Clinical and genetic heterogeneity in laminopathies

Mutations in the LMNA gene encoding lamins A/C are responsible for more than ten different disorders called laminopathies which affect various tissues in an isolated (striated muscle, adipose tissue or peripheral nerve) or systemic (premature aging syndromes) fashion. Overlapping phenotypes are also observed. Associated with this wide clinical variability, there is also a large genetic heterogeneity, with 408 different mutations being reported to date. Whereas a few hotspot mutations emerge for some types of laminopathies, relationships between genotypes and phenotypes remain poor for laminopathies affecting the striated muscles. In addition, there is important intrafamilial variability, explained only in a few cases by digenism, thus suggesting an additional contribution from modifier genes. In this regard, a chromosomal region linked to the variability in the age at onset of myopathic symptoms in striated muscle laminopathies has recently been identified. This locus is currently under investigation to identify modifier variants responsible for this variability.     

Possible genetic heterogeneity in the Saethre-Chotzen syndrome

Saethre-Chotzen syndrome is an autosomal dominant acrocephalosyndactyly syndrome whose gene has been assigned to chromosome 7p. Cytogenetic and linkage analyses have enabled the interval encompassing the disease gene to be delimited to a short region of chromosome 7p15.3–p21.2. Based on the genetic analysis of three unreported families, we confirm the location of the disease gene(s) in the interval defined by loci D7S664 and D7S493 (Z_max = 4.78 at * = 0 at the D7S488 locus) but fail to decide whether one or more disease-causing genes map in this genetic interval. Received: 2 January 1996 / Revised: 21 March 1996     

Incidence in Italy, genetic heterogeneity, and segregation analysis of cystic fibrosis

Taking advantage of the availability of an archive of consanguineous marriages that gives accurate estimates of consanguinity in Italy, it has been possible to calculate the increase of first- and second-cousin marriages among 624 couples of cystic fibrosis (CF) parents over the general population. From these estimates, the incidence of CF in Italy has been found to correspond approximately to 1/2,000. In turn, the same data have been used to test the hypothesis of genetic heterogeneity of CF, recently proposed, which is based on the presence of two distinct genetic disorders having similar frequencies. If such a hypothesis were true, the number of first-cousin marriages among CF parents should be significantly higher than that observed in our present study. Finally, the segregation analysis of 624 CF sibships has yielded under multiple selection a segregation ratio of 0.252, confirming the recessive mode of inheritance.     

Clinical and genetic heterogeneity in Meckel syndrome

Meckel syndrome (MKS) is a lethal malformation syndrome characterised by posterior meningoencephalocele, polycystic kidneys, fibrotic changes of the liver, and polydactyly. We have previously shown a linkage to chromosome 17q in 17 Finnish Meckel families. In this study we have analysed one Italian, one Austrian (of Turkish origin) and three British MKS families (Caucasian, Pakistani, and Bangladeshi families) for linkage to the MKS locus on chromosome 17q22–q24. We did not observe co-segregation of the disease and marker haplotypes in the Austrian family or in the three British families, of which two represented classical MKS and one a slightly atypical MKS phenotype with longer survival of the patient. In the Italian family the affected and non-affected children did not share the same maternal chromosome and thus this family could represent the same allelic disease as the Finnish MKS families. These results suggest locus heterogeneity in Meckel syndrome – a feature previously suspected based on the highly variable clinical phenotype. Received: 2 June 1997 / Accepted: 12 June 1997     

Implications of genetic heterogeneity in cancer

DNA sequencing studies have established that many cancers contain tens of thousands of clonal mutations throughout their genomes, which is difficult to reconcile with the very low rate of mutation in normal human cells. This observation provides strong evidence for the mutator phenotype hypothesis, which proposes that a genome-wide elevation in the spontaneous mutation rate is an early step in carcinogenesis. An elevated mutation rate implies that cancers undergo continuous evolution, generating multiple subpopulations of cells that differ from one another in DNA sequence. The extensive heterogeneity in DNA sequence and continual tumor evolution that would occur in the context of a mutator phenotype have important implications for cancer diagnosis and therapy.     

Clinical and genetic heterogeneity in retinitis pigmentosa

Summary The clinical course of defective vision and blindness has been investigated in relation to different modes of genetic transmission in a large series of 93 families with retinitis pigmentosa (RP). For autosomal dominant RP, two clinical subtypes could be distinguished according to the delay in macular involvement. In the severe form, macular involvement occurred within 10 years, while in the mild form, macular involvement occurred after 20 years. Interestingly, a significant increase of mean paternal age (38.8 years, mean controls in France = 29.1 years, P < 0.001) was found in this form of RP, a feature which is suggestive of new mutations. For autosomal recessive RP, four significantly different clinical subtypes could be recognized, according to both age of onset and the pattern of development (P < 0.001), namely cone-rod dystrophy and early-onset severe forms on the one hand (mean age of onset = 7.6 years), late-onset mild forms and senile forms on the other. Similarly, two significantly different clinical subtypes could be recognized in X-linked RP, according to both mode and age of onset, which were either myopia (mean age = 3.5±0.5 years) or night blindness (mean age = 10.6±4.1 years, P < 0.001). By contrast, no difference was noted regarding the clinical course of the disease, which was remarkably severe whatever the clinical subtype (blindness before 25 years). In addition, all obligate carriers in our series were found to have either severe myopia or pigment deposits in their peripheral retina. Finally, sporadic RP represented the majority of cases in our series (42%). There was a considerable heterogeneity in this group, and at least three clinical forms could be recognized, namely cone-rod dystrophy, early onset-severe forms and late onset moderate forms. At the beginning of the disease, the hereditary nature of the sporadic forms was very difficult to ascertain (especially between 7–10 years) and only the clinical course could possibly provide information regarding the mode of inheritance. However, the high level of consanguinity, and the high sex ratio in early onset and severe sporadic forms (including cone-rod dystrophy), was suggestive of an autosomal or X-linked recessive inheritance, while increased paternal age in late onset forms was suggestive of autosomal dominant mutations.     

Evaluating genetic heterogeneity in complex disorders

OBJECTIVES: The Admixture test is routinely used in linkage analysis to take account of genetic heterogeneity, and yields an estimate of the proportion of families (alpha) segregating the linked disease gene. In complex disorders, the assumptions of the Admixture test are violated. We therefore explore how the estimate of alpha relates to the true proportion of linked families with a complex disorder in a population or dataset. METHODS: We simulated a two-locus heterogeneity model and varied genetic parameters, ascertainment scheme and phenocopy frequency. RESULTS: In this model, alpha is almost always overestimated, by as little as 5% to as much as 60%. The bias is largely attributable to (1). intrafamilial heterogeneity arising from ascertainment of families with many affected members or from analysis of dense pedigrees; (2). low informativeness, which occurs in the presence of reduced penetrance; and (3). differences in the evidence for linkage in linked and unlinked families. This bias is also affected by the analysis phenocopy frequency, but only if the linked locus is dominant and the unlinked locus is recessive. CONCLUSIONS: We conclude that, in complex diseases, the Admixture test has greater value in detecting linkage than in estimating the proportion of linked families in a dataset.     

A new definition of genetic distance

Summary A stochastic measure of genetic distance between populations is proposed; unlike currently used measures, it is invariant with respect to union and subdivision of loci. This measure enables a unified quantitative approach to genetic diversity within populations and genetic distance between populations.     

Study of the genetic heterogeneity of gangliosidoses in humans

A study of genetic heterogeneity of GM1 and GM2 gangliosidoses was performed using a wide set of cultured fibroblast lines of patients with leukodystrophies. In addition to commonly used methods for enzyme diagnosis and for isozyme fractionating, following assays were developed for locus and allele differentiation: loading tests with 3H-GM1 and 3H-GM2, analytical chromatofocusing and activity determination of activator protein for GM2.     

Mitochondrial dysfunction and genetic heterogeneity in chronic periodontitis

We performed an extensive study on mitochondrial dysfunction in chronic periodontitis (CP). Electron microscopic analysis of gingival cells revealed abnormal mitochondria in 60% of the patients. Mitochondrial membrane potential and oxygen consumption of gingival cells were reduced by 4 fold and 5.8 fold, respectively; whereas ROS production was increased by 18%. The genetic analysis by complete mitochondrial DNA sequencing revealed the identification of 14 novel mutations only in periodontal tissues but not in the blood, suggesting a role of oxidative stress on periodontal tissues. Thus, our functional and genetic analysis provided an evidence for the mitochondrial dysfunction in CP.     

A genetic interpretation of the variation in inbreeding depression

Inbreeding depression is expected to play an important but complicated role in evolution. If we are to understand the evolution of inbreeding depression (i.e., purging), we need quantitative genetic interpretations of its variation. We introduce an experimental design in which sires are mated to multiple dams, some of which are unrelated to the sire but others are genetically related owing to an arbitrary number of prior generations of selfing or sib-mating. In this way we introduce the concept of "inbreeding depression effect variance," a parameter more relevant to selection and the purging of inbreeding depression than previous measures. We develop an approach for interpreting the genetic basis of the variation in inbreeding depression by: (1) predicting the variation in inbreeding depression given arbitrary initial genetic variance and (2) estimating genetic variance components given half-sib covariances estimated by our experimental design. As quantitative predictions of selection depend upon understanding genetic variation, our approach reveals the important difference between how inbreeding depression is measured experimentally and how it is viewed by selection.     

医学遗传学中遗传异质性含义的解析

遗传异质性是医学遗传学中的重要概念。介绍了遗传异质性的产生原因,基本类型及研究意义。通过实例,解析了等位基因异质性和基因座异质性两大类型,阐述了遗传异质性在医学教学和临床实践中的作用。     

医学遗传学中遗传异质性含义的解析

介绍了遗传异质性的产生原因,基本类型及研究意义。通过实例,解析了等位基因异质性和基因座异质性两大类型,阐述了遗传异质性在医学教学和临床实践中的作用。     

Evidence for genetic heterogeneity in Carvajal syndrome

Carvajal syndrome is a rare syndrome with woolly hair, palmoplantar keratosis and dilated cardiomyopathy. The inheritance of the mutation is autosomal recessive. As a causal gene, the desmoplakin gene (DSP) has so far been identified; it encodes an essential component of desmosomes, a cell-cell structure aimed at keeping cells attached to each other in tissues in which cells are often exposed to strong shear forces. Recently, familial cases of an autosomal dominant Carvajal syndrome were documented with a new feature: hypo/oligodontia. A mutation in the DSP gene was also evidenced in these latter cases. A patient was seen for cardiogenetic consultation at the University Hospital of Lyon with cardiac failure involving first degree atrioventricular block, complete left bundle branch block, non-compaction of the apex of the left ventricle and a dilated cardiomyopathy. A coronarography disclosed a complete thrombosis of the right coronary artery. At examination, he had also woolly hair, mild palmoplantar keratosis and missing teeth (essentially molars and premolars). His family history was uninformative. His DNA was screened for mutations in the DSP and plakoglobin genes but no mutation could be found. This case suggests that Carvajal syndrome with hypo/oligodontia is a heterogeneous condition in which genes other than DSP might be involved, although we cannot rule out a mutation in this gene consisting in a deletion of a single exon or a gene rearrangement.     

Costs and benefits of genetic heterogeneity within organisms

An increasing number of studies have recently detected within-organism genetic heterogeneity suggesting that genetically homogeneous organisms may be rare. In this review, we examine the potential costs and benefits of such intraorganismal genetic heterogeneity (IGH) on the fitness of the individual. The costs of IGH include cancerous growth, parasitism, competitive interactions and developmental instability, all of which threaten the integrity of the individual while the potential benefits are increased genetic variability, size-specific processes, and synergistic interactions between genetic variants. The particular cost or benefit of IGH in a specific case depends on the organism type and the origin of the IGH. While mosaicism easily arise by genetic changes in an individual, and will be the more common type of IGH, chimerism originates by the fusion of genetically distinct entities, and is expected to be substantially rare in most organisms. Potential conflicts and synergistic effects between different genetic lineages within an individual provide an interesting example for theoretical and empirical studies of multilevel selection.