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PubMed2005

Familial recurrence of nonsyndromic congenital heart defects in first degree relatives of patients with deletion 22q11.2.

The majority of nonsyndromic congenital heart defects (CHDs) are considered to follow a multifactorial model of inheritance. Multiple family members affected by CHD can occasionally be detected, and the involvement of several genetic loci interacting with environmental factors is suspected to be implicated. The DiGeorge/velo-cardio-facial syndrome related to microdeletion 22q11.2 (del22) is a genetic condition associated with CHD in most of the cases. We report here on five pedigrees of patients with del22, showing occurrence of nonsyndromic CHD in a first-degree relative of the proband case. Familial aggregation of syndromic and nonsyndromic CHD as observed in our series is to be considered as an unusual pattern of recurrence. The interaction between several different genes and environmental factors, a familial susceptibility predisposing to a specific cardiac malformation, or chance association can all be hypothesized searching an explanation for these particular observations.

Chromosome Deletion↗

PubMed1987

Genetic analysis of febrile convulsions: twin and family studies.

Thirty-two twin pairs and 673 sibship-cases with febrile convulsions (FC) were studied. Twin study: The pairwise concordance rate for FC was 56% (10/18 pairs) in monozygotic and 14% (2/14 pairs) in dizygotic twins (P less than 0.05). Intra-pair similarity of clinical symptoms in concordant twin pairs was greater than that in sibship-cases. Sibship-pair study (population): In sibship-pair study a large positive correlation of some clinical symptoms - in particular, age at onset of FC, exogenous factors, and degree of fever (P less than 0.001 for each) - was indicated. Compared with FC children with no family history, those with such family history had a higher frequency of age at onset between 8 and 19 months, exogenous factors, low degree of fever before onset of convulsions, many recurrences, and recurrence after age 3 (P less than 0.01-0.001 for each). Morbidity risk among near relatives was highest in first-degree relatives (16%) than in second (4.0%) or third-degree relatives (4.1%). The following differences were found: siblings (24%) greater than parents (12%), uncles (4.5%) greater than aunts (3.5%), male cousins (4.4%) greater than female cousins (3.8%). Segregation ratio, influence by affection of father or mother, and maternal preponderance were analysed. Similar findings were also observed in the clinic study. A multifactorial mode of inheritance for FC receives some support from this study, and the heritability was estimated to be 75% in the population study. The results may be useful for genetic counselling for FC.

Child, Preschool↗

PubMed1990

Mixed-model segregation analysis of schizophrenia in the Lindelius Swedish pedigrees.

To test if familial transmission of schizophrenia is consistent with a model of monogenic inheritance with a multifactorial background, a mixed-model segregation analysis was applied to Swedish pedigrees consisting of 270 probands in 263 nuclear families. Results of the best-fitting mixed-model solutions are consistent with multifactorial transmission and no major gene. However, numerical instabilities prevented formal hypothesis testing, so an irrefutable genetic mechanism remains unidentified. Alternative research strategies that exploit recent advances in molecular genetics are discussed.

Female↗

PubMed1994

Genetic factors in the etiology of idiopathic Parkinson's disease.

Overshadowed by a vigorous search for an environmentally-derived toxin that would be possibly relevant for the pathogenesis of idiopathic Parkinson's disease (PD), genetic factors have largely been neglected for this condition during the last two decades. Recent descriptions of kindreds over three or more generations with several family members affected have renewed the interest in genetics of PD. Concurring with this, diagnostic concepts and pathologic criteria for PD and for idiopathic Lewy-body (LB) disease have been reevaluated such that LB-proven parkinsonism is sufficiently differentiated from familial parkinsonism without LB pathology. Surveys on genetic epidemiology in PD have confirmed the 19th century's notion that 10 to 15% of PD index cases report a further family member with PD. These figures were, however, substantiated on a statistical basis only in single surveys when comparisons were made with the numbers of PD relatives in control index cases. Twin studies did not reveal a higher rate of concordance within monozygotic pairs than in dizygotic pairs. Tests of striatal 18-F-Dopa uptake in clinically unaffected mono- and dizygotic co-twins did not alter the ratio between the concordance rates. Though not excluded by the twin studies, multifactorial (or polygenic) inheritance as well as mitochondrial inheritance are at present less likely to cover most of the inheritance pattern in familial LB parkinsonism. Instead, autosomal dominant inheritance with reduced penetrance is the most probable inheritance pattern for most of the reported pedigrees. Molecular genetic investigations have to consider the biochemical basis of the age- and region-specific pathology of PD. The first analyses of linkage and allelic associations gave inconclusive results in sporadic and familial PD. The hunt for metabolic factors that link geno- and phenotype expression in PD will continue.

Adolescent↗

PubMed2005

[Genetic and molecular biological aspects of the bladder exstrophy-epispadias complex (BEEC)].

The bladder exstrophy and epispadias complex (BEEC) is an anterior midline defect with variable expression involving the infraumbilical abdominal wall including the pelvis, urinary tract, and external genitalia. The incidence varies with regard to ethnical background, sex, and phenotypic expression, and an incidence of 1:20,000 to 1:80,000 has been observed in the middle European population. No gene defect has been attributed to BEEC thus far and chromosomal aberrations or genetic syndromes associated with BEEC have only rarely been reported. According to epidemiological data, a complex genetic as well as a multifactorial mode of inheritance could underlie BEEC. However, no single teratogenic agent or environmental factor has been identified, which could play a dominant role in the expression of the BEEC.A risk of recurrence of 0.5-3% has been described in families with one affected subject. These values correspond to an increased recurrence risk estimated to be as high as 200- to 800-fold when compared to the common population. Due to the paucity of affected sib pairs and suitable multiplex families, conventional linkage analysis to identify candidate genes causally related with BEEC appears to be unfeasible. Large association studies and consecutive linkage disequilibrium mapping should therefore lead to the identification of candidate genes. Also new methods including matrix-based comparative genomic hybridization (CGH) are promising and have successfully been used in the past (e.g., CHARGE association). Moreover, the low incidence of the BEEC requires close cooperation between clinicians in the operative and nonoperative specialties as well as geneticists for successful gene search.

Bladder Exstrophy↗

PubMedDate not supplied

A case of hypoplastic left heart syndrome and bicuspid aortic valve in monochorionic twins.

The etiology of hypoplastic left heart syndrome (HLHS) remains unclear. Since a genetic cause for HLHS has not been obvious, it is generally considered to be inherited in a multifactorial manner. Studies of twins are valuable in elucidating the genetic contribution to a birth defect such as HLHS. We report a case of monochorionic twins in whom one has HLHS and the other has a bicuspid aortic valve. Predisposing genetic and environmental influences on individuals with identical genotypes, such as twins, may result in discordance of left-sided flow lesions.

Aortic Valve↗

PubMed1993

Further evidence that a mouse chromosome 4 locus influences cerebellar folial pattern.

The cerebellar folial pattern of mice displays marked variation among inbred strains. Previous studies of progeny of crosses of C57BL/6 mice with DBA/2J and BALB/cByJ mice indicated a multifactorial mode of inheritance in both cases. The cross with DBA/2J led to the mapping, to Chromosome 4, of a locus (Cfp-1) that influences the frequency of the intraculminate fissure. Here we report that Cfp-1 influences the frequency of the declival sulcus, and appears to influence the frequency of the intraculminate and precentral fissures, in F2 hybrid offspring from crosses of C57BL/6J and BALB/cByJ mice.

Analysis of Variance↗

PubMed1992

Familial increase in plasma glutamic acid in epilepsy.

Plasma levels of glutamic acid and leukocyte glutamate dehydrogenase (GDH) activity were determined in patients with primary generalized epilepsy, patients with partial epilepsy and in the first-degree relatives of these subjects. The results show a significant increase in plasma glutamic acid in both groups of patients and their relatives compared to non-epileptic controls. The leukocyte GDH activity in the patients and the relatives was not different from controls. The data support a genetic basis for plasma glutamic acid increase in both primary generalized and partial epilepsy and are compatible with the multifactorial mode of inheritance of these disorders. This is the first study showing a familial plasma glutamic acid increase in epilepsy in a Japanese population.

Adolescent↗

PubMed2005

Attention-deficit/hyperactivity disorder endophenotypes.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable disorder with a multifactorial pattern of inheritance. For complex conditions such as this, biologically based phenotypes that lie in the pathway from genes to behavior may provide a more powerful target for molecular genetic studies than the disorder as a whole. Although their use in ADHD is relatively new, such "endophenotypes" have aided the clarification of the etiology and pathophysiology of several other conditions in medicine and psychiatry. In this article, we review existing data on potential endophenotypes for ADHD, emphasizing neuropsychological deficits because assessment tools are cost effective and relatively easy to implement. Neuropsychological impairments, as well as measures from neuroimaging and electrophysiological paradigms, show correlations with ADHD and evidence of heritability, but the familial or genetic overlap between these constructs and ADHD remains unclear. We conclude that these endophenotypes will not be a quick fix for the field but offer potential if careful consideration is given to issues of heterogeneity, measurement and statistical power.

Adoption↗

PubMed1979

Hypospadias: a familial study.

The families of 177 boys with varying degrees of hypospadias were evaluated prospectively to determine the occurrence of hypospadias and other congenital anomalies within this population. A significant number of male subjects in each family member category were affected, with first degree relatives (brothers and fathers) having a 14 and 9 per cent incidence, respectively. Siblings were at a greater risk for having this anomaly when the proband had a more severe degree of hypospadias and when the abnormality also was present in other relatives. A multifactorial mode of inheritance is suggested as the basis for transmission of this congenital defect.

Abnormalities, Multiple↗

PubMed2003

Obstetric cholestasis with elevated gamma glutamyl transpeptidase: incidence, presentation and treatment.

BACKGROUND: Obstetric cholestasis (OC) may cause severe pruritus in the mother and lead to fetal distress and stillbirth. The etiology of OC is multifactorial, but includes inherited dysfunction of bile canalicular transporters. One of these, multidrug resistant protein 3 (MDR3), a phospholipid transporter, when dysfunctional is associated with elevated levels of gamma glutamyl transpeptidase (GGT). The aim of the present study was to assess the incidence of OC associated with elevated GGT. We compared the natural history of a cholestatic pregnancy and the efficacy of ursodeoxycholic acid (URSO) in OC patients grouped according to a normal or raised GGT level. METHODS: Eighty-one patients with OC were analyzed. OC was diagnosed in patients with pruritus and elevated serum bile acids (SBA). Fifty-seven consenting volunteer patients (70%) were treated with URSO. RESULTS: Elevated GGT at presentation was found in 21 patients (30%) and was associated with significantly higher serum levels of aspartate transaminase (AST), bilirubin (BIL) and SBA. OC presented at approximately the same gestation week in both groups of patients. In patients not treated with URSO, liver function tests (LFT) showed no significant change from the time of diagnosis to delivery. Patients from both groups responded to URSO with significant improvement in their AST and alanine aminotransferase (ALT) levels, but SBA fell significantly only in the normal GGT group. CONCLUSIONS: An elevated GGT occurs in less than one-third of patients with OC in the UK and, when present, is associated with greater impairment of LFT, but no difference in gestational age at onset. Treatment with URSO appears to be safe and significantly improves LFT in patients with OC, with the exception of SBA in the high GGT group.

Alanine Transaminase↗

PubMed2006

Bladder exstrophy-epispadias complex: Investigation of suppressor of variegation, enhancer of zeste and Trithorax (SET) as a candidate gene in a large cohort of patients.

OBJECTIVE: The bladder exstrophy-epispadias complex (BEEC) describes a rare anterior midline defect with variable expression involving the infra-umbilical abdominal wall, including the pelvis, urinary tract and external genitalia. It is assumed that the underlying cause of BEEC is a multifactorial mode of inheritance; however, its aetiology remains unknown. Only a few BEEC patients with distinctive cytogenetic features such as numeric or structural chromosomal abnormalities have been reported. The observation of translocations concerning the region of chromosome 9q32-q34.1 in two patients implies that this region bears a candidate gene which, during early blastogenesis, governs the development of this primary field. In this context, we considered the suppressor of variegation, enhancer of zeste and Trithorax (SET) gene, located at chromosome 9q34, to be a good candidate, as the protein encoded is involved in the regulation of cell proliferation and differentiation. Moreover, SET expression was detected in embryonic kidney. MATERIAL AND METHODS: A total of 33 patients affected with BEEC were analysed for mutations in the SET gene. RESULTS: SET analysis did not reveal either a mutation or the presence of four single-nucleotide polymorphisms (dbSNP124) already described in the database. CONCLUSIONS: The data obtained in this study most likely exclude the SET gene as a possible genetic cause of BEEC. Hence, other genes in this region may contribute to the development of this midline defect.

Bladder Exstrophy↗

PubMed1989

Genotypic and phenotypic similarities in pulmonary function among family members of adult monozygotic and dizygotic twins.

Population studies have demonstrated that obstructive airways disease aggregates within families. The authors used a twin family model of analysis to estimate the genetic and environmental influences on pulmonary function. A total of 1,635 members of 414 families of adult twins (252 monozygotic, 162 dizygotic) enrolled in the Greater Boston Twin Registry were studied between 1981 and 1982. Correlations in levels of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), adjusted for age, sex, height, and current smoking status, were compared among 16 groups of relatives sharing various degrees of genetic relatedness. A direct relation between shared genotype and the magnitude of the familial correlations for pulmonary function was observed. For FEV1, the correlations were 0.71 for monozygotic twins (100% shared genotype), 0.16 to 0.29 for relatives with 50% shared genotype, 0.09 to 0.27 for relatives with 25% shared genotype, 0.06 for cousins with 12.5% shared genotype, and -0.14 to 0.14 for unrelated family members. Correlations for FVC were similar. Stratification of the analysis by concordance or discordance for passive tobacco smoke exposure or for frequency with which families visited one another did not systematically alter these relations. These data suggest that phenotypic similarities in pulmonary function relate directly to genetic similarities, and are consistent with a multifactorial mode of inheritance.

Adolescent↗

PubMedDate not supplied

Common white facial markings in bay and chestnut Arabian horses and their hybrids.

Common white facial and leg markings have a multifactorial mode of inheritance in Equus caballus. Evidence for the complexity of the genetic component is the observation that chestnut (e/e) horses have more extensive white markings than do bay (E/-) horses. Computerized records obtained from the Arabian Horse Registry of America, Inc., were used to determine if heterozygous (E/e) bay horses have more extensive white facial markings than do homozygous (E/E) bay horses. Thirty-five sire families were analyzed. Each sire family consists of a sire, his foals, and the dams of those foals. The facial region was divided into five areas, and each horse was given a score from 0 to 5 according to the number of areas with whiteness. Since dams and foals with E/E genotypes cannot be identified in these sire families, mean facial scores were compared in dams and foals that were E/e and E/-. It was assumed that if a difference exists between E/e and E/E horses, the presence of E/E horses in the E/- group would reduce the mean of the E/- group. The results show that Arabian horses with the genotype E/e have more white markings than do horses with the genotype E/-, leading to the conclusion that horses with the genotypes e/e, E/e, and E/E vary as to the quantitative expression of white facial markings, with heterozygotes having an intermediate expression.

Animals↗

PubMedDate not supplied

Influence of stochastic events on the phenotypic variation of common white leg markings in the Arabian horse: implications for various genetic disorders in humans.

One method of assessing the influence of stochastic events on phenotypic variation is to study morphological differences in paired limbs of the same individual. These limbs have identical genotypes and similar intra-uterine environments and are analogous to monozygotic twins. Common white leg markings have a multifactorial mode of inheritance in the Arabian horse. Asymmetry occurs frequently for these markings. Using computerized registration records obtained from the Arabian Horse Registry of America, Inc., the types of markings were quantified in the left foreleg and left hind leg of bay and chestnut horses when a specific marking occurred in (1) a paired right leg, (2) both right legs, and (3) both right legs and the other left leg. The variation in the markings in the left legs of these horses is evidence of the role of stochastic events during development. The relatively high frequency of a specific type of asymmetry, with one leg being completely pigmented, is of special biological interest and has implications for various human disorders that are characterized by reduced penetrance and variable expressivity.

Animals↗

PubMed1978

Genetic counselling and genetics of cleft lip and cleft palate.

Modern neonatal care and advanced plastic surgical correction have led to the survival of most newborns with oral clefts. These children are likely to reproduce. A slight increase in the incidence of oral clefts may be expected in the future. The genetics of cleft lip and cleft palate is reviewed. The inheritance is usually multifactorial. With normal parents the risk of having a first affected child with cleft lip is about one per thousand, the risk of having a second affected child 4 per cent and the risk of having a third affected child 10 per cent. If a parent has already a cleft lip, the risk of having a first affected child now is 4 per cent, while the risk of having a second affected child is 10 per cent. The methodology of genetic counseling is given.

Abnormalities, Drug-Induced↗

PubMed1992

Genetic aspects of the Klippel-Trenaunay syndrome.

An extensive search for a genetic pattern in Klippel-Trenaunay syndrome (KTS) revealed two other cases of KTS in the families of two of the 86 patients with this vascular syndrome who were questioned. Patients with KTS also had family members with other malformations: e.g. hemihypertrophy in one family, and a prevalence of 7/400 of naevi flammei in first-degree relatives of KTS patients was observed. We suggest that KTS can be inherited in a multifactorial way and a range of vascular malformations can be observed in the family members of patients with this syndrome.

Adolescent↗

PubMed1984

Fetal mortality in sibships of cases with neural tube defects.

It has been suggested that rates of fetal mortality in sibships of probands with a malformation inherited as a multifactorial threshold trait may reflect their liability to the malformation. If so, spontaneous abortion rates should be more frequent in sibships thought to have greater liability. For anencephaly and spina bifida (ASB), then, spontaneous abortion should be higher in the sibships of male probands and in families with more than one affected case (multiplex families). This hypothesis was tested using data on cases from The Montréal Children's Hospital and from the literature. Approximately 5000 pregnancies were analyzed. Rates of abortion did not vary with the sex or diagnosis of the proband. The spontaneous abortion rate was slightly higher in multiplex than in simplex families, but the difference was not statistically significant and most likely reflects the differing reproductive patterns in the two types of families. Thus, if male probands and multiplex sibships do have, on average, more liability for ASB, this liability cannot be detected in spontaneous abortion rates in the sibships available for this analysis.

Abortion, Spontaneous↗