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PubMed1981

Genetic analysis of Tourette syndrome suggesting major gene effect.

Data on Gilles de la Tourette syndrome are analyzed by multiple threshold models in inheritance that incorporate sex effect. The polygenic-multifactorial model is rejected. Single major locus inheritance can account for the data, although many of the occurrences of Tourette are due to nongenetic phenocopies. In both models, males and females share a common genetic environmental liability, but the less prevalent sex, that is, females, has a higher genetic loading for the disorder. The predicted population prevalences in the single major locus model are 2.3% for males and 0.8% for females. The implications for genetic and biological research in Tourette syndrome are discussed.

Female↗

PubMed1993

Molecular investigation of familial Beckwith-Wiedemann syndrome: a model for paternal imprinting.

In familial Beckwith-Wiedemann syndrome (BWS), the mode of inheritance is uncertain and possible patterns include autosomal dominant, multifactorial and autosomal dominant sex-dependent inheritance. Genomic imprinting has recently been invoked to explain the unusual inheritance patterns in several disorders. We have previously reviewed 28 published kindreds of BWS and shown that paternal imprinting is probably responsible for familial BWS. In the present paper, highly informative RFLP markers in the 11p15.5 region have been shown to segregate with the disease gene as an autosomal dominant, but phenotypic manifestations in an offspring are dependent on the sex of the parent contributing the defective gene. In contrast to previous reports in which imprinting of the growth stimulator gene, IGF2, has been invoked as the mechanism explaining sporadic cases of BWS (especially in situations where uniparental disomy and trisomy of the 11p15.5 region has occurred), it is suggested that paternal imprinting of a growth suppressor gene, e.g., H19, may be one of the causes of familial BWS.

Alleles↗

PubMed1998

Evidence for a Mendelian gene in a segregation analysis of generalized radiographic osteoarthritis: the Framingham Study.

OBJECTIVE: To investigate the inheritance of generalized osteoarthritis (OA). METHODS: OA was identified on hand and knee radiographs obtained from members of the Framingham Study cohort (the parents) in 1967-1970 and 1992-1993, and from their adult children in the Framingham Offspring Study in 1993-1994. All hand and knee radiographs evaluated for OA were graded using the Kellgren and Lawrence (K/L) scale. A measure of generalized OA was defined as the count of the number of hand and knee joints affected, as determined by the proportion of joints with a K/L grade > or =2. The OA count, treated as a continuous variable, was adjusted for age, body mass index, and a measure of physical activity for each joint area (hand or knee). Calculations were made separately for each generation and each sex, and correlations were analyzed against the standardized residual of OA. Segregation analysis was used to test whether OA aggregated in families, and if its transmission fit a Mendelian pattern. RESULTS: A total of 337 nuclear families with 2 parents and at least 1 biologic offspring were studied. In parents, the mean age was 61.2 years at the time of hand radiographs and 72.8 years at the time of knee radiographs, which were mostly obtained at a later examination. The mean age at the time of radiographs in offspring was 53.9 years. Using standardized residuals, parent-offspring and sibling-sibling correlations ranged from 0.115 to 0.306. In segregation analyses, models testing the hypotheses of no familial aggregation, no familial transmission, or a Mendelian gene alone were all rejected (P < 0.001 for each of these models). The best-fitting models were mixed models with a Mendelian mode of inheritance and a residual multifactorial component. The Mendelian recessive model provided the best fit. CONCLUSION: These analyses support a significant genetic contribution to OA, with evidence for a major recessive gene and a multifactorial component, representing either polygenic or environmental factors.

Adult↗

PubMed1986

Complex segregation analysis of low levels of plasma high-density lipoprotein cholesterol in a sample of nuclear families in Jerusalem.

Low levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased risk of coronary heart disease (CHD). Therefore, assessment of the mode of inheritance of HDL-C is of importance. HDL-C concentrations in 3,074 nuclear families in the multiethnic Jerusalem Lipid Research Center study population were analyzed for possible involvement of major genes in determination of low levels of this trait. Complex segregation analysis under the mixed model of inheritance (major gene and multifactorial components) was performed on transformed HDL-C concentrations after adjustment for age, sex, and environmental measures. Evidence for segregation of a recessive major gene for depressed HDL-C, with an allele frequency of q = 0.06, in addition to multifactorial transmission (H = 0.45) was found in these families. Estimates from the mixed model were homogeneous across the different ethnic groups. When the substantial multifactorial background was excluded from the model, we found evidence for an additive (codominant) Mendelian gene (d = 0.48), which demonstrates the necessity of using the mixed model. Our previous results were inconclusive with respect to the involvement of a major gene in determination of high levels of HDL-C. However, we tentatively postulate an uncommon recessive gene for low levels of HDL-C in the Israeli population in addition to polygenic and environmental determinants.

Adolescent↗

PubMed1990

Transmission of a psychometric indicator for liability to schizophrenia in normal families.

The genetic analysis of schizophrenia would be facilitated by identification of a heritable correlate of liability. Deviance on an index of Minnesota Multiphasic Personality Inventory (MMPI) signs is associated with the disease phenotype; the familial aggregation and mode of transmission of this continuous psychometric indicator have yet to be established. In this paper, we examine the indicator through commingling analysis and segregation analysis with both the mixed and unified models on 65 nuclear families containing 211 normal individuals. Evidence for a high degree of familiality is found. Analysis of untransformed data under a conditional likelihood provides evidence for Mendelian transmission of a major gene with commingling of two distributions. The frequency of the "high index score" allele is 0.15, with the gene accounting for 31% of the total population variance; such a locus would be relevant to the study of psychopathology as 28% of the population would carry at least one deviant allele. When power-transformed scores are used to eliminate skewness, there is evidence for one distribution and it is not possible to distinguish single gene from multifactorial (polygenic or cultural) inheritance. While our findings regarding mode of transmission must be interpreted cautiously and confirmation of a single locus requires further study, demonstration of familiality warrants continued investigation of the index as an indicator of liability for schizophrenia.

Adolescent↗

PubMed1976

Inbred mice and their hypbrids as an animal model for atherosclerosis research.

1. The inbred strain of mouse is a relatively inexpensive and easily controlled animal that produces consistent results within each of the P1, P2, F1, F2, B1 and B2 generations. 2. The mother and father exert an equal influence on the development of fatty deposits in the aortic sinus wall and on serum total cholesterol levels. 3. Different strains of inbred mice react to the high-fat, high-cholesterol diet in different ways. 4. The control mice of the CBA/J (P2) strain had significantly lower values of serum total cholesterol and size of the largest lesion at some weeks than the control mice of the C57BR/cdJ and F1, F2, B1 and B2 generations. 5. The experiments indicate a multifactorial (polygenic) system of inheritance.

Animals↗

PubMed1987

Infantile hypertrophic pyloric stenosis after prenatal exposure to thalidomide.

In a retrospective study of 832 cases of thalidomide embryopathy (ThE) between October 1, 1959 and July 31, 1962, a highly significant accumulation of cases with infantile hypertrophic pyloric stenosis (IHPS) was registrated. Clinical course, X-ray and surgical findings and the sex ratio (male preponderance) were identical to IHPS occurring spontaneously. In the order of frequency of defects in ThE, IHPS is on position 11; among inner organ abnormalities, IHPS is on position 3 after heart and kidney defects. Thus, IHPS is the predominant gastrointestinal abnormality in ThE. For the first time, a substance (thalidomide) could be identified which obviously is able to influence manifestation of IHPS. There is a remarkable coincidence of IHPS and malformations such as hiatus hernia and tracheo-oesophageal fistula with or without oesophagus atresia. From the male preponderance, which is also observed in the ThE type of IHPS, it is concluded that thalidomide is not a primary cause in this process, but that disease manifestation is decisively influenced by thalidomide on the base of a genetic or familiar predisposition. Cause and development of IHPS are multifactorial; the mode of inheritance is polygenic. Probably, other substances may replace thalidomide.

Female↗

PubMed1991

Familial Hirschsprung's disease: report of autosomal dominant and probable recessive X-linked kindreds.

Multifactorial sex-modified inheritance has been proposed as the model of transmission in familial Hirschsprung's disease (HD). A review of two separate kindreds suggests that aganglionosis may be inherited as an X-linked recessive or an autosomal dominant trait. Chromosomal anomalies and other syndromes, including G6PD deficiency, may occur with familial HD. Recurrence risk counseling for family members depends on accurate pedigree analysis and a comprehensive understanding of the genetic factors involved.

Female↗

PubMed1998

Genetics of the febrile seizure susceptibility trait.

Febrile seizures are the commonest form of convulsion, occurring in 2-5% of infants in Europe and North America and 6-9% of infants in Japan. In large families, the febrile seizure susceptibility trait is inherited by the autosomal dominant pattern with reduced penetrance. In the other families, inheritance appears to be multifactorial. Recent linkage studies provide evidence that regions of chromosomes 8 and 19 contain febrile convulsions (FC) susceptibility genes. This opens up the way to cloning a febrile seizure gene and determining the contributions of these gene loci to febrile seizures in the sporadic cases and the small families. Cloning a febrile seizure gene will make possible new approaches to prevention and therapy. It will also be possible to determine whether a febrile seizure gene contributes to other types of seizures.

Chromosomes, Human, Pair 19↗

PubMed2005

From bases to basis: linking genetics to causation in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a multifactorial autoimmune disease with inherited and environmental components in pathogenesis. It is exceptional among autoimmune diseases in showing strong heritability according to familial occurrence and monozygotic twins concordance, yet with weak associations with the usual genetic risk elements for autoimmunity, such as the HLA alleles. Among the latter, there is risk (at least in some populations) conferred by HLA DRB1*08 and possibly some protection by DRB1*11. However, the inconsistency among studies on HLA is surprising, given that PBC is a relatively homogenous disease entity. Among non-HLA genes, some studies implicate polymorphisms of genes for cytotoxic T-lymphocyte antigen-4, interleukin-2, or interleukin-10; polymorphisms of the vitamin D receptor could synergize with low sunlight exposure to create deficiency of the immunoregulatory factor, activated vitamin D. A new lead is available from the finding in female subjects with PBC of an increase in the degree of monosomy of the X chromosome that is presumed to carry immune response genes. A further suggested source of inquiry is the apparent protection of African-American women from PBC. Finally, data on inheritance should be sought in PBC by descent methodology, rather than by cross-sectional association studies in cases and control subjects, and based on analysis of a large number of families with an affected member through a worldwide effort.

Autoimmune Diseases↗

PubMed1990

Syncope in childhood: a case control clinical study of the familial tendency to faint.

We investigated the possibility of an inherited tendency to faint by studying 30 consecutively referred well children with vasodepressor or vasovagal syncope. The family history of each patient was reviewed for syncope and for 24 cases was compared with the family history of the child's best friend. None of the best friends had syncope. 27/30 cases and 8/24 best friends had at least one first degree relative with syncope (p less than 0.01). Of the 8 best friend controls with a parent or sibling with syncope, the mother was affected in 7; 4/7 of these mothers had first degree relative(s) with syncope. In 11/30 patients both a sibling and parent had syncope compared with 1/24 of control families (p less than .01). We conclude that there is an inherited tendency to faint since most children who faint have a first degree relative who faints, a useful fact in differential diagnosis. This inherited tendency may be multifactorial but requires an environmental stimulus for expression.

Adolescent↗

PubMed2002

Channelopathies can cause epilepsy in man.

Idiopathic epilepsies, which account for up to 40% of all epilepsies, are mainly caused by genetic factors. Most idiopathic epilepsies are due to oligogenic or multifactorial rather than monogenetic inheritance. Nevertheless, most of what is known today about the molecular genetics of idiopathic epilepsies has been found by analysing large families with rare monogenetic forms of the disease. For the first time, gene defects can be linked to certain epilepsies. Mutations in the CHRNA4 or CHRNB subunits of the neuronal nicotinic acetylcholine receptor lead to familial nocturnal frontal lobe epilepsy, while defects in the voltage-gated potassium channels KCNQ2 and KCNQ3 have recently been found to cause benign familial neonatal convulsions. The voltage-gated sodium channel subunits SCN1B, SCN1A and SCN2A as well as the GABRG2 subunit of the GABA(A) receptor are involved in the pathology of the newly described syndrome generalized epilepsy with febrile seizures plus. These rare monogenetic epilepsies can serve as models for further genetic analysis of the common forms of idiopathic epilepsies.

Animals↗

PubMed1980

Genetic heterogeneity of congenital glaucoma.

Analysis of 126 families comprising 205 patients with congenital glaucoma demonstrates that in Gypsies this disease follows the pattern of autosomal recessive inheritance with complete penetrance, while in the non-Gypsy population, its mode of inheritance is most probably multifactorial. In Gypsy patients with congenital glaucoma, the eyes are always bilaterally affected, the onset of the disease is in the prenatal period, and its course is rather severe. The population frequency of the disease is extremely high (among Gypsies), and the consanguinity rate among parents is as high as 41%. In non-Gypsy patients, 26.6% of all cases are only unilaterally affected, and the course of the disease is generally milder with a later onset. The population frequency in a non-Gypsy population is much lower, the consanguinity rate is not increased, and an excess of males (1.55:1) is significant.

Consanguinity↗

PubMed1988

Evaluation of genetic counselling: recall of information, post-counselling reproduction, and attitude of the counsellees.

Of the families who had received genetic counselling between 1972 and 1981, 791 replied to a questionnaire which covered recall of information, post-counselling reproduction and attitudes towards counselling and prenatal diagnosis. Eighty percent had adequate knowledge of mode of inheritance and 74% of recurrence risk. Knowledge of mode of inheritance was poorest in multifactorial transmission (63%) and knowledge of recurrence risk in X-chromosomal disorders (61%). Forty-five per cent of the families had started a pregnancy after the counselling. 25%). Early lethality of the disorder and feasibility of a prenatal study contributed to positive reproductive decisions. Nine per cent of the children born after the counselling were affected by the disorder in question. The observed risks tended to match well with the expected ones. Sixty-two per cent of the respondents felt that the counselling had had a great or moderate impact on their reproductive plans. Forty-two per cent expressed a wish to hear the counsellor's opinion in addition to the facts. This was more common when the disorder was severe. Although most couples (53%) wished to have a prenatal study, if feasible, and abort an affected foetus, 16% were against abortion in such a case and 31% wished to have the study but were ambiguous about an abortion.

Evaluation Studies as Topic↗

PubMed1983

Validity of the ICD-9 schizophrenia classification. A blind family history study.

Within the framework of the multifactorial-polygenic model of inheritance, multiple threshold strategy was applied to a large set of pedigree data to examine the clinico-genetical position of some subtypes within the ICD-9 classification of schizophrenic psychoses. It appeared highly probable that the ICD-9 subtypes examined, based mainly on the classical Kraepelin-Bleulerian classification (simplex, hebephrenic, catatonic, paranoid, schizo-affective) are not homogeneous from the clinico-genetical point of view and genetical factors cannot be held primarily responsible for the clinical differences between the subtypes.

Adolescent↗

PubMed1978

Congenitally bicuspid aortic valves. Clinicogenetic study of 41 families.

The families of 41 patients with surgically proved isolated bicuspid aortic valves were examined. There were 275 first degree relatives of whom 220 were living, and 188 (85.5%) of these were examined. Seven first degree relatives were found to have aortic valve disease, and in a further 11 there was 'doubtful' evidence of bicuspid aortic valves. In 6 families there was more than 1 affected member and in an additional 7 families there was 1 or more 'doubtful' first degree relative. The minimum family incidence was therefore 14.6 per cent, or 31.7 per cent if 'doubtful' cases were included. The inheritance is most probably multifactorial, but occasionally the condition may occur as an autosomal dominant. The difficulties of diagnosing bicuspid aortic valves before the development of obstruction of left ventricular outflow were encountered and are discussed. The association of a bicuspid aortic valve with asymmetric septal hypertrophy, hypertrophic cardiomyopathy, and Marfan's syndrome was also noted.

Aortic Valve↗

PubMed1979

Familial infantile scoliosis associated with bilateral paralysis of conjugate gaze.

A family with two sibs suffering from idiopathic infantile scoliosis associated with bilateral paralysis of conjugate gaze is reported. Although the parental consanguinity and the involvement of patients of both sexes in this family are suggestive of an autosomal recessive mode of inheritance, a dominant or multifactorial pattern remains a possibility.

Child, Preschool↗

PubMed1995

Identification of women at high genetic risk of breast cancer through the National Health Service Breast Screening Programme (NHSBSP).

Breast cancer is a multifactorial disease with an inherited predisposition being implicated in around 5% of all cases. Using previous epidemiological data assessing risks for the relatives of women with breast cancer, we have identified 154 women (from a screened population of 35,505) and 289 of their relatives between 50 and 64 years who have more than twice the age related risk of developing breast cancer. This constitutes 1.24% of the breast screening population attending the North East Scotland NHSBSP. For each woman identified to be at high risk, we have found 1.87 female relatives between 50 and 64 years and 1.85 relatives under 50 years also to be at high risk. Around 78% of the women identified with a significant family history of breast or other cancer have attended for counselling about their risks. The breast screening programme can be used to identify women at high risk of breast cancer in order to offer them (and their relatives) access to genetic counselling and appropriate screening.

Adenocarcinoma↗