145 research outputs found
Rare diseases: phenomics and genetic counselling.
No full textRare diseases (RD) – life menacing or slowly emaciating diseases of extremely low incidence (less than 5 cases in 10,000 EU inhabitants). The term was launched by Neil A. Holtzman in 1978. There are about 5,000 – 8,000 RD, each manifesting itself in some life stage of about 6% of EU population, that amounts from 29 to 36 million people. In Lithuania that would make about 200,000 people. The majority of RD are genetic (80%), the remaining consist of rare cancer forms, autoimmune diseases, inborn developmental anomalies, toxic or contagious illnesses. The author presented an analytical review of 22 publications on RD. Historical indications about RD could be found in anatomical museums, ancient medical books, and folk art. In the collection of anatomical specimens of Medical Faculty of Vilnius University the author has discovered a unique case of human anotocephaly and eleven more nosological entities of RD (congenital anomalies). The main sources for information on RD are registers and data bases. This is the only way to obtain sufficient samples for epidemiologic and/or clinical research. Lithuanian Register of Congenital Anomalies (LIRECA) and autopsies data base were reviewed by the author and analyzed by statistical research models applicable in registration of RD, in particular Poisson linear model and logistic (binomic) regression. Analysis of standardized remainders confirmed their adequacy and suitability. Biological asymmetry was evaluated by analysis of polysyndactyly syndrome. The established increase of general and fluctuating asymmetry reflects unequal expression of developmental plan in both bilaterally symmetric sides of the organism in genetic diseases. Interdisciplinary biomics (systeomics) and separate “omics” of today’s science strive to explicate biological and chemical rules of organism functioning. Phenomics is one of the branches of biomics. This term is usual in plant genetics, and means the analysis of mutant phenotypes. Analysis of patient’s phenotypes is one of important methods in genetic counselling. In the strict meaning “phenotype” is understood as the characteristics of patient’s external features. The term “phenomics” would be suitable for the holistic analysis of patients’ phenotypes. RD amount to 10.1% patients counselled by the author. Quantitative and qualitative characteristics were analyzed in patients with monogenic, chromosomal diseases, teratogenic syndromes and congenital anomalies due to other factors. Further tasks in RD phenomics are foreseen: organization of the RD monitoring system in Lithuania, and development of expert system
Influence of CYP2D6 and CYP2C19 genes polymorphisms on clinical antidepressant efficiency in treatment of moderate and severe depression.
No full textPsychopharmacology is an important and effective way of therapy in treatment of many mental health disorders and their symptoms. Depression is one of the most common mental health disorders, and treatment with antidepressants is one of the principal methods of its treatment. However, it is known, that only 25 % to 60 % of medical treatment is successful when using standard doses of medications. CYP450 enzyme activity is responsible for drug metabolism and is one of the most important determinants of drug effectiveness. Activity of these enzymes is dependant on the genotype and its polymorphisms. The aim of this work is to determine CYP2D6 and CYP2C19 genes polymorphisms influence on the clinical antidepressant efficacy when treating Lithuanian patients with moderate and severe depression. The study included 78 patients, the data obtained was compared with the data of 104 people in the control group. After evaluating the influence from CYP2D6 genotype predicted phenotype on treatment responses, it was found that CYP2D6 genes polymorphisms did not affect the clinical antidepressant efficacy or the impact could not be evaluated statistically due to the very unequal sample sizes. After assessing the influence from CYP2C19 genotype predicted phenotype, it was found that CYP2C19 genes polymorphisms did affect clinical antidepressant efficacy: patients who had altered metabolism recovered more slowly, experienced statistically significantly more and more severe symptoms of depression. Results of genetic tests do not change throughout a person's lifetime, therefore obtained genetic information remains relevant not only in retrospective assessment of unsuccessful treatment cases but also in the future when applying personalised treatment
Įgimto / paveldimo klausos sutrikimo genomika: įtaka patogenezei ir fenotipinei išraiškai Lietuvos populiacijoje.
No full textHearing loss (HL) is a considerable issue of modern medicine and society. The disorder is highly heterogeneous and hereditary factors play significant role in disease pathogenesis. The advancement of new technologies requires the development of scientific knowledge, in order to develop new treatment options and improve the social integration of patients. The aim of this study is to assess the influence of genetic factors to pathogenesis and phenotypic manifestation of HL in Lithuanian population. The group of 315 affected individuals was formed, their clinical, genealogy and genetic testing data were collected and analysed (DEAFGEN). Also, the analysis of the whole exome sequencing data in the group of healthy individuals from ethnic Lithuanian population was performed (LITGEN). Etiologic structure of HL was determined: genetic factors account 55.6 % of isolated HL cases (51.4 % GJB2 gene pathogenic variants), clinical diagnosis was identified to 64.4 % of participants in syndromic HL subgroup. Genetic factors in general lead to more severe (OR 3.3) and symmetric (OR 3.0) HL with positive family history (OR 2.6). The high frequency of carriers of pathogenic variants of genes associated with autosomal recessive HL (21.4 % with prevailing GJB2 gene alterations – 7.1 %) in the group of healthy participants corresponds to the substantial frequency of hereditary HL in Lithuania (~1 in 557 individuals). The recommendations for genetic diagnostics of congenital/hereditary HL in Lithuania were prepared
Paveldimų tinklainės distrofijų klinikinių ir genetinių charakteristikų vertinimas.
No full textInherited retinal dystrophies (IRD) is a vast group of genetically determined diseases characterized by significant both clinical and genetic heterogeneity. IRD differ in their heredity, character of visual impairment and ocular fundus findings. To date more than 190 genes are known and alterations in more than 40 gene areas are identified responsible for the IRD. The aim of the research was to evaluate the clinical and genetic characteristics of inherited retinal dystrophies in Lithuanian patient group. One hundred and nineteen subjects met the inclusion criteria, 13 different IRD were identified clinically, and in 16.8% of subjects’ pathogenic changes confirming molecular diagnosis of IRD were found. In the group of subjects with X-linked juvenile retinoschisis 2 new alterations of RS1 gene were identified. Biostatistical analysis showed statistically significant correlations between different phenotype characteristics and single nucleotide polymorphisms in the largest subject group of retinitis pigmentosa. During this study, visual electrophysiology tests were implemented into clinical practice, and one of them, multifocal electroretinography, was applied in Lithuania for the first time. This study was the first research conducted in Lithuania allowing identify, analyze, group, perform genetical testing and assess genotype-phenotype correlations of IRD
Identification of deletions and duplications in the phenylalanine hydroxylase gene in lithuanian patients with phenylketonuria.
No full textPhenylketonuria (PKU) is one of the most common inherited disorder transmitted by an autosomal recessive mode of inheritance. The disease is mostly (97-98% of cases) caused by mutations in the phenylalanine hydroxylase (PAH) gene. PAH gene encodes enzyme which catalyzes the conversion of L-phenylalanine to L-tyrosine, the rate-limiting step in the catabolism of phenylalanine. More than 950 PAH gene mutations have been identified in patients with PKU. The clinical PKU polymorphism is explained by the variety of mutations because each mutation is distinguished by its unique metabolic phenotype. Studies of patients with PKU estimated that genotype may be useful in predicting metabolic phenotype and providing a baseline for the correct treatment. Molecular research of the PAH gene in Vilnius University Hospital Santariškių klinikos Centre for Medical Genetics (CMG) has been in place since 1989. During that time 92.6% of mutant PAH gene alleles carrying point mutations, small deletions and insertions have been identified. The main aim of the study was to identify large PAH gene deletions and duplications and also to evaluate the frequency of these mutations in Lithuanian patients with PKU. The study involved Lithuanian PKU patients in whom only one or no PKU-causing mutations have been identified despite the analysis performed with classical methods in the CMG. The study of this work includes the deletion/duplication analysis of 3-7 PAH gene exons by using relative real-time polymerase chain reaction (qPCR) technique. According to qPCR analysis, one duplication and two deletions of several exons of the PAH gene were detected in 5 out of 19 tested patients. These mutations included (i) a large heterozygous deletion of exons 3-5 in one patient, a homozygous deletion of exon 5 in three patients and (iii) a heterozygous duplication of exon 4 in one patient. Statistical analysis of the data stored in the CMG and the results obtained in this study suggested that large deletions and duplications account for 1,81% of all PAH mutant alleles investigated in Lithuanian PKU patients. The comparison of the distribution of PAH gene alleles carrying large deletions and duplications revealed that frequencies of PAH gene exonic deletions/duplications are similar in Lithuanian, Italian (1,7%), Slovenian (1,7%), Australian (2,0%) and Slovak (2,2%) populations. The analysis of the PAH gene repetitive sequences in the region spanning from intron 2 to intron 5 allowed us to make the assumption that mechanisms of deletion/duplication generation may be homologous recombination or non-homologous end joining. Genotype-phenotype correlation showed that large PAH gene deletions and duplications result in classic (severe) PKU with initial L-Phe blood level higher than 1000 µmol/l
The genomics of congenital / hereditary hearing loss: influence on pathogenesis and the phenotypic manifestation in the Lithuanian population.
No full textHearing loss (HL) is a considerable issue of modern medicine and society. The disorder is highly heterogeneous and hereditary factors play significant role in disease pathogenesis. The advancement of new technologies requires the development of scientific knowledge, in order to develop new treatment options and improve the social integration of patients. The aim of this study is to assess the influence of genetic factors to pathogenesis and phenotypic manifestation of HL in Lithuanian population. The group of 315 affected individuals was formed, their clinical, genealogy and genetic testing data were collected and analysed (DEAFGEN). Also, the analysis of the whole exome sequencing data in the group of healthy individuals from ethnic Lithuanian population was performed (LITGEN). Etiologic structure of HL was determined: genetic factors account 55.6 % of isolated HL cases (51.4 % GJB2 gene pathogenic variants), clinical diagnosis was identified to 64.4 % of participants in syndromic HL subgroup. Genetic factors in general lead to more severe (OR 3.3) and symmetric (OR 3.0) HL with positive family history (OR 2.6). The high frequency of carriers of pathogenic variants of genes associated with autosomal recessive HL (21.4 % with prevailing GJB2 gene alterations – 7.1 %) in the group of healthy participants corresponds to the substantial frequency of hereditary HL in Lithuania (~1 in 557 individuals). The recommendations for genetic diagnostics of congenital/hereditary HL in Lithuania were prepared
Evaluation of genetic and phenotype heterogeneity in hereditary neuropathies.
No full textHereditary neuropathies are a broad clinically and genetically heterogeneous group of neurodegenerative disorders. Our aim was to identify the most common and novel genetic defects and to evaluate the genetic and phenotype heterogeneity in a group of patients with hereditary neuropathies. The fact that hereditary neuropathies are caused by a wide variety of variants in a large number of different genes, restricts the number of patients who suffer from a specific mutation. As a result, we retrospectively analysed the phenotypes of the patients with CMT1A. We further prospectively investigated the most common hereditary neuropathies genes GJB1, MFN2, MPZ, and we performed NGS for the selected patients. Furthermore, genotype-phenotype relationships have been described in patients with previously reported and novel pathogenic variants. Our study gives important insights to apply targeted NGS for patients who are negative for the most common genetic causes
Genotipo ir fenotipo heterogeniškumo įvertinimas paveldimų neuropatijų grupėje.
No full textHereditary neuropathies are a broad clinically and genetically heterogeneous group of neurodegenerative disorders. Our aim was to identify the most common and novel genetic defects and to evaluate the genetic and phenotype heterogeneity in a group of patients with hereditary neuropathies. The fact that hereditary neuropathies are caused by a wide variety of variants in a large number of different genes, restricts the number of patients who suffer from a specific mutation. As a result, we retrospectively analysed the phenotypes of the patients with CMT1A. We further prospectively investigated the most common hereditary neuropathies genes GJB1, MFN2, MPZ, and we performed NGS for the selected patients. Furthermore, genotype-phenotype relationships have been described in patients with previously reported and novel pathogenic variants. Our study gives important insights to apply targeted NGS for patients who are negative for the most common genetic causes
Evaluation of Clinical and Genetic Characteristics of the Inherited Retinal Dystrophies.
No full textInherited retinal dystrophies (IRD) is a vast group of genetically determined diseases characterized by significant both clinical and genetic heterogeneity. IRD differ in their heredity, character of visual impairment and ocular fundus findings. To date more than 190 genes are known and alterations in more than 40 gene areas are identified responsible for the IRD. The aim of the research was to evaluate the clinical and genetic characteristics of inherited retinal dystrophies in Lithuanian patient group. One hundred and nineteen subjects met the inclusion criteria, 13 different IRD were identified clinically, and in 16.8% of subjects’ pathogenic changes confirming molecular diagnosis of IRD were found. In the group of subjects with X-linked juvenile retinoschisis 2 new alterations of RS1 gene were identified. Biostatistical analysis showed statistically significant correlations between different phenotype characteristics and single nucleotide polymorphisms in the largest subject group of retinitis pigmentosa. During this study, visual electrophysiology tests were implemented into clinical practice, and one of them, multifocal electroretinography, was applied in Lithuania for the first time. This study was the first research conducted in Lithuania allowing identify, analyze, group, perform genetical testing and assess genotype-phenotype correlations of IRD
Statistical analysis of congenital anomlies in children in Lithuania.
No full textTrends, prevalence and some influential (risk) factors of congenital anomlies in children in Lithuania are investigated using logistic regression model
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