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.

[The molecular genetic and clinical findings in two probands with Stargardt disease]. / Molekulárne genetická prícina a klinický nález u dvou probandu se Stargardtovou chorobou.

PURPOSE: The aim of our study was to describe the phenotype and to perform molecular genetic investigation in two probands of Czech origin diagnosed with Stargardt disease (STGD). METHODS: Both males underwent ocular examination including assessment by high-resolution spectral domain optical coherence tomography (SD-OCT). DNA was isolated from venous blood. Mutation detection was performed using the ABCA4 genotyping microarray (Asper Ophthalmics, Estonia). RESULTS: The best corrected visual acuity in proband 1 (aged 39 years) was 0.1 bilaterally, and 0.05 in proband 2 (aged 26 years). Fundus examination showed typical multiple yellow-white lesions and macular atrophy. Alterations of retinal pigment epithelium, retinal thinning and disruption of the photoreceptor inner segment ellipsoid band were detected with an SD-OCT. Two known disease-causing mutations in ABCA4 were identified in proband 1; c.4234C>T, p.(Gln1412*) in exon 28; and c.5882G>A, p.(Gly1961Glu) in exon 42. Only one pathogenic change was detected in proband 2; c.1988G>A, p.(Trp663*) in exon 14. A second change, anticipated because of the recessive status of the disease, was not identified. CONCLUSION: The frequency and full spectrum of ABCA4 mutations in Czech patients with inherited retinal disorders is yet to be established. The inability to detect a second pathogenic change in ABCA4 coding sequences in proband 2 warrants further investigation.

[Molecular analysis of Wilson disease]. / Molekulární analýza Wilsonovy choroby.

BACKGROUND: Wilson disease is an autosomal recessive disorder, characterized by cooper accumulation and intoxication of the organism. Molecular basis of the disease represent mutations in the gene for the copper-transporting ATPase (ATP7B). METHODS AND RESULTS: The submitted paper deals with results of molecular-genetic examination in 130 unrelated families in which Wilson disease was diagnosed. By denaturing gradient gel electrophoresis (DGGE), the exons with abnormal sequences were detected. Followed by sequencing, 17 causal mutations and 9 silent polymorphism were found. Five novel mutations were detected. After analysis of 260 mutant alleles, 214 (82.3%) were identified. The most frequent mutation, H1069Q, occurred in our population with the frequency of 65.8%. Incidence of other mutations, however, did not exceed 5%. CONCLUSIONS: DNA analysis of the Wilson disease offers prompt and reliable results in affected families. It can help to identify asymptomatic and heterozygote siblings at genetic counselling.

[Turner syndrome: overview of problems, present status, proposals for care and a protocol for monitoring in childhood, adolescence and adulthood]. / Turneruv syndrom: prehled problematiky, soucasný stav, návrh koncepce péce a protokol sledování v detství, adolescenci a v dospelosti.

BACKGROUND: Girls and adolescents with Turner syndrome (TS) usually receive intensive medical care in a multidisciplinary team, coordinated by paediatric endocrinologist. Majority of them are discharged from specialist clinics following the induction of puberty and attainment of final height. Patients with Turner syndrome have a reduced life expectancy, they are known to have multi-system impairments in addition to the short stature and to the absence of sexual development. Aim of this study is to propos a continuous follow-up by multidisciplinary team of physicians starting in childhood and following the discharge from the paediatric care. METHODS AND RESULTS: This paper highlights the medical and psychosocial problems associated with Turner syndrome in childhood, adolescence and in adulthood. Analysis of these problems served as a background to management strategy. CONCLUSIONS: Women with Turner syndrome are at risk of number of medical problems. Quality of their life and the life expectancy can be improved with increasing awareness to comorbities associated with Turner syndrome. Assisted reproduction technologies has recently offered a chance for pregnancy and delivery of a healthy child also to women with Turner syndrome. Therefore, long-term follow-up by multidisciplinary team of physicians knowledgeable about these medical problems is necessary. Introduction of a centralised system of systematic multidisciplinary approach to patients with Turner syndrome from childhood and adolescence to adulthood seems to be very important.