Congenital cardiovascular malformations: questions on inheritance. Baltimore-Washington Infant Study Group.

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 Down's 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 associated 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 population-based study emphasizes biologic questions on the nature of the inheritance of cardiovascular malformations.

Pentalogy of Cantrell and associated midline anomalies: a possible ventral midline developmental field.

Five cases of the Pentalogy of Cantrell (PC), ascertained through the Baltimore-Washington population-based study of infants with congenital cardiovascular malformations, represent a regional prevalence of 5.5/1 million liveborn infants for this disorder. Three of these patients had cleft lip with or without palate. Review of the reported literature of the Pentalogy of Cantrell and various combinations of the anomalies within the spectrum of this pentad suggests that the PC defines a specific midline ventral developmental field. Cleft lip with or without cleft palate and encephalocele tend to specifically associate with ventral midline anomalies within the spectrum of PC. These associations might either illustrate the previously observed tendency of specific occurrence of certain combinations of midline defects or represent defined subunits of the midline developmental field.

Assessment of clinical variables and counseling needs in patients with retinitis pigmentosa.

Many medical and personal factors must be considered when attempting to provide comprehensive genetic counseling to families with retinitis pigmentosa (RP). Adequate diagnostic evaluation, the initial step in the counseling process, is not always readily obtained. Prognosis is difficult to assess, and genetic type may be impossible to establish in certain pedigrees. A nationwide questionnaire survey of 899 probands with RP and allied disorders was conducted, and generated data on the patient's perceptions of the clinical aspects of the disease, family history, and the understanding of the disorder by affected persons and their relatives. This study emphasizes the clinical variability of RP and summarizes differences in age of onset of the different genetic types. Clearly, patients must be evaluated extensively and carefully to diagnose retinitis pigmentosa accurately. The extent and limitations of the diagnostic evaluation should be clearly understood by the counselor because some patients with sporadic phenocopies may be diagnosed as having retinitis pigmentosa. Counseling about prognosis should include information regarding the great variation among and within inheritance groups, families, and individuals with respect to age of onset and natural history of the disorder. All patients should be considered for hearing evaluations since as many as 30% of RP patients may have hearing impairments. Because no treatment is currently available for most RP patients, genetic counseling and supportive follow-up should be viewed as an essential service for this common group of genetic disorders, and co-operation with the ophthalmologic diagnostician should be actively sought.

Problems in detecting etiological heterogeneity in genetic disease illustrated with retinitis pigmentosa.

Simulated data were generated under four etiologic mechanisms for each of 20 different pedigree structures drawn from a study of families ascertained through a proband with retinitis pigmentosa. These simulated data were then used to identify subgroups of pedigrees which best supported each of three genetic mechanisms (autosomal dominant, autosomal recessive, X-linked recessive with 10% penetrance of disease in heterozygous females) and a non-genetic, sporadic mechanism. Results of these studies show that pedigrees identified as supporting one genetic model in a 'model choice' approach tend to be etiologically homogeneous, but are not truly representative of all the phenotypic combinations possible under that mechanism. The problem of etiologic heterogeneity is most acute when dealing with pedigrees less than size 10. Pedigrees lumped under a non-genetic, sporadic mechanism are extremely heterogeneous and studies of the natural history of diseases where both genetic and non-genetic mechanisms may be operating (such as with retinitis pigmentosa) should avoid using this group of largely simplex pedigrees.

Endocardial cushion defect: further studies of "isolated" versus "syndromic" occurrence.

The isolated occurrence of endocardial cushion defect (ECD) has been suggested to differ from its occurrence within the context of a syndrome, with regard to the nature (complete or partial) of the defect and the associated cardiovascular malformations. Analysis of data derived from the Baltimore-Washington Infant Study of congenital cardiovascular malformations supports the observation that "syndromic" ECD tends to be of the complete atrioventricular canal type and is less frequently associated with left cardiac anomalies than the isolated form. However, each syndrome has a unique impact on the overall cardiovascular "phenotype", including the ECD. This is especially true for Down and Ivemark syndromes, which are most frequently associated with ECD, but also for other syndromes as well. It is also suggested that isolated ECD is specifically associated with gastrointestinal and urinary tract anomalies. However, in Down syndrome ECD appears to be a specific cardiovascular expression of the trisomic state that is unrelated to other noncardiac malformations. Additional information on the association of ECD with other less common genetic syndromes is needed in order to further investigate the possible genetic basis of this cardiac defect.

Segregation distortion in inheritance of progressive rod cone degeneration (prcd) in miniature poodle dogs.

Segregation distortion was observed in inheritance of progressive rod-cone degeneration (prcd) in a colony of Miniature Poodle dogs. Breeding results, from both retrospective records and prospectively planned matings, were classified into five mating types: (1) affected to affected, (2) homozygous normal sire to any dam, (3) heterozygous to heterozygous, (4) heterozygous sire to affected dam, and (5) affected sire to heterozygous dam. For all but the last category, results were in accord with mendelian expectations for autosomal-recessive inheritance. However, litters of mating type 5 had fewer affected pups (20/77) than expected. The observed segregation ratio for this mating type (0.26) was significantly (P less than 0.001) less than the expected (0.50). The segregation distortion could not be accounted for by either pre- or postnatal loss of affected pups, as litter size and litter survivability were uniform among litters of different mating types. Either the prcd locus, or a linked locus, would appear to influence either gametic or zygotic fitness in the heterozygous mother. Comparison is drawn to the inheritance of retinitis pigmentosa in humans, in which decreased segregation ratios are also recognized.

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.

Genetic epidemiologic study of hearing loss in an adult population.

Previous population studies of hearing loss have been limited to children with moderate to profound impairment, and have reported that heritability accounts for at least 50% of congenital or early-onset cases. The present study was designed to assess genetic factors associated with late-onset hearing impairment in an adult population. A brief family history and audiologic questionnaire was sent to approximately 11,200 members of the consumer organization, Self Help for the Hard of Hearing, Inc., and 4,039 questionnaires were returned. All respondents reported having at least one previous audiologic exam. Reported data were verified against audiograms when available. Regardless of the reported causes, 49% of early-onset cases (< or = 20 years of age) had one or two parent(s) with some form of hearing loss compared with 62% in later-onset cases. As expected, mean age at onset was substantially younger for cases with positive family histories than cases with negative family histories. Results from nuclear segregation analysis showed that fully recessive and dominant models failed to explain the early- or late-onset hearing loss data. In this nationwide survey, the large proportion of cases with positive family histories clearly indicates the importance of genetic factors in adult-onset forms of hearing loss. Comparison with younger-onset cases will permit further delineation of differences in inheritance patterns. This study should identify more homogeneous groups of adult-onset families for further genetic study, and provide empiric information for use in genetic counselling.

Familial risks of congenital heart defect assessed in a population-based epidemiologic study.

Congenital heart defects (CHD) represent a heterogeneous group of disorders caused by chromosome abnormalities, mendelian disorders, teratogenic exposures, and unknown etiologic mechanisms. A large group of various isolated defects is presumably multifactorial in origin. Previous studies of familial risks for specific anatomic defects obtained from clinical series may include significant biases and obscured pathogenic relationships. In this population-based study we analyzed all cases of CHD in infants and a control birth cohort in the Baltimore-Washington area. The rates of CHD were defined for first-degree relatives of cases with isolated defects, grouped by a pathogenic classification scheme. Precurrence risks were found to vary among the groups, and risks for flow lesions were higher than previously reported. The sibling precurrence risk for hypoplastic left heart syndrome (13.5%) was not significantly different from that expected for an autosomal recessive mechanism; the risks for different types of ventricular septal defects (VSD) varied among mechanistic groups. The results indicate that the additive multifactorial model does not adequately account for the risks in all forms of isolated CHD of unknown etiology.

Lack of an association between diffuse systemic sclerosis and HLA-DR1 or HLA-DR5.

The HLA-DR locus of the major histocompatibility complex encodes class II molecules which participate in immune responses through regulation of T cell interaction with antigen presenting cells. Previous association studies between HLA-DR antigens and the autoimmune disease, systemic sclerosis (or scleroderma), have yielded conflicting results. Some investigators have reported an association between this disease and HLA-DR1, while others have demonstrated an association with HLA-DR5. In this study, we used restriction fragment length polymorphisms in the HLA-DR locus to compare allelic frequencies of HLA-DR1 and HLA-DR5 in scleroderma patients with diffuse disease and healthy control subjects. No significant difference in the allelic frequency of either antigen was observed between the groups. These results suggest that HLA-DR1 and HLA-DR5 antigens are unlikely to contribute significantly to disease susceptibility in scleroderma.

Accuracy of detection of the retinoblastoma gene by esterase D linkage.

The gene for hereditary retinoblastoma (Rb), an autosomal dominant trait localized to the long arm of chromosome 13, is linked to the locus for the enzyme esterase D (EsD). We analyzed a three-generation family that demonstrates cosegregation of alleles at the EsD locus and the Rb locus. This kindred yields a logarithm of the odds ratio (LOD) score of 2.46 at a recombination fraction (0) of 0.0. When combined with five other recently reported families, the resulting maximum score was 11.08 at 0 = 0.0. This combined LOD score and the lack of demonstrable crossovers in more than 65 individuals indicate that predictions of the Rb gene carrier state based on EsD genotyping are at least 90% accurate.

Chemical clastogenicity in lymphoid cell lines of chromosomal instability syndromes.

Long-term lymphoid cell lines (LCL) derived from normal individuals, patients with ataxia telangiectasia (A-T), xeroderma pigmentosum (XP), and Fanconi anemia (FA) were exposed to various concentrations of 11 chemical clastogens. The agents were chosen to represent a variety of suggested modes of action. In contrast to all other genotypes, the FA lines demonstrated significant rates of spontaneous chromosomal breakage and showed hypersensitivity to all of the clastogens employed. Variability among lines within a genotype suggested individual responses to specific agents. Computation of "corrected values" to address the problem of baseline disparity removed some of the significant differences between the FA and other lines. Nonetheless, following correction, the FA genotype was still delineated by clastogens which are not DNA cross-linkers. The A-T lines were specifically identified by the induction of chromosome damage by bleomycin and neocarzinostatin.

A genetic analysis of retinitis pigmentosa.

Genetic analysis of 457 patients with retinitis pigmentosa (RP) included categorisation of families by recognised mendelian pattern of inheritance and formal segregation analysis of all informative sibships. Of the 368 probands a surprisingly high 18% (68) had significant congenital loss of hearing and were diagnosed as having Usher syndrome. The RP probands were categorised as: 21.7% autosomal dominant, 9.0% X-linked, 16.0% autosomal recessive, 3.3% genetic type uncertain, and 50.0% simplex. Segregation analysis reflected this high proportion of simplex cases, accounting for reduced penetrance in dominant families; only 20% remain classified as sporadic (possibly nongenetic). In the matings between normal persons estimates of the segregation ratio also indicate lower values than expected. Unlike in RP sibship, segregation in the Usher syndrome is consistent with the hypothesis of recessive inheritance. Therefore RP with significant hearing loss segregates as expected, while even if a proband is classified as a dominant or recessive the recurrence risk for the RP phenotype may be below mendelian expectation.

Congenital heart disease in adolescents and adults. Teratology, genetics, and recurrence risks.

This brief review has described historic highlights of etiologic knowledge, current concepts in the categorization of cardiovascular anomalies based upon ongoing advances in teratology, and epidemiologic evaluations of biologic and xenobiotic risk factors with emphasis on the teratogenic roles of maternal diabetes, hyperphenylalaninemia, and parental exposures to alcohol, drugs, solvents, pesticides, lead, and other toxic substances. Evidence is presented for a strong genetic basis of cardiovascular maldevelopment requiring further studies to define at-risk families. Counseling and personal and societal preventive interventions may reduce the occurrence of some forms of CHD.

Linkage analysis and predicting genetic disease.

Linkage analysis is an important and clinically applicable method of predicting risk for genetic disorders and traits. When a gene cannot be detected directly, evaluation of a closely linked marker may be used in risk assessment. This review of linkage analysis provides basic information and examples of the application of these methods in genetic counseling situations.

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.

Problems of genetic model testing in early onset periodontitis.

Familial aggregation of early onset or juvenile periodontitis (JP), a disorder that varies in expression and age of onset, has been recognized for some time. Autosomal recessive and X-linked inheritance patterns have been suggested, and one large pedigree has demonstrated autosomal dominant inheritance. The variability and age limitations in clinical phenotypic diagnosis present several problems to genetic analysis, because information on members of the youngest and older generations may be lost to the analysis. The purpose of the present study was to elucidate the genetic basis of JP by formal pedigree analysis and comparison of competing genetic models. Twenty-eight families were included, with general and specific autosomal models, and an X-linked model being compared. The autosomal recessive model provided the most parsimonious explanation of the data, and its likelihood was not significantly different from the more general model. Likelihoods for the sporadic (nongenetic) and X-linked models were considerably lower than the autosomal models. While comparison of genetic models suggests recessive inheritance of JP, the serious complications to pedigree analysis posed by limitations warns against acceptance of this conclusion, without more exhaustive evaluation of: (1) a more extensive collection of family data, (2) more complete investigation of the effects of age limitations on comparisons among competing models, and (3) elucidation of the importance of diagnosis and phenotype assignment of adults through past dental records.

Clinical and laboratory characterization of early onset periodontitis.

Clinical and laboratory data were compared in 72 patients with localized periodontitis (LP) and 103 patients with generalized periodontitis (GP). Significantly more LP than GP cases had decreased neutrophil chemotaxis (CTX), and were seropositive for Actinobacillus actinomycetemcomitans (Aa). Significantly, more GP cases were seropositive for Bacteroides gingivalis (Bg). All clinical indices were similar on affected teeth in LP and GP, but the attachment loss was greater on clinically unaffected teeth in GP when compared with LP. LP cases with CTX defects had a significantly lower mean age, were more often seropositive for Aa antibodies, and were more often female than LP patients with normal CTX. Significantly more GP cases with CTX defects were seropositive for Aa antibody. GP patients with normal CTX had a higher plaque index on both affected and unaffected teeth than did GP patients with a CTX defect. Our data suggest that chemotaxis and/or specific bacteria may be contributory, but not always necessary, factors in these disorders. The overlap in clinical and laboratory profiles of LP and GP continues to cloud the distinction of these early onset forms of periodontitis.