Birth certificate form

ABBREVIATIONS. MACDP, Metropolitan Atlanta Congenital Defects Program; FISH, fluorescence in situ hybridization; CI, confidence interval.

During the 2 decades after its initial identification in some children with the DiGeorge phenotype (1,2) and 1 decade after the recognition of submicroscopic lesions in still more patients, (3,4) the 22q11.2 deletion has been the subject of numerous studies. These studies have increased our understanding of many clinical aspects of the condition, noting the frequent occurrence of certain heart defects and velopharyngeal anomalies but also underscoring the variability of the overall clinical presentation, which can range from subtle isolated findings to severe multisystem involvement. (5-19) More recently, as affected children are followed into adolescence and adulthood, their neurologic, developmental, and psychiatric findings are increasingly appreciated. (20-31) This growing body of information, regularly summarized and reviewed, (20,21,23,32-39) is beginning to answer some fundamental questions on the relative frequency, variability, and severity of structural anomalies associated with the deletion, the specificity and predictive value of cardiac findings, and the prevalence of the deletion in the population.

Although the existing knowledge base is useful, much of the evidence on 22q11.2 deletion to date has been derived from hospital-based case series, which may be subject to limitations regarding internal and external validity. In particular, case series rely on cases ascertained at selected hospitals or clinics and thus might not be representative of all cases in the general population regarding the severity or spectrum of associated conditions. Also, because the underlying birth population is not defined for many case series, one cannot reliably estimate the population-based prevalence of the deletion and its variation by race and ethnicity and measures of population impact.

Thus, well-designed population-based studies are needed to elucidate the findings from studies of hospital-based series, but their cost and complexity represent a major challenge and, perhaps for this reason, have been rarely attempted for the 22q11.2 deletion. Favorable circumstances made it possible to conduct a population-based study of the clinical, epidemiologic, and genetic aspects of the 22q11.2 deletion using a large, recent, well-defined, and racially diverse birth cohort in metropolitan Atlanta. These circumstances include the collaboration of 3 large centralized programs: a population-based birth defects registry with active case ascertainment from multiple sources; a center of pediatric cardiology and cardiovascular surgery that provides integrated diagnostic, clinical, and surgical services to children with heart defects; and a university-based department of medical genetics that provides comprehensive clinical and laboratory evaluation of genetic conditions.

This report describes our findings relative to 4 key issues: 1) the population-based prevalence of the 22q11.2 deletion, including its distribution by gender, race, and year of birth; 2) the underlying genetic findings and family history; 3) the associated congenital anomalies, with attention not only to specific congenital heart anomalies but also to extracardiac and multiple congenital anomalies; and 4) the contribution of the deletion to the overall occurrence of certain birth defects.

METHODS

Study Population

The study population comprised infants who were born from January 1, 1994, through December 31, 1999, to women who resided in 1 of 5 counties in metropolitan Atlanta (Clayton, Cobb, Dekalb, Fulton, and Gwinnett) at the time of birth of their child. County of residence was ascertained from the child's birth certificate. During this period, 255 849 infants were born to resident mothers.

Data Sources and Methods

We used data from 3 main sources. One source was the Metropolitan Atlanta Congenital Defects Program (MACDP), managed by the Centers for Disease Control and Prevention and active since 1968. MACDP is a population-based birth defects registry that actively ascertains birth defects among infants who are born to women who reside in the 5-county Atlanta area. Trained abstractors regularly visit birth hospitals, pediatric and specialty wards, and cytogenetic laboratories to identify cases of birth defects from medical records, hospital logs, and laboratory logs. They also obtain and review birth and death certificates from the Georgia Department of Human Resources. The goal of the process is to ascertain all major structural birth defects among live-born children up to 6 years of age, among stillborn infants, and among pregnancies terminated at or after 20 weeks of gestation. The abstracted information is reviewed by MACDP's medical staff, which includes clinical geneticists and pediatricians. For this study, we also reviewed data from prenatal diagnostic procedures. During the study period, MACDP ascertained 8379 cases of major birth defects and selected genetic conditions.

The second source of data was the Sibley Heart Center at Children's Healthcare of Atlanta. Sibley Heart Center is the major provider of diagnostic services and the sole provider of surgical services for children with heart defects for metropolitan Atlanta and most of Georgia. In 2001, Sibley Heart Center's outpatient service performed >30 000 evaluations, and the surgical team performed >880 surgical procedures. Sibley Heart Center participates in MACDP case ascertainment and is visited regularly by MACDP staff. In late 1995, staff at Children's Healthcare of Atlanta and Sibley Heart Center started an educational campaign to increase knowledge of and testing for the 22q11.2 deletion. The campaign targeted in-hospital and community-based cardiologists, physician's assistants, and nursing staff, with in-service seminars held approximately twice each year. In 1996, it became standard to screen with the 22q11.2 fluorescence in situ hybridization (FISH) probe all infants and children who have heart defects and are admitted for cardiac surgery and to reevaluate older patients with major heart defects.

The third main source of data was the Division of Medical Genetics at Emory University. The division provides clinical genetic services for individuals within the Atlanta area and much of Georgia. The Emory Genetics Laboratory annually processes approximately 5000 cytogenetic specimens. During the study period, the laboratory performed ~1400 analyses for 22q11.2 deletion. In the laboratory, the deletion status was determined by FISH using a commercially prepared DNA probe mixture that included the D22S75 locus in chromosome region 22q11.2 (N25 probe) and a distal control locus in chromosome region 22q13 (probes supplied initially by Oncor, Inc, Gaithersburg, MD, and then by Vysis, Inc, Downers Grove, IL). Metaphase chromosomes were prepared by standard cytogenetic methods for cultured peripheral blood lymphocytes. FISH was performed following the manufacturer's protocols. A positive result, consistent with deletion in 22q11, was determined by absence of the D22S75 hybridization signal on 1 chromosome 22 along with a normal pattern of hybridization for the distal control locus.

Even before formal matching, the 3 data sources (the registry, the Sibley Heart Center, and the laboratory) partially overlapped. For example, abstractors from the registry regularly visit the Sibley Heart Center and the laboratory, and physicians at the Sibley Heart Center primarily use the laboratory of the Division of Medical Genetics for genetic testing. Although the reason for genetic testing was difficult to evaluate in individual cases, common reasons would have included the presence of heart defects that required surgery, regardless of whether they were associated with extracardiac anomalies or dysmorphic features; features of the DiGeorge or velocardiofacial syndrome; velopharyngeal insufficiency; and an affected relative in the presence of even minimal clinical features.

Data Matching and Analysis

Institutional review boards at the 3 institutions approved the study, which included matching the data sets from Centers for Disease Control and Prevention's MACDP registry, Emory University's Division of Medical Genetics, and Sibley Heart Center at Children's Healthcare of Atlanta. To ensure confidentiality protections, data went from the Division of Medical Genetics (laboratory records of people tested for the deletion) and Children's Healthcare of Atlanta (records of children with 22q11.2 deletion and heart defects) to the MACDP data set. Only MACDP staff who were directly connected to data matching had access to the merged data set with personal identifiers. The analytic files did not include personal identifiers.