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Results for “Phenotypic variability”

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PubMed1993

Velo-cardio-facial syndrome. Intrafamilial variability of the phenotype.

We describe a mother and son with velo-cardio-facial syndrome (VCFS) in whom cytogenetic and DNA molecular studies demonstrate an interstitial deletion of the long arm of chromosome 22. Although these two individuals manifest the typical facial and cognitive features of VCFS, they are discordant for the cardiovascular and palatal anomalies, which are seminal manifestations of the disorder. Previously, this degree of phenotypic variability had not been well appreciated within a single family segregating the VCFS deletion. A review of other familial cases of VCFS suggests that the family described in this article is not atypical. Because a microdeletion would be expected to be inherited without alteration within individual families, the phenotypic variability observed in these families appears to be an intrinsic quality of the syndrome and not wholly due to genetic heterogeneity.

Abnormalities, Multiple↗

PubMed2006

Genetic influences in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a metabolic liver disease with widely variable phenotypes extending from simple steatosis, through nonalcoholic steatohepatitis (NASH) to cirrhosis and hepatocellular carcinoma. Inevitably, this reflects the interplay of well-recognized environmental factors and disease associations such as obesity and insulin resistance with host genetic factors, which are polygenic or complex in nature. Most of the observed phenotypic variability will probably be explained by variations in single nucleotide polymorphism frequency, although knowledge of the effect of most polymorphisms on biologic function is currently limited. Several observational studies of kindred with NASH suggest a genetic contribution. Most data characterizing genetic variation in different NAFLD phenotypes is derived from case-control association studies involving putative candidate genes. These candidate genes have been selected largely based upon the "two-hit hypothesis" of the pathogenesis of NAFLD, although other hypothesis-independent approaches can also be informative in gene selection. Thus far, candidate gene association studies have had significant limitations such as small cohort sizes and poor reproducibility. Rapid technologic developments are increasing the capability of detecting genetic variation. Identification of the genetic contribution to NAFLD will inform theories of disease pathogenesis and progression and ultimately improve management.

Fatty Liver↗

PubMed2006

Clinical and functional characterization of a human ORNT1 mutation (T32R) in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome.

We studied two related families (HHH013 and HHH015) with the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, a disorder of the urea cycle and ornithine degradation pathway, who have the same novel ornithine transporter (ORNT1) genotype (T32R) but a variable phenotype. Both HHH015 patients are doing well in school and are clinically stable; conversely, the three affected HHH013 siblings had academic difficulties and one suffered recurrent episodes of hyperammonemia and ultimately died. Overexpression studies revealed that the product of the ORNT1-T32R allele has residual function. Ornithine transport studies in HHH015 fibroblasts, however, showed basal activity similar to fibroblasts carrying nonfunctional ORNT1 alleles. We also examined two potential modifying factors, the ORNT2 gene and the mitochondrial DNA lineage (haplogroup). Haplogroups, associated with specific diseases, are hypothesized to influence mitochondrial function. Results demonstrated that both HHH015 patients are heterozygous for an ORNT2 gain of function polymorphism and belong to haplogroup A whereas the HHH013 siblings carry the wild-type ORNT2 and are haplogroup H. These observations suggest that the ORNT1 genotype cannot predict the phenotype of HHH patients. The reason for the phenotypic variability is unknown, but factors such as redundant transporters and mitochondrial lineage may contribute to the neuropathophysiology of HHH patients.

Adolescent↗

PubMed2006

Roberts syndrome: study of 4 new Rgyptian cases with comparison of clinical and cytogenetic findings.

Roberts syndrome is a rare autosomal recessive genetic disorder (MIM 268300). It is characterized by pre and postnatal growth retardation, severe shortening of limbs with radial defects, oligodactyly and characteristic facial features. The present study reports 4 new cases of Roberts syndrome from 3 families presenting variable phenotypes. Patients were thoroughly investigated clinically and cytogenetically. By reviewing literature, we compared our cases to those previously reported. The rating severity system proposed by Van den Berg and Francke (30) was applied to correlate the phenotypic and cytogenetics changes. We observed more severe reduction defects in the upper limbs than in the lower limbs. While the main reduction defects in the upper limbs involved the thumb and radius ranging to phocomelia, absent or severely hypoplastic fibula was the main lower limb involvement. We emphasize this finding in the present investigation. Heterochromatin repulsion of chromosomes derived from Roberts syndrome patients is a characteristic cytogenetic abnormality. It was a constant finding in our studied patients demonstrated by DABI stain which supports the possibility that mutations in Roberts syndrome lie in centromere related proteins which may also play a role in body patterning. This was proved recently by Vega et al. (31). Application of the clinical rating score and its correlation with cytogenetic changes showed negative results. Cytogenetic studies in normal obligatory heterozygotes parents showed no changes. Phenotypic variability within the same family as well as between different families was observed. The ascertainment of 4 cases with Roberts syndrome from 3 Egyptian consanguineous families during one year in our department may indicate a high frequency of the Roberts syndrome allele among Egyptians. This confirms the need for molecular studies for early and accurate prenatal diagnosis to prevent such dramatic malformation syndrome.

Abnormalities, Multiple↗

PubMed2006

A family with features overlapping Okihiro syndrome, hemifacial microsomia and isolated Duane anomaly caused by a novel SALL4 mutation.

The SALL4 gene encodes a putative zinc finger transcription factor and is located on chromosome 20q13.13-13.2. Mutations in SALL4 have been identified in patients with Okihiro syndrome, which is characterized by radial ray anomalies associated with a Duane anomaly. Here, we report an unusual family in which affected persons show an extremely variable phenotype consistent with either Okihiro syndrome, hemifacial microsomia, or isolated Duane anomaly. A novel nonsense mutation in the SALL4 gene was detected in all affected family members and obligate carriers. This mutation is located in exon 3, only 29 bp 5' of the most 3' intron, and would therefore be expected to escape the nonsense mediated mRNA decay pathway, which might explain the phenotypic variability and mild degree of limb involvement.

Abnormalities, Multiple↗

PubMed1996

Dominantly inherited cerebello-olivary atrophy is not due to a mutation at the spinocerebellar ataxia-I, Machado-Joseph disease, or Dentato-Rubro-Pallido-Luysian atrophy locus.

The dominantly inherited ataxias are characterized both by phenotypic variability (phenotypic heterogeneity) within the same genotype and overlapping phenotypes from different genotypes (genotypic heterogeneity). Therefore it is important to characterize specific clinical-neuropathologic phenotypes as precisely as possible at the genetic level. We describe a family with dominantly inherited ataxia of late adult onset with relatively "pure" cerebellar signs. Neuropathologic examination in two individuals from this family revealed findings consistent with cerebello-olivary atrophy, suggesting that this neuropathologic phenotype many run true within f families. Mutations at the spinocerebellar ataxia-I, Machado-Joseph disease, and dentatorubropallidoluysian atrophy loci were excluded by direct DNA analysis on the leukocytes of one living affected member. Thus we provide evidence that these mutations are not responsible for this particular phenotype of dominantly inherited ataxia.

Adult↗

PubMed2006

Mutations of the mitochondrial holocytochrome c-type synthase in X-linked dominant microphthalmia with linear skin defects syndrome.

The microphthalmia with linear skin defects syndrome (MLS, or MIDAS) is an X-linked dominant male-lethal disorder almost invariably associated with segmental monosomy of the Xp22 region. In two female patients, from two families, with MLS and a normal karyotype, we identified heterozygous de novo point mutations--a missense mutation (p.R217C) and a nonsense mutation (p.R197X)--in the HCCS gene. HCCS encodes the mitochondrial holocytochrome c-type synthase that functions as heme lyase by covalently adding the prosthetic heme group to both apocytochrome c and c(1). We investigated a third family, displaying phenotypic variability, in which the mother and two of her daughters carry an 8.6-kb submicroscopic deletion encompassing part of the HCCS gene. Functional analysis demonstrates that both mutant proteins (R217C and Delta 197-268) were unable to complement a Saccharomyces cerevisiae mutant deficient for the HCCS orthologue Cyc3p, in contrast to wild-type HCCS. Moreover, ectopically expressed HCCS wild-type and the R217C mutant protein are targeted to mitochondria in CHO-K1 cells, whereas the C-terminal-truncated Delta 197-268 mutant failed to be sorted to mitochondria. Cytochrome c, the final product of holocytochrome c-type synthase activity, is implicated in both oxidative phosphorylation (OXPHOS) and apoptosis. We hypothesize that the inability of HCCS-deficient cells to undergo cytochrome c-mediated apoptosis may push cell death toward necrosis that gives rise to severe deterioration of the affected tissues. In summary, we suggest that disturbance of both OXPHOS and the balance between apoptosis and necrosis, as well as the X-inactivation pattern, may contribute to the variable phenotype observed in patients with MLS.

Amino Acid Sequence↗

PubMed1998

MELAS and MERRF. The relationship between maternal mutation load and the frequency of clinically affected offspring.

The majority of pathogenic mitochondrial DNA (mtDNA) mutations are heteroplasmic, with both mutant and wild-type alleles present within the same individual. MtDNA is transmitted only from females to their offspring but a single female can bear offspring who harbour different levels of mutant mtDNA and have a variable phenotype. In single families, this complex genetic and phenotypic variability has confounded the identification of any relationship between the level of mutant mtDNA (mutation load) in the mother and the clinical features of her offspring. To obtain a more accurate description of the inheritance of pathogenic mtDNA mutations, we studied a large number of pedigrees that carried either the mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (A3243G MELAS) or the myoclonic epilepsy with ragged-red fibres (A8344G MERRF) mutations. We made two principal observations. First, for both mutations, higher levels of mutant mtDNA in the mothers' blood were associated with an increased frequency of affected offspring. Secondly, at any one level of maternal mutation load there was a greater frequency of affected offspring for the A3243G MELAS mutation than for the A8344G MERRF mutation. Although these results should not be used to give absolute risks to a female contemplating pregnancy, they suggest that the outcome of pregnancy is related to the level of mutant mtDNA in the mother and that the risks of having affected offspring may differ between different mtDNA mutations.

Adolescent↗

PubMed2003

The genetic origin of atrioventricular conduction disturbance in humans.

Atrioventricular (AV) conduction disturbance (block) describes impairment of the electrical continuity between the atria and ventricles. Clinical classification of AV block has utilized biophysical characteristics, usually the extent (1st, 2nd, 3rd degree) and site of block (above or below His bundle recording site). The genetic significance of this classification is not known. In some cases AV block occurrence is associated with intrauterine exposure to maternal antibody (anti-Ro, anti-La), and other cases are associated with injury (e.g. surgery). Based on familial clustering of idiopathic AV block, a genetic cause has also been suspected. Published pedigrees show autosomal dominant inheritance, and associated heart disease is common (e.g. congenital heart malformation, cardiomyopathy, etc.). The latter finding is not unexpected given the common origin of working myocytes and elements of the specialized conduction system. Using genetic models incorporating reduced penetrance (presence of disease genotype in absence of phenotype), variable expressivity (presence of a disease genotype with variable phenotypes) and genetic heterogeneity (similar phenotypes, different disease genotypes), molecular genetic causes of AV block are being identified. These findings are significant as they provide insight into the molecular basis of a clinical condition previously defined only by biophysical characteristics.

Animals↗

PubMed1998

Intrafamilial variability of the ocular phenotype in a Polish family with a missense mutation (A63D) in the Norrie disease gene.

PURPOSE: To describe the phenotypic variability in a Polish Norrie disease (ND) family associated with the missense mutation A63D. METHODS: A patient with spared vision from a Polish ND family underwent detailed ophthalmological examinations including slit-lamp biomicroscopy, ultrasound (USG), angiography, Goldmann kinetic visual field, and electroretinography (ERG). Mutation screening was carried out using the single-strand conformation polymorphism (SSCP) technique and subsequent DNA sequencing of the coding part of the ND gene. RESULTS: A mutation was detected (exon 3, A63D) in a large Polish family with 12 affected males, all but one presenting with classical ND symptoms. In one male, partially preserved vision was observed up to 40 years of age (distance acuity of the right eye 1/50 and left eye 2/50). Slit-lamp examination revealed remnants of a persistent primary vitreous and hyaloid artery. Upon angiography, the retina was vascularized within the posterior pole but not in the periphery. The ERG revealed pathological changes characteristic for chorioretinal degenerations. CONCLUSION: Within one family, individuals with identical sequence alterations in the ND gene can show remarkable phenotypic variability of the ocular symptoms. These findings indicate the involvement of additional factors (epigenetic or genetic) in ocular pathogenesis of ND.

Adult↗

PubMed2000

Variability in the phenotypic expression of fryns syndrome: A report of two sibships.

We report on two sibships with four fetuses of 12, 15, 17, and 20 weeks of gestation, respectively, and 1 preterm baby of 31 weeks of gestation affected by a multiple congenital disorder with manifestation suggestive of Fryns syndrome. In addition to the characteristic malformation pattern in Fryns syndrome, they presented with fetal hydrops, cystic hygroma, and multiple pterygias, allowing prenatal ultrasound diagnosis as early as in the 11th week of gestation. The two affected fetuses of family 1 showed severe craniofacial anomalies with bilateral cleft lip and palate, acral hypoplasia, postaxial oligodactyly, persistent truncus arteriosus, and interrupted aortic arch, asplenia sequence, and complex central nervous system midline malformations. In family 2 with three affected sibs, ear anomalies with atresia of the auditory canals, postaxial hexadactyly, intestinal atresias, callosal defects, and eye colobomas were the most outstanding features. On the basis of the present findings and former reports, the inter- and intrafamiliar phenotypic variability in Fryns syndrome, possible pathogenetic mechanisms, and the value of prenatal diagnosis are discussed. In the pathogenetic discussion, a special emphasis is put on the neural crest cell developmental field.

Abnormalities, Multiple↗

PubMed2004

Comparative analysis of morphological traits among Drosophila melanogaster and D. simulans: genetic variability, clines and phenotypic plasticity.

The two sibling cosmopolitan species, Drosophila melanogaster and D. simulans, are able to proliferate under very different climatic conditions. This has resulted in local adaptations, which are often arranged in latitudinal clines. Such clines are documented for body weight, wing and thorax length, sternopleural and abdominal bristle number, ovariole number and thoracic pigmentation. The overall magnitude of geographical differentiation is, however, much less in D. simulans than in D. melanogaster, and latitudinal clines are less pronounced. The fact that natural populations live under different climates raises the problem of interaction between temperature and phenotype. The reaction norms of morphometrical traits have been investigated as a function of growth temperature. The shapes of the response curves vary according to the investigated trait. They are generally curvilinear and can be described by calculating characteristic values after polynomial adjustments. For a given trait, the reaction norms of the two species are similar in their shape, although some significant differences may be observed. Within each species, significant differences are also observed between geographic populations: reaction norms are not parallel and the divergence is better marked when more distant populations (e.g., temperate and tropical) are compared. It thus appears that besides mean trait value, phenotypic plasticity is also a target of natural selection. A specific analysis of wing shape variation according to growth temperature was also undertaken. Reaction norms with different shapes may be observed in various parts of the wing: the major effect is found between the basis and the tip of the wing, but in a similar way in the two species. By contrast, some ratios, called wing indices by taxonomists, may exhibit completely different reaction norms in the two species. For a single developmental temperature (25 degrees C) the phenotypic variability of morphometrical traits is generally similar in the two species, and also the genetic variability, estimated by the intraclass correlation. A difference exists, however, for the ovariole number which is less variable in D. simulans. Variance parameters may vary according to growth temperature, and a detailed analysis was made on wing dimensions. An increase of environmental variability at extreme, heat or cold temperatures, has been found in both species. Opposite trends were, however, observed for the genetic variability: a maximum heritability in D. simulans at middle temperatures, corresponding to a minimum heritability in D. melanogaster. Whether such a difference exists for other traits and in other populations deserves further investigations. In conclusion, morphometrical analyses reveal a large amount of significant differences which may be related to speciation and to the divergence of ecological niches. Within each species, numerous geographic variations are also observed which, in most cases, reflect some kinds of climatic adaptation.

Animals↗

PubMed1993

Genetic and molecular characterization of P element-induced mutations reveals that the Drosophila ovarian tumor gene has maternal activity and a variable null phenotype.

The mutations in the ovarian tumor (otu) gene arrest oogenesis at several stages in development. A series of deletion mutations in the otu region were characterized, each of which causes the absence or reduction of the otu transcript. These alleles range from the most severe class, which results in ovaries lacking egg cysts, to relatively mild mutations that allow the development of late stage oocytes. Heteroallelic combinations of these mutations demonstrate that the phenotypic complexity of otu mutant ovaries is due to a dosage dependent requirement for otu activity. Reciprocal cross and developmental Northern blot studies suggest a maternal requirement for otu in the development of the female germline. In addition we demonstrate that the otu zygotic null phenotype is variable, ranging from the absence of cysts in the most extreme cases, to the presence of tumorous egg chambers.

Alleles↗

PubMed1997

Antibody-mediated selection of a Mycoplasma gallisepticum phenotype expressing variable proteins.

A variant phenotype of Mycoplasma gallisepticum S6 was isolated from an in vitro antibody-culture system utilizing metabolism-inhibiting antibodies against the 64 kDa lipoprotein (LP64). M. gallisepticum populations grown in medium alone or medium containing normal rabbit serum maintained expression of the parental phenotype. This paper describes the identification of proteins which undergo variable expression. Several of these were integral membrane proteins, with estimated molecular masses of 91, 43, 41, 38, 37, and 18 kDa, which were expressed in the variant phenotype but not in the parental phenotype. Three proteins (LP64, p63 and p47) were expressed in the parental phenotype, but not in the variant phenotype. The data suggest that the interaction of specific immunoglobulins with target epitopes resulted in the selection of a subpopulation of organisms expressing an alternative array of membrane proteins which, lacking the target epitopes, was able to escape the metabolism-inhibiting effects of the specific antibodies.

Animals↗

PubMed1976

Variability of red cell phenotypes between and within individuals in an unbiased sample of 77 heterozygotes for G6PD deficiency in Sardinia.

The distribution of G6PD red blood phenotypes in an unbiased sample of 77 Sardinian certain heterozygotes for the GdMediterranean mutant was found to be skewed in favor of the G6PD (+) cells. Four of these individuals exhibited the normal hemizygous phenotype in all of their cells, but two of them had a mosaic population of G6PD (+) and (-) red blood cells when reexamined after 1 year. These findings suggest that somatic selection may be the main factor determining the phenotype variability of individual somatic cells in highly differentiated tissues of heterozygotes at the G6PD locozygotes for the GdMediterranean mutant should not be used as a criterion for precise estimation of the embryonic or stem tissue cell pool at X inactivation.

Erythrocytes↗

PubMed1997

Localized reversible frameshift mutation in an adhesin gene confers a phase-variable adherence phenotype in mycoplasma.

The variable adherence-associated (Vaa) antigen of Mycoplasma hominis is an abundant surface lipoprotein adhesin that may mediate important interactions of this wall-less prokaryotic pathogen with the human host. Extensive mutational variation of Vaa size, as well as sequence and antigenic divergence, has been described previously. Using a series of clonal isolates representing an isogenic lineage of variants oscillating in Vaa expression, Vaa is further shown in this study to undergo high-frequency phase variation in expression, which correlated precisely with the ability of M. hominis to adhere to cultured human cells. Although no DNA rearrangements or sequence differences in the 5' regions flanking vaa alleles were detected between Vaa+ and Vaa variants, intragenic vaa sequences from this lineage revealed an oscillating mutation involving a single nucleotide deletion/insertion in a short tract of adenine residues near the 5' end of the mature Vaa coding sequence, which created a translational frameshift resulting in either a complete Vaa ORF or an in-frame UAG stop codon immediately downstream of the poly-A tract. Evidence for the occurrence of this high-frequency frameshift mutation in vivo was obtained from analysis of PCR-generated vaa sequences amplified from the joint synovial fluid of a patient with M. hominis-associated arthritis, which indicated that Vaa phase variation occurs during M. hominis infection in the natural host. These results identify a distinctive frameshift mutator element in the vaa gene that governs M. hominis adherence and highlight the importance of mutational alteration of primary gene products on the mycoplasma surface as a means of generating and maintaining functional diversity in the host.

Adhesins, Bacterial↗

PubMed2006

Plasticity to soil water deficit in Arabidopsis thaliana: dissection of leaf development into underlying growth dynamic and cellular variables reveals invisible phenotypes.

Genetic variability in the plasticity of leaf area expansion in response to water deficit has been reported in Arabidopsis thaliana. Here, the objective was to identify the underlying dynamic and cellular processes involved in this variability. Twenty-five accessions were subjected to identical soil water deficit treatments. In all accessions, the plasticity of leaf production was low compared with that of individual leaf expansion. A subset of accessions was selected for further dissection of individual leaf expansion into its underlying variables: the rate and duration of leaf expansion and epidermal cell number and area. In all accessions, water deficit had opposite effects on the rate and duration of leaf expansion. The accumulation of these effects was reflected in changes in final leaf area. At the cellular level, moderate water deficits had opposite effects on cell number and cell size, but more severe ones reduced both variables. The importance of these opposing effects is highlighted by the behaviour of the accession An-1, for which the compensation between the decrease in leaf expansion rate and the increase in the duration of expansion is total. This dynamic plasticity in response to water deficit is not detectable when only final measurements are done.

Arabidopsis↗

PubMed1994

The variable clinical phenotype in thyroid hormone resistance syndrome.

Thyroid hormone resistance syndrome (RTH) is a rare disorder characterized by elevated levels of circulating free thyroid hormones, inappropriate TSH secretion, and reduced peripheral tissue responses to iodothyronine action. On the basis of clinical features, at least two different forms of RTH have been described: generalized resistance (GRTH) in which patients are asymptomatic with few clinical signs and pituitary resistance (PRTH) where patients present with some signs and symptoms associated with thyrotoxicosis. However, a review of the literature and our own experience indicates that there is a wide overlap of symptoms and signs exhibited by individuals with GRTH or PRTH. Assessments using biochemical and physiological indices of thyroid hormone action are useful, but limited by their lack of precision and also show an overlap between values recorded in GRTH and PRTH. In addition, we have observed significant temporal variations in clinical signs as well as in parameters of thyroid hormone action in the same individuals, with no correlation with their subjective symptoms. Recent genetic analyses indicate that patients with either GRTH or PRTH are heterozygous for mutations in the thyroid hormone receptor beta (TR beta) gene. Indeed, different clinical features have been observed in affected individuals within a kindred harboring the same Tr beta mutation, and identical mutations have been identified in unrelated kindreds classified as GRTH or PRTH. These data support the view that GRTH and PRTH are variable manifestations of a single genetic entity. Nevertheless, this clinical distinction will remain useful as a guide to the most appropriate treatment. The variable phenotypic spectrum of thyroid hormone resistance may be related to factors other than mutations in Tr beta that have yet to be elucidated.

Diagnosis, Differential↗