratory, Salisbury, United Kingdom

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    Supported in part by the Wessex Cardiac Trust (Dr. Daubeney).

    Reprint requests: Steven A. Webber, MBChB, Division of Cardiology, Children's Hospital of Pittsburgh, 3705 Fifth Avenue at De Soto Street, Pittsburgh, PA 15213.

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