Molecular genetic analysis in 14 Czech Kabuki syndrome patients is confirming the utility of phenotypic scoring.

Kabuki syndrome (KS) is a dominantly inherited disorder mainly due to de novo pathogenic variation in KMT2D or KDM6A genes. Initially, a representative cohort of 14 Czech cases with clinical features suggestive of KS was analyzed by experienced clinical geneticists in collaboration with other specialties, and observed disease features were evaluated according to the 'MLL2-Kabuki score' defined by Makrythanasis et al. Subsequently, the aforementioned genes were Sanger sequenced and copy number variation analysis was performed by MLPA, followed by genome-wide array CGH testing. Pathogenic variants in KMT2D resulting in protein truncation in 43% (6/14; of which 3 are novel) of all cases were detected, while analysis of KDM6A was negative. MLPA analysis was negative in all instances. One female patient bears a 6.6 Mb duplication of the Xp21.2-Xp21.3 region that is probably disease causing. Subjective KS phenotyping identified predictive clinical features associated with the presence of a pathogenic variant in KMT2D. We provide additional evidence that this scoring approach fosters prioritization of patients prior to KMT2D sequencing. We conclude that KMT2D sequencing followed by array CGH is a diagnostic strategy with the highest diagnostic yield.

[Case reports of patients with a marker chromosome]. / Kazuistiky pacientu s marker chromozómy.

Small, usually supernumerary chromosomes, denoted as marker chromosomes or markers, can be represented by various phenotypic expression, that depends on their origin and extent. Our article presents results of molecular cytogenetic analysis (FISH) of 34 patients with identified marker chromosome. In 21 cases a marker derived from acrocentric chromosome was identified, in 9 cases markers of gonosomal origin [der(X), der(Y)], and in 4 patients markers of some other chromosomes (5, 17, 18) were proved. The most frequent marker was that originating from chromosome 15 (8 cases). Two patients with different phenotype, markedly influenced by the extent of pseudoizodicentric chromosome 15 are described. In accordance with hitherto presented data, presence of supernumerary copies of the critical region PWACR (it is the partial trisomy, resp. tetrasomy 15q11-q13) in majority of cases brings about serious affection described as syndrome of the inverted duplication of chromosome 15. The most typical symptoms are psychomotoric retardation, hypotony, neurological symptoms and autistic features. The article stresses the importance of FISH method in the prenatal examination of marker chromosomes.

[Psychosocial factors associated with genetic testing for certain hereditary types of neoplasms]. / Psychosociální faktory spojené s genetickým testováním nekterých dedicne podmínených nádorových onemocnení.

Mutations in predisposing genes for some of the hereditary forms of cancer exhibit autosomal dominant mode of inheritance. Introduction of genetic tests for these mutations to the clinical practice initiated studies focused on the psychosocial factors associated with genetic testing. Undergoing the genetic testing is a stressful experience for both the healthy individuals in risk and the patients already affected with cancer. The psychosocial characteristics of the tested individual influence not only the psychological functioning during the testing but also the acceptance of the test, and generally his life style and health practices. Psychological support during the genetic testing process is mostly provided by the genetic counsellor. The findings of psychosocial studies might be therefore helpful for the focusing of the genetic consultation, and fulfilling the client needs and expectations towards testing. Factors of motivation, psychological state, influence of family situation and support, and optionally the involvement of a psychologist into the process of genetic testing are observed.

[Genetic study of 20 patients with autism disorders]. / Genetická studie dvaceti pacientu s poruchami autistického spektra.

BACKGROUND: Many observations indicate that genetic factors play an important role in the aetiology of autism. Up to now, however, no genetic markers have been convincingly identified which influence the predisposition to this disorder. Complex genetic analysis of autistic patients and their families may therefore lead to the identification of features which could help to direct further search for the predisposing genes. METHODS AND RESULTS: We have analysed a sample of 20 patients with autism spectrum disorders. The patients have been subjected to clinical genetic examination, cytogenetic analysis and DNA analysis of the FMR1 gene. In the sample studied we have observed more boys (15/20), various degree of mental retardation (18/20), high frequency of complications during pregnancy (10/20) and delivery (10/20), increased incidence of psychiatric disorders, behavioural abnormalities and suicides among the relatives, and increased head circumference and unusually formed ears in the probands. Three patients had different chromosomal aberrations or variants (t(21;22), inv(9) and inv(10)). One patient harboured expansion of the trinucleotide repeat sequence in the FMR1 gene on the full mutation level which is characteristic for the fragile X syndrome, and one patient is suspected to suffer from the Rett syndrome. CONCLUSIONS: Our observations confirm and extend the results reported in the literature. Most interesting are mainly the macrocephaly which may be associated with the recently described increased neonatal levels of neural growth factors in autistic individuals, ear malformations which may indicate aberrations in the HOXA1 gene pathway, the occurrence of chromosomal inversions recurrent in autism, and peculiarities in the pedigrees of the patients.

[Genetics of autism]. / Genetika autismu.

Autism is a severe psychiatric disorder characterised by deficits in social interaction, disturbed communication and adherence to stereotype routines and interests. Nowadays it is completely clear that this disorder has a biological basis and many observations show strong genetic determination of autism. The importance of genetic factors is supported by frequent association of this disorder with known hereditary diseases or with various chromosomal aberrations, by high concordance of the disorder in monozygotic twins, higher risk for the siblings of autistic patients and also by the frequent occurrence of milder symptoms of the autistic spectrum in more distant relatives. All these findings show that the autistic phenotype results from unfavourable combination of alleles of several genes in interplay with factors of the environment. This model of multifactorial inheritance of autism serves at present as the starting point for the search for predisposing genes in the human genome. The association is tested between autism and alleles of candidate genes selected based on known biochemical and physiological role of their protein products, or based on their location close to recurrent chromosomal rearrangements or in regions identified by whole-genome linkage analyses. Studies of most of these genes have not yielded clear-cut results yet, but the participation of some of them in the aetiology of autism is possible.

[Specialized genetic counseling in pediatric and adult oncology patients]. / Specializované genetické poradenství u detských a dospelých onkologických pacientu.

Five to ten percent of oncological diseases exhibit monogenic mode of inheritance. They occur as a consequence of the germline mutations of tumor suppressor genes and of the genes engaged in reparative processes. Most common monogenically determined oncological diseases are: AD form of breast and ovarian cancer, hereditary nonpolyposis colorectal cancer (HNPCC, Lynch sy.) and familiar adenomatous polyposis (FAP). The aim of the genetic investigation is to evaluate whether the index family deals with the hereditary form of tumor predisposition, than, if possible, to perform DNA analysis in the family and to propose preventive screening program (methods) for the probands in risk.

[DNA diagnosis of the fragile X chromosome syndrome--FRAXA using PCR]. / DNA diagnostika syndromu fragilního X chromozomu--FRAXA pomocí PCR.

BACKGROUND: Fragile X syndrome is gonosomal recessive mental retardation with the frequency 1:1000 in male population. Fragile X syndrome is caused by amplification of CGG repeat in 1. exon of FMT-1 gene. The aim of this study was to set up and validate a rapid and efficient PCR diagnosis to select FRAXA negative patients in population of mental retarded patients. METHODS AND RESULTS: In the set up phase of the method, 196 patients were diagnosed. We were using modified radioactive PCR of CGG. Obtained PCR fragments were separated on 6% denaturing PAGE. Results were correlated with Southern blot analysis using pE5.1 probe. STR-PCR was verified on a large set of patients and shows validity and efficiency of results in the case of pre- and full mutations in male hemizygous patients too. For estimation of carriers with pre- and full mutation by females modified diagnostic approach was developed. There was no difference found between results from PCR and Southern blot analysis. CONCLUSIONS: The PCR method is convenient not only for selection of FRAXA negative patients, but for diagnosis of full mutation and premutation of affected probands.