Joann A. Boughman

Congenital cardiovascular malformations associated with chromosome abnormalities: an epidemiologic study.

The Baltimore-Washington Infant Study is a population-based case-control study that seeks to identify risk factors for cardiovascular malformations. Between 1981 and 1986, a total of 2102 infants with cardiovascular malformations were ascertained, among whom 271 (12.9%) also had a chromosome abnormality. Among 2328 random control subjects, only two had a chromosome abnormality. Down syndrome with cardiovascular malformations had a maternal age-adjusted regional prevalence of 4.33/10,000 for the white population and 3.70/10,000 for the nonwhite population. Endocardial cushion defect, the predominant cardiac abnormality in Down syndrome (60.1%), rarely occurred as an isolated cardiac lesion (2.8%). The absence of transpositions and the rarity of heterotaxias and of right- and left-sided obstructive lesions in trisomies indicate that there may be a genetic influence on specific embryologic mechanisms. Alimentary tract lesions were more common in Down syndrome than among euploid patients with heart disease and more severe than in control subjects. Urinary tract lesions also occurred in excess of the rate in control subjects. The coexistence of these major malformations with heart disease raises the possibility of incomplete expression of the VA(C)TER (vertebral, anal, cardiac, tracheal, esophageal renal) association. The selective association of chromosome abnormalities with certain cardiovascular defects is now beginning to be explained by reported embryologic studies on cellular characteristics. An explanation of the negative association with transposition and obstructive lesions requires further multidisciplinary studies on genetic and epigenetic factors.

Congenital cardiovascular malformations: Questions on inheritance

Abstract The Baltimore-Washington Infant Study, an epidemiologic investigation of congenital heart disease, searches for genetic and environmental risk factors. Among 2,102 infants with heart disease, 17.5% had a noncardiac abnormality of chromosomal or genetic origin, whereas among 2,328 control infants, only 0.7% had a genetic abnormality. Familial cardiovascular malformations encountered can be grouped into five distinct etiologic mechanisms. Single gene effects may be responsible for the specific histologic and biochemical changes in familial atrial septal defect with conduction disturbance and also in idiopathic ventricular hypertrophy. Left heart lesions showed familial concordance by the presumed morphogenetic mechanism of abnormal embryonic blood flow with phenotypes of varying severity. Pulmonary stenosis appeared with familial heritable disorders, as well as a partially concordant lesion with tetralogy of Fallot. Ventricular septal defect with transposition of the great arteries (one sibling pair) and with truncus arteriosus (two sibling pairs) indicate forme fruste expression of conotruncal defects. Endocardial cushion defect occurred with and without Downs syndrome in members of three families, suggesting inheritance of a defect affecting cellular migration. Heritable blood coagulopathies occurred in case families and not in control families. The association of hemophilia and transposition, observed also by others, is extremely unlikely by chance and suggests genetic errors of endothelial cell function. The description of specific families from a populationbased study emphasizes biologic questions on the nature of the inheritance of cardiovascular malformations.

Prenatal detection of cardiovascular malformations by echocardiography: An indication for cytogenetic evaluation

Prenatal diagnosis of congenital cardiovascular malformations by echocardiography may signal associated chromosome abnormalities. The exact proportion of these associations is not known but is expected to be higher than that with live-birth. To estimate the risk that a fetus with an echocardiographically detected heart defect has an autosomal trisomy or Turner syndrome, we adjusted the known frequency of aneuploidy in live-born infants with congenital cardiovascular malformations by the reported rate of spontaneous abortion, with data from a population-based case-control study of congenital cardiovascular malformations in which 268 cases (12.7%) had both congenital cardiovascular malformations and a chromosome abnormality. Included in the present analysis were 188 aneuploid infants with congenital cardiovascular malformations that would have been detectable by fetal echo. When data are adjusted for the high spontaneous abortion rate of aneuploid fetuses, we estimate that there would have been more than a threefold increase in aneuploidy over the 13% seen at live-birth. Thus cytogenetic analysis is appropriate in a fetus with echo-diagnosed congenital cardiovascular malformations.

Gonadal (ovarian) dysgenesis in 46,XX individuals: Frequency of the autosomal recessive form

Gonadal (ovarian) dysgenesis with normal chromosomes (46,XX) clearly is a heterogeneous condition. In some forms, the defect is restricted to the gonads, whereas other affected females show neurosensory hearing loss (Perrault syndrome). In another form, brothers may have germ cell aplasia [Granat et al., Fertil Steril 1983; 40:215-219]. Nongenetic causes exist as well. To elucidate the proportion of XX gonadal (ovarian) dysgenesis due to autosomal recessive genes, we analyzed published (N = 17) and unpublished (N = 8) families having at least two female offspring. Analysis was restricted to cases in whom ovarian failure was documented by the presence of streak ovaries (published cases) or elevated gonadotropins (unpublished cases). We reasoned that the closer to that segregation ratio expected for an autosomal recessive trait (0.25), the lower the frequency of nongenetic forms. Segregation analysis utilized standard correction for single ascertainment, with only females included in the preliminary analysis. The segregation ratio estimate was 0.16. Our results suggest that many 46,XX females with gonadal (ovarian) dysgenesis represent a disorder segregating as an autosomal recessive trait, placing sisters of these cases at a 25% risk for this disorder.

Congenital cardiovascular malformations (CCVM) and structural chromosome abnormalities: a report of 9 cases and literature review.

Nine cases of congenital cardiovascular malformations (CCVM) with associated unbalanced structural chromosomal abnormalities were ascertained in a population‐based study of heart defects, constituting 0.4% of the 2,103 cases of CCVM in the Baltimore‐Washington Infant Study (BWIS). This represents a four‐fold increase over the general population rate. In an effort to determine possible phenotype/karyotype correlations, the literature was searched for cases with similar karyotypic abnormalities. This comparison of 223 literature cases of karyotypic abnormalities with nine similar cases ascertained by heart malformation has provided the opportunity to review cardiac defects reported in cases of structural abnormalities of chromosomes 1, 3, 7, 8, 9, 10, 11, 15, and 18. The most common cardiac malformation present in the chromosomal cases was ventricular septal defect (VSD) (39%); similarly VSD is the most common CCVM among children with heart defects, although it is the primary defect in only 20% of the BWIS cases. Among all heart defects in the BWIS, atrial septal defect (ASD) represents 5.5% of all cases, but in cases of 8p duplication, ASD is present in 41%. In addition, 40% of cases of 9p duplication had an ASD. Similarly, 35% of cases of 11q duplication had an ASD. While the suggestion of specific karyotype/phenotype associations is premature, information on additional cases might clarify the possibility that genetic determinants related to septum formation may reside on chromosome 8, 9, and/or 11. The variety of chromosomal abnormalities in cases with ventricular septal defect indicates one type of genetic heterogeneity that may be involved in this very common heart defect.

Genetic control of variation in human gingival fibroblast proliferation rate

SummaryLogarithmic proliferation rate (Days 1 to 6) of gingival fibroblasts derived from 15 pairs of monozygotic (MZ) and 9 pairs of dizygotic (DZ) human twins was compared under optimal and suboptimal growth conditions. Cell proliferation rates exhibited considerable variability among strains. For Caucasian donors (13 MZ, 6 DZ pairs) DZ twins demonstrated significantly greater (P<0.01) within-pair variance in cell proliferation rate compared to MZ twins when evaluated under optimal growth conditions. Heritability analysis indicated strong genetic control of proliferation rate of human gingival fibroblasts (HGF) under optimal growth conditions (1.0±0.67), whereas proliferation rate of HGF under suboptimal growth conditions revealed less genetic control (0.42±0.61). These findings emphasize the importance of carefully matching control and test HGF in assays dependent on cellular proliferation.

Repeated measurement of spontaneous and clastogen-induced sister-chromatid exchange☆

Sister-chromatid exchanges (SCE), both spontaneous and chemically-induced [bleomycin (BLM), mitomycin-C (MMC), streptonigrin (SN), and 4-nitroquinoline-1-oxide (4NQO)], were studied in the lymphocytes of 24 normal individuals on 2 or 3 different occasions, separated by periods of up to 2 years. For all BLM-induced SCEs, the variation in SCE frequency among the samples from a single individual was significantly greater than the variation between replicate cultures on a given day. These results raise questions concerning the validity of conclusions based on a single observation of chemically-induced SCEs.

Variation in Expression of Congenital Cardiovascular Malformations within and Among Families

Congenital cardiovascular malformations (CCVM) constitute a major portion of clinically significant birth defects, with the clinical literature suggesting population frequencies estimated to be 4 to 8 per 1,000 (reviewed by Ferencz et al., 1985). Approximately 30% of children with CCVM have other major congenital malformations as well (Hoffman and Christianson, 1978). The etiologies of CCVM are heterogeneous, and include well defined Mendelian syndromes (McKusick, 1986), chromosomal abnormalities (DeGrouchy, 1984), and specific teratogenic causes (Smith, 1982). It is supposed that approximately 5% of CCVM are single gene disorders (Neill, 1972), and about 5–6% have been suggested to be associated with chromosomal anomalies, especially autosomal trisomies (Nora and Nora, 1983). Specific teratogenic agents are known to cause CCVM, but these exposures account for only a small proportion of cases.

Analysis of translocations observed in three different populations. I: Reciprocal translocations

A sample of 437 reciprocal translocations was classified into three groups according to their method of ascertainment (Group I = couples with repeated abortions; Group II = karyotypically unbalanced carriers; Group III = balanced translocation heterozygotes). Statistical analysis showed that the distributions of chromosome breaks observed in the three groups could not be accounted for by chromosome arm length alone. In couples with repeated abortions, an excess of breaks in 7p, 17p, and 22q was found, whereas in the balanced translocation heterozygotes an excess of breaks was found only in 11q. An excess of breaks was found in arms 9p, 14p, 18p, 18q, 21q, and 22q in karyotypically unbalanced probands. A significant decrease of breaks in the medial chromosome regions was accompanied by a concomitant increase in the terminal regions in all groups. The three groups demonstrated different distributions of chromosome arm involvement in the observed translocations. Balanced translocation heterozygotes had the highest frequency of large (greater than the length of 4p) translocated segments and an excess in the frequency of large-large translocations, whereas karyotypically unbalanced probands had the highest frequency of small (shorter than 21q) translocations and an excess in the frequency of small-small translocations. For each type of chromosomal imbalance observed, the balanced translocation heterozygotes demonstrated the greatest potential imbalance and the karyotypically unbalanced probands the least.