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PubMed1991

Genetic epidemiology of childhood brain tumors.

The study goal was to determine the genetic (heritable) contribution to childhood brain tumors (CBT) which cause nearly one quarter of all childhood cancer deaths. Their etiology remains unknown, but previous studies have suggested a proportion of CBT may be heritable. In this study we collected family histories of 243 confirmed CBT patients referred to The University of Texas M. D. Anderson Cancer Center between the years 1944 and 1983, diagnosed before age 15, and residents of the United States or Canada. Family histories were obtained for all the probands' first degree relatives (parents, siblings, and offspring) and extended to include selected second degree relatives (aunts, uncles, grandparents) using sequential sampling. To determine if these CBT families exhibited excess cancer, we compared their cancer experience to age-, race-, sex-, and calendar-year specific rates from the Connecticut Tumor Registry. No cancer excess was observed among 1,099 first and second degree relatives [39 cancers observed (O) and 44 expected (E) for a standardized incidence ratio (SIR) of 0.88]. For colon cancer, although small numbers, five cases were observed among the probands' first degree relatives with 1.6 expected, for a significant SIR of 3.10. Segregation analysis demonstrated that chance alone could not account for the observed cancer distribution with a multifactorial model providing the best overall explanation of the data. Overall, heredity played a role in the etiology of CBT in 4% of the study families: four (1.7%) due to known hereditary syndromes (nevoid basal cell carcinoma syndrome and von Recklinghausens neurofibromatosis--NF-1), four (1.7%) with multifactorial inheritance, and two additional families with cancers aggregating similar to the clinical criteria described for the Li-Fraumeni cancer family syndrome.

Adolescent↗
PubMed1976

Craniosynostosis. I. Sagittal synostosis: its genetics and associated clinical findings in 214 patients who lacked involvement of the coronal suture(s).

The clinical and genetic findings in 214 patients with sagittal synostosis are described. Seventy-three per cent of the patients were male. Children with sagittal synostosis were treated earlier than those with coronal synostosis. Major malformations occurred in 22%, and 8.9% were mentally retarded. The retardation was clearly unrelated to the synostosis in almost half the patients. The remaining retarded patients had a significantly lower mean birth weight, higher frequency of malformations, and later age at operation than the control group. We believe the late age at operation was due to bias in the ascertainment of this group of retarded children, and that sagittal synostosis was simply one of a number of malformations that can occur in children with intrinsic retardation. Familial data and the skull measurements of a sample of parents of affected children were compatible with multifactorial inheritance; however there is need for prospective family studies and parental measurements on ethnically uniform groups.

Adolescent↗
PubMed1992

Tetralogy of Fallot in three siblings: a familial study and review of the literature.

We report a family in which three out of four siblings had tetralogy of Fallot (TOF). The family history showed TOF in the daughter of a maternal cousin, while no other congenital heart diseases were discovered. Although no teratogenic environmental agent was discovered, the absence of parental consanguinity and the presence of another affected relative suggest multifactorial inheritance. Autosomal recessive inheritance cannot be ruled out.

Female↗
PubMed1978

Bilateral renal agenesis (Potter's syndrome) in two consecutive infants.

Bilateral renal agenesis is a relatively rare congenital anomaly; its frequency is 1 : 3000-4000 deliveries, with a remarkable predominance of male infants. This anomaly is most often found in combination with characteristic facial features ('Potter's face') and pulmonary hypoplasia, the combination being known as Potter's syndrome. In the course of pregnancy an increasing oligohydramnios becomes manifest; during labor, virtual absence of amniotic fluid is found in most cases. This oligohydramnios should alert the obstetrician to suspect Potter's syndrome; serial ultrasonography may confirm the diagnosis. Most affected children are born alive but die within a few hours due to respiratory difficulties caused by the pulmonary hypoplasia. Despite the remarkable facial characteristics of these infants, it was only in a small minority that the diagnosis was considered before autopsy. This stresses the need for a full post-mortem examination in all cases of perinatal death. The etiology is still uncertain, though multifactorial inheritance is the most likely. As a consequence, the recurrence risk is not negligible; the small number of 'familial occurrence' observations, however, does not allow estimation of a risk figure. Genetic counseling is indicated in any family giving birth to a child with bilateral renal agenesis. A family is described in which two consecutive male infants with bilateral renal agenesis were born alive and survived 19 and 38 h.

Abnormalities, Multiple↗
PubMed1991

Hereditary unstable DNA: a new explanation for some old genetic questions?

Fragile X syndrome, associated with the fragile X chromosome, is the most common cause of familial mental retardation. The condition is characterised by a heritable DNA sequence that consists of an abnormal number of CCG repeats, and which is unstable in both mitosis and meiosis. We suggest that such heritable unstable DNA sequences could be present in other parts of the genome and that these might explain a number of genetic events that are not well understood in terms of classic genetic mechanisms. Such poorly explained observations include anticipation, incomplete penetrance, variable expression, and possibly imprinting, variegation, and multifactorial inheritance.

Chromosome Fragility↗
PubMed1979

Idiopathic scoliosis in identical (monozygotic) twins.

The exact nature of the primary predisposing cause of idiopathic scoliosis is unknown. Hereditary and/or environmental factors may be responsible. Two sets of identical twins presenting in adolescence with concordant scoliotic curves were studied and lend support for a hereditary predisposition favoring a multifactorial inheritance.

Adolescent↗
PubMed1979

Familial congenital diaphragmatic hernia: prenatal diagnostic approach and analysis of twelve families.

Congenital diaphragmatic hernia is generally recognized as a sporadic malformation with little or no risk of recurrence. A family with three affected individuals in two generations is presented. In addition, new prenatal diagnostic techniques including ultrasonography and amniography are discussed. A comparison of associated physical characteristics in isolated versus twelve familial cases of diaphragmatic hernia is presented. In the familial group, there was a higher incidence of affected males (M:F ratio = 2.1 versus 0.67), a higher incidence of bilateral defects (20% versus 3%) and a lower incidence of additional life-threatening malforamtions 3.6% versus 47%). Analysis of available pedigree data favors multifactorial inheritance with a high male: female sex ratio as the most probable mode of transmission.

Abnormalities, Multiple↗
PubMed1979

The use of multiple thresholds and segregation analysis in analyzing the phenotypic heterogeneity of multifactorial traits.

(1) Three models based on multifactorial inheritance are introduced to account for phenotypic heterogeneities. These models are used to determine whether subforms of a triat are: (a) different degrees of the same process, (b) non-familial environmental variants of the same process, and (c) independently transmitted processes. (2) The parameters of each model consist of two population prevalences and either one, two, or three correlation coefficients which reflect the three hypotheses given above. The models are formulated so that a likelihood ratio test may be performed to discriminate between them. (3) The following types of analyses are described: (a) analysis of prevalence data with separate population prevalence estimates, (b) analysis of prevalence data with the proband a parent with specified spouse, (c) analysis of prevalence data with the proband an offspring with specified parents, and (d) the full segregation distribution of families using Complex Segregation Analysis. (4) When compared with the Analysis of Prevalences, Complex Segregation Analysis has the following advantages: (a) the number of degrees of freedom for parameter estimates is greater and separate estimates of the population prevalences are not necessary, (b) standard errors of the parameters are smaller, and (c) the power to discriminate models is increased. (5) Phenotypic heterogeneities such as age of onset, severity, and sex effect can be more completely understood by the methods of analyses described above. The nosology of familial disorders can also be clarified, and environments relevant to the transmission of the trait can be detected. This approach is particularly suitable for the analysis for behavioural traits since it does not require the assumption that environmental effects common to relatives be ignored. (6) Finally, our experience indicates that incorporating both prevalence and pedigree data into a single analysis decreases the time required to perform the analysis.

Environment↗
PubMed1992

Immunoglobulin and HLA-DP genes contribute to the susceptibility to juvenile dermatitis herpetiformis.

HLA-DQ genes and gluten diet are the main factors involved in the pathogenesis of Dermatitis Herpetiformis (DH), as well as Coeliac Disease (CD). However other genetic factors are probably relevant, since about 10% of the patients with DH and CD lack the DQA1*0501/B1*0201 heterodimer while the majority of individuals presenting this genotype and also being exposed to gluten diets did not suffer from these diseases. To evaluate the role of other genes, 36 Northern Italian children with DH were analysed for DNA polymorphisms at HLA-DP and immunoglobulin (Ig) heavy chain loci. DPA1*0201 and DPB1*1301 frequencies were higher in patients than in controls (Pc = 0.0357 and Pc = 0.0273). With respect to immunoglobulin heavy chain restriction fragment length polymorphisms (RFLP), the 4.6 kb SacI RFLP at the switch alpha 2 gene was more frequent in patients (0.13) than in controls (0.019; Pc = 0.036). Moreover, rare alleles or duplications in the switch regions occurred more frequently in the patients than in the controls. These results support the hypothesis of a multifactorial inheritance of DH, the HLA and Ig constant heavy chain genes being some of the loci contributing to the susceptibility. In accordance with previous CD studies, these data also confirm that DP subregion is probably involved in the pathogenesis of DH.

Adolescent↗
PubMed1975

Two family studies on congenital dislocation of the hip after early orthopaedic screening Hungary.

Two family studies involving 1767 and 379 index patients in Budapest and Bekes county, respectively, were undertaken to examine the effect of early orthopaedic screening on the recurrence risk of congenital dislocation of the hip. About 14%, 2.1-2.3%,1.2-1.4%, and 4.7-6% of sibs, parents, uncles and aunts, and cousins, respectively, had congenital dislocation of the hip in these two surveys. The recurrence risks were eight-fold and four-fold higher in brothers and sisters, four times higher in parents, 2.5-fold higher in uncles and aunts, and 2.0-2.5 times higher in cousins, respectively, than in the general population. This family pattern seems to fit best with a model of polygenic-multifactorial inheritance. In earlier studies higher recurrence risks were found. These may be explained by the change of diagnosis due to early orthopaedic screening which may increase the possibility of over diagnosis and the treatment of mild cases which previously recovered spontaneously.

Adult↗
PubMed1976

A family study of coarctation of the aorta.

Families of 100 patients with coarctation of the aorta and 50 controls for age, sex, and social status were studied to assess the influence of genetic and environmental variables in the aetiology. A tendency to familial aggregation of the condition and other congenital heart defects compatible with multifactorial inheritance was discerned. Recurrence risk for sibs is approximately 1 in 200 for coarctation of the aorta, and 1% for any form of congenital heart defect. The heritability of coarctation is estimated at 58%. The tendency for other non-cardiac defects to occur in the patients with coarctation does not appear in their sibs and is not so pronounced as in some other congenital heart conditions. Of the several environmental variables examined, there was no definitive association with any other than season of birth, which implies a possible association with maternal infection; there is also a suggestion of a paternal age effect, but these require investigation in a prospective survey.

Abnormalities, Multiple↗
PubMed1976

Recurrence risks in children having one parent with a congenital heart disease.

The risk of recurrence of a congenital cardiovascular malformation in a child having one parent with congenital heart disease has been determined for each of the seven most common anomalies presently compatible with survival to reproductive age. The range of risk is 2.5% to 4.3% depending on the lesion. This is within the range of expectation for the model of multifactorial inheritance previously used to predict recurrence in other first-degree relatives of probands (siblings and parents) with congenital heart disease. The cardiovascular abnormality occurring in the child was most often the same as in the parent or was a closely related variant of it.

Adult↗
PubMed2026

Combinatorial multiomic analysis from a pedigree of Sox10Dom Hirschsprung mice identifies multiple high confidence candidate modifiers of Enteric Nervous System development.

Hirschsprung disease (HSCR) is characterized by absence of enteric ganglia (aganglionosis) along variable lengths of the distal intestine. This disorder results from deficient colonization of fetal intestine by enteric neural crest-derived cells (ENCDCs). HSCR exhibits complex, multifactorial inheritance with penetrance and severity varying widely even within families. SOX10 is among causal genes that predispose to aganglionosis. Yet, how gene interactions influence severity of HSCR aganglionosis is not understood. Prior mapping of aganglionosis modifiers was achieved in a standard F1-intercross utilizing the Sox10Dom HSCR mouse model. Here we deploy a novel strategy of genotyping an extended pedigree pedigree of Sox10Dom mice on a mixed genetic background. GWAS in this pedigree points to novel aganglionosis modifier intervals with replication and refinement of prior modifier regions. Complementary omics analysis of the developing Enteric Nervous System (ENS) enabled identification of multiple high-priority candidate genes within these modifier intervals based on gene expression, chromatin accessibility, and presence of conserved SOX10 binding motifs. We implemented a prioritization pipeline for ranking potential modifiers that generated candidate lists including several well-known for effects on ENS development as well as multiple novel genes. Among the novel genes, Dach1 ranked as a top priority candidate gene for modifying migration of ENCDCs and thus influencing aganglionosis severity. The results identify genome intervals with intrinsic genes that are logical candidates for modifying Sox10Dom aganglionosis severity. We also note that several human orthologs to aganglionosis modifier candidate genes are within linkage disequilibrium blocks containing genetic variants associated with human gut motility disorders, which offers opportunity for gaining biological insight into human HSCR severity.

Animals↗
PubMed1975

The treatment of genetic disorders.

Dermatologists see many patients with disorders that have an important but variable genetic component. Conditions caused by multifactorial inheritance, which account for many patients seen in dermatologic practice, have a strong environmental component in their cause and are generally the most responsive to therapy. Treatment is also possible for many conditions of dermatologic importance that are caused by mutant genes of large effect. At this time, there is little chance of treating the patient in the sense of genetic engineering, but some understanding of the theoretic basis for laboratory manipulation of DNA is a prerequisite to understanding the possible potential of new forms of therapy.

Animals↗
PubMed1975

[Genetic studies in hypoplastic left heart syndrome (author's transl)].

The families of the 18 patients with hypoplastic left heart syndrome (HLH), who died in the Universitätskinderklinik Erlangen between 1967 and January 1974, have been investigated. There was no consanguinity of the parents. Only one sib has died of a cardiac failure which possibly could have been HLH. Therefore it could be excluded that HLH is an autosomal-recessive disorder. The overall incidence of cardiac failure in the sibs of patients was 3. Most of the patients with HLH have been born in June-August and December-January. Environmental factors seem to be of importance in the genesis of HLH. Our results suggest multifactorial inheritance of the hypoplastic left heart syndrome.

Abnormalities, Multiple↗
PubMed1976

Prenatal diagnosis and genetic counseling.

Since the early 1960's knowledge regarding human genetics has increased at an exponential rate. Because genetics was not commonly taught in medical schools before the late 1960's, this review article is intended to acquaint physicians or refresh their knowledge regarding chromosomal, mendelian and multifactorial inheritance and the indications for prenatal diagnosis. Establishing an accurate diagnosis and mode of inheritance is essential in identifying and selecting those families at risk for genetic disease in their offspring. Medical genetics is evolving as a specialty in order to provide consultation and, if needed, management of those families who would benefit by genetic services. Families who would benefit from genetic counseling include, for example, those in whom any of the following conditions is present: known chromosomal disorders, known disorders due to mendelian inheritance, mental retardation of unknown origin, failure of sexual maturation or failure of sexual development, congenital malformations, floppy infant syndrome or leukemia.A list of more than 70 disorders now detectable in a fetus by means of amniocentesis provides a beginning in the prevention of genetic disease. Knowledge regarding these diseases allows a physician to provide families with accurate risk figures so that they may make informed decisions about having children. Also, a compassionate and nonjudgmental approach to counseling is essential. Decisions, in the final analysis, must be made by the family but aided and supported by the physician.

Chromosome Aberrations↗
PubMed1992

[Studies of distribution of subtypes of transferrin, group-specific component, alpha 1-antitrypsin in gastric cancer patients from Shanghai area].

The genetic polymorphism of transferrin (Tf) and alpha 1-Antitrypsin (alpha 1-AT) in 202 gastric cancer patients and 202 controls in Shanghai Hans were analyzed by isoelectric focusing. In transferrin, the phenotype frequency of C1C1 and gene frequencies of c1 and c2 were 0.3713, 0.5718 and 0.4109 respectively in gastric cancer patients, and 0.5149, 0.6782 and 0.2970 separately in controls. The frequencies of the c1c1 phenotype and the C1 gene increased significantly (p < 0.01) among the controls, while the frequency of the C2 gene greatly increased (p < 0.01) among the patients. The frequencies of the C2C2 in gastric cancer patients and controls were 0.2228 and 0.1436 respectively, showing a significant difference between them (p < 0.05). The genetic polymorphisms of group-specific component (Gc) in 200 gastric cancer patients and 200 controls in Shanghai Hans were studied with isoelectric focusing followed by immunofixation. The Gc1F1F phenotype frequency and 1Fgene frequency were 0.22 and 0.4375 in gastric cancer patients, and 0.14 and 0.3600 in controls, respectively. The frequencies of the Gc1F1F phenotype and the 1F gene were significantly increased (p < 0.05) among the patients. In alpha 1-Antitrypsin, there was no significant difference in phenotype frequencies and gene frequencies between the patients and controls. The data reported here indicate that the gastric cancer is associated positively with TfC2 and Gc1F, and negatively with TfC1. These facts support the notion that cancerogenesis is a multi-step process controlled by multifactorial inheritance.

Adult↗