Home About us Contact
|
Home About us Contact | ||
|
|
||
Genotype Correlations (genotype + correlation)
Selected AbstractsHot spot mutations in keratin 2e suggest a correlation between genotype and phenotype in patients with ichthyosis bullosa of SiemensEXPERIMENTAL DERMATOLOGY, Issue 1 2000Y. Suga Abstract: Ichthyosis bullosa of Siemens (IBS) is a rare disorder of cornification characterized by blister formation in the upper suprabasal layers of the epidermis. Molecular analysis of IBS has identified mutations in the keratin 2e (K2e) gene, which is located in the type II keratin gene cluster on chromosome 12q. We have studied two IBS families and have identified heterozygous point mutations in codon 493 of the K2e gene in both families. Whereas a non-conservative amino acid substitution at position 117 of the 2B region of K2e (E117K) was associated with a severe phenotype in family 1, family 2 showed mild clinical features as a result of a conservative substitution (E117D). These data suggest a phenotype,genotype correlation in these families. [source] Family data in Rett syndrome: Association with other genetic disordersJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 4 2000H Leonard Background: Rett syndrome is a neurological disorder, almost exclusively affecting girls. Methodology: Between 1993 and 1995 pedigree data were obtained from families of girls registered with the Australian Rett syndrome database. Results: Although 21 individual disorders were reported to be present in family members of affected girls, there was no apparent clustering of the same disorder in different families. However it was certain that a geneticist had been involved in only 10.9% of cases. Conclusions: Mutations in the MECP2 gene have now been reported in a proportion of sporadic cases. Thus, it will be important to examine this phenotype,genotype correlation in the Australian cohort. Where a mutation is found, prenatal diagnosis in a subsequent pregnancy will be a possibility. Using the Australian population database and in conjunction with the clinical genetic services in each state it is planned to contact families with an affected girl to offer testing and counselling. [source] Novel and recurrent germline LEMD3 mutations causing Buschke,Ollendorff syndrome and osteopoikilosis but not isolated melorheostosisCLINICAL GENETICS, Issue 6 2009Y Zhang Mutations in the LEMD3 gene were recently incriminated in Buschke,Ollendorff syndrome (BOS) and osteopoikilosis, with or without melorheostosis. The relationship of this gene with isolated sporadic melorheostosis is less clear. We investigated LEMD3 in a two-generation BOS family showing an extremely variable expression of the disease, in a sporadic patient with skin features of BOS, and in an additional subject with isolated melorheostosis. We identified two different mutations, both resulting in a premature stop codon, in the two cases of BOS. The mutation (c.2564G>A) reported in the familial case is novel, while that observed in the sporadic case (c.1963C>T) has been previously reported in an American woman with osteopoikilosis and melorheostosis who had a family history of isolated osteopoikilosis. The search for mutations in DNA extracted from the peripheral blood, as well as skin and bone biopsies of the patient with melorheostosis failed to identify any pathogenic change. Our results further expand the LEMD3 mutation repertoire, corroborate the extreme interfamilial and intrafamilial clinical variability of LEMD3 mutations, and underline the lack of a clear phenotype,genotype correlation in BOS. The present study supports the general conclusion that LEMD3 mutations do not contribute to isolated sporadic melorheostosis. The genetic or epigenetic influences that are responsible for the development of melorheostosis require further investigation. [source] Candidate-gene association studies with pedigree data: Controlling for environmental covariatesGENETIC EPIDEMIOLOGY, Issue 4 2003S.L. Slager Abstract Case-control studies provide an important epidemiological tool to evaluate candidate genes. There are many different study designs available. We focus on a more recently proposed design, which we call a multiplex case-control (MCC) design. This design compares allele frequencies between related cases, each of whom are sampled from multiplex families, and unrelated controls. Since within-family genotype correlations will exist, statistical methods will need to take this into account. Moreover, there is a need to develop methods to simultaneously control for potential confounders in the analysis. Generalized estimating equations (GEE) are one approach to analyze this type of data; however, this approach can have singularity problems when estimating the correlation matrix. To allow for modeling of other covariates, we extend our previously developed method to a more general model-based approach. Our proposed methods use the score statistic, derived from a composite likelihood. We propose three different approaches to estimate the variance of this statistic. Under random ascertainment of pedigrees, score tests have correct type I error rates; however, pedigrees are not randomly ascertained. Thus, through simulations, we test the validity and power of the score tests under different ascertainment schemes, and an illustration of our methods, applied to data from a prostate cancer study, is presented. We find that our robust score statistic has estimated type I error rates within the expected range for all situations we considered whereas the other two statistics have inflated type I error rates under nonrandom ascertainment schemes. We also find GEE to fail at least 5% of the time for each simulation configuration; at times, the failure rate reaches above 80%. In summary, our robust method may be the only current regression analysis method available for MCC data. Genet Epidemiol 24:273,283, 2003. © 2003 Wiley-Liss, Inc. [source] Protein- and mRNA-based phenotype,genotype correlations in DMD/BMD with point mutations and molecular basis for BMD with nonsense and frameshift mutations in the DMD gene,HUMAN MUTATION, Issue 2 2007Nathalie Deburgrave Abstract Straightforward detectable Duchenne muscular dystrophy (DMD) gene rearrangements, such as deletions or duplications involving an entire exon or more, are involved in about 70% of dystrophinopathies. In the remaining 30% a variety of point mutations or "small" mutations are suspected. Due to their diversity and to the large size and complexity of the DMD gene, these point mutations are difficult to detect. To overcome this diagnostic issue, we developed and optimized a routine muscle biopsy,based diagnostic strategy. The mutation detection rate is almost as high as 100% and mutations were identified in all patients for whom the diagnosis of DMD and Becker muscular dystrophy (BMD) was clinically suspected and further supported by the detection on Western blot of quantitative and/or qualitative dystrophin protein abnormalities. Here we report a total of 124 small mutations including 11 nonsense and frameshift mutations detected in BMD patients. In addition to a comprehensive assessment of muscular phenotypes that takes into account consequences of mutations on the expression of the dystrophin mRNA and protein, we provide and discuss genomic, mRNA, and protein data that pinpoint molecular mechanisms underlying BMD phenotypes associated with nonsense and frameshift mutations. Hum Mutat 28(2), 183,195, 2007. © 2006 Wiley-Liss, Inc. [source] Brain metabolism in rett syndrome: Age, clinical, and genotype correlations,ANNALS OF NEUROLOGY, Issue 1 2009Alena Horská PhD Objective Brain metabolism, as studied by magnetic resonance spectroscopy (MRS), has been previously shown to be abnormal in Rett syndrome (RTT). This study reports the relation of MRS findings to age, disease severity, and genotype. Methods Forty RTT girls (1,14 years old) and 12 age-matched control subjects were examined. Single-voxel proton MRS of left frontal white matter was performed. Results NAA/Cr ratios decreased and myoinositol/Cr ratios increased with age in RTT patients (both p < 0.03), whereas these ratios were stable in control. The mean glutamate and glutamine/Cr ratio was 36% greater in RTT patients than in control (p = 0.043). The mean NAA/Cr ratio was 12.6% lower in RTT patients with seizures compared with those without seizures (p = 0.017). NAA/Cr ratios decreased with increasing clinical severity score (p = 0.031). Compared with patients with T158X, R255X, and R294X mutations, and C-terminal deletions, patients with the R168X mutation tended to have the greatest severity score (0.01 , p , 0.11) and the lowest NAA/Cr ratio (0.029 , p < 0.14). Interpretation Decreasing NAA/Cr and increasing myoinositol/Cr with age are suggestive of progressive axonal damage and astrocytosis in RTT, respectively, whereas increased glutamate and glutamine/Cr ratio may be secondary to increasing glutamate/glutamine cycling at the synaptic level. The relations between NAA/Cr, presence or absence of seizures, and disease severity suggest that MRS provides a noninvasive measure of cerebral involvement in RTT. Ann Neurol 2009;65:90,97 [source] How much phenotypic variation can be attributed to parkin genotype?ANNALS OF NEUROLOGY, Issue 2 2003Ebba Lohmann MD To establish phenotype,genotype correlations in early-onset parkinsonism, we have compared the phenotype of a large series of 146 patients with and 250 patients without parkin mutations. Although no single sign distinguished the groups, patients with mutations had significantly earlier and more symmetrical onset, dystonia more often at onset and hyperreflexia, slower progression of the disease, and a tendency toward a greater response to levodopa despite lower doses. After forward stepwise multiple logistic regression analysis, dystonia at onset and brisk reflexes were not longer significantly different but were correlated with age at onset rather than the presence of the parkin mutation. Age at onset in carriers of parkin mutations varied as did the rate of progression of the disease: the younger the age at onset the slower the evolution. The genotype influenced the phenotype: carriers of at least one missense mutation had a higher United Parkinson's Disease Rating Scale motor score than those carrying two truncating mutations. The localization of the mutations was also important because missense mutations in functional domains of parkin resulted in earlier onset. Patients with a single heterozygous mutation had significantly later and more asymmetrical onset and more frequent levodopa-induced fluctuations and dystonia than patients with two mutations. Ann Neurol 2003 [source] Epidermolysis bullosa simplex in Japanese and Korean patients: genetic studies in 19 casesBRITISH JOURNAL OF DERMATOLOGY, Issue 2 2006K. Yasukawa Summary Background, Epidermolysis bullosa simplex (EBS) comprises a group of hereditary bullous diseases characterized by intraepidermal blistering caused by mutations in either keratin gene, KRT5 or KRT14. Significant correlation between the position of mutations within these proteins and the clinical severity of EBS has been noted. A recent report showed EBS cases in Israel had unique genetic features compared with European or U.S.A. associated families, which suggests that the ethnic and geographical features of EBS patients may be different. Objectives, To assess the possibility that EBS may present with certain specific features in Japanese and Koreans and to identify additional EBS mutations for genotype/phenotype correlation. Methods, EBS was clinically diagnosed and confirmed by transmission electron microscopic examination of a skin biopsy. Mutation analysis of KRT5 and KRT14 was performed by direct sequencing in 17 Japanese and two Korean EBS patients. Results, We have identified six novel KRT5 missense mutations (V143D, D158V, V186M, Q191P, R352S, G517D). R352S is the first mutation in the 2A domain. Most of these novel mutations changed amino acids that were evolutionarily conserved. Eight including all five mutations in EBS-Dowling,Meara patients have been previously reported. We were unable to detect mutations in five sporadic EBS-Koebner patients. The proportion of mutations in KRT5 (11 of 14; 78%) is higher than that for KRT14 mutations (3 of 14; 21%) in these Japanese and Korean EBS patients. Conclusions, Japanese and Korean patients with EBS showed very similar phenotype and genotype correlations with patients from Western countries. Whether the higher proportion of KRT5 mutations is a definite characteristic of Japanese and Korean patients with EBS or not, requires further research into mutations in Japanese and Korean people. [source] Clinical phenotype of posterior polymorphous corneal dystrophy in a family with a novel ZEB1 mutationACTA OPHTHALMOLOGICA, Issue 6 2010Dan Q. Nguyen Acta Ophthalmol. 2010: 88: 695,699 Abstract. Purpose:, To describe the clinical phenotype in a family with posterior polymorphous corneal dystrophy (PPCD) and a novel mutation in the ZEB1 gene. Methods:, Clinical examination, anterior segment photography, specular microscopy and electrophysiological investigations were performed and quantified. Genomic DNA extracted from peripheral blood was sequenced for ZEB1 exons. Cosegregation of identified mutation with the disease status in the family was confirmed using polymerase chain reaction and restriction fragment length polymorphism. Results:, Ocular examination was performed on five family members from two generations. Three had anomalies of the corneal endothelium that were consistent with PPCD. Endothelial cell counts ranged from 2306 to 2987 mm2 (ref. 2000,4000 cells/mm2). No evidence of glaucoma or retinal abnormalities was observed. Extraocular abnormalities such as inguinal herniation, hydrocoele and possible bony or connective tissue anomalies were part of the disease spectrum in this family. Mutation analysis revealed a novel change in exon 5 of ZEB1 (c.672delA) that cosegregated with the affected disease status. Conclusion:, The detailed clinical features of PPCD associated with a novel ZEB1 mutation are supportive of the previously proposed range of phenotype parameters. Further phenotype,genotype correlations may provide insights into the clinical variability and pathological processes affecting the corneal endothelium, Descemet's membrane, retinal photoreceptor function and extraocular tissues of some patients. [source] Advances in the genetics of sarcoidosisCLINICAL GENETICS, Issue 5 2008G Smith Sarcoidosis is an uncommon disease of granulomatous inflammation. Genetic predisposition to sarcoidosis is indicated by observations of familial clustering, increased concordance in monozygotic twins over other siblings, and variations in susceptibility and disease presentation among different ethnic groups. Published studies on sarcoidosis have investigated a variety of genetic associations. These studies used techniques ranging from classic human lymphocyte antigen genotype correlations to genome-wide linkage scans. Results have both supported and refuted disease associations with a number of genes potentially involved in the pathogenesis of sarcoidosis. Here, we review representative studies concerning the genetics of sarcoidosis. While investigations to date have failed to identify a unifying genetic signature associated with sarcoidosis, numerous studies have identified genetic associations with disease subtypes or within specific populations. These studies suggest that genetic susceptibility to sarcoidosis is complex and polygenic in nature. Future studies will help clarify the genetics of sarcoidosis and allow for the development of diagnostic, prognostic and therapeutic technologies. [source] 2465: Phenotype/genotype evolution in corneal embryologic malformationsACTA OPHTHALMOLOGICA, Issue 2010KK NISCHAL Purpose To describe the evolution of a clinically useful classification of corneal developmental anomalies which has also allowed more accurate phenotype/genotype correlation. Methods The use of clinical documentation using anterior segment photography, normal ultrasound of the eyeball, and high frequency ultrasound and where available histology of host tissue has allowed detailed phenotypes to be developed . Intraoperative recordings of phenotype have also been noted. Genotyping of specific patterns groupings of corneal developmental anomaly phenotypes. Retrospective analysis of clnical outcome with or without surgical intervention. Results Corneal developmental anomalies are best considered in terms of primary corneal disease and secondary corneal disease. The former includes dystophies ( CHED, PPCD and X-L ECD) , corneal dermoids and isolated sclerocornea ( CNA 1 and 2 ).Secondary corneal disease includes secondary to, iridotrabecular anomalies ( eg congenital glaucoma, aniridia, axenfeld -rieger anomaly), kerato-irido-lenticular dysgenesis ( iridolenticular adhesions( Peters type I), failure of lens to form,separate or move away from the cornea). Conclusion Using this classification prognosis for intervention can be shown to be mor successful in primary corneal developmental anomalies. Also by considering groups of patients with similar disease eg primary aphakia, appropriate genotyping can be done eg FOXE3 analysis for children with primary aphakia . More acccurate phenotype allows better clinical classification and ultimately better genotyping of corneal developmental anomalies [source] | |||||||||||||