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Background: Pontocerebellar hypoplasia type 1 (PCH1) is characterized by a central and peripheral motor dysfunction associated with anterior horn cell degeneration, similar to spinal muscular atrophy (SMA)., Objectives: We analysed three probands (later discovered to be siblings) suspected to have severe SMA, however, not confirmed by genetic test., Methods: Clinical-exome analysis (Illumina) was performed to identify causative variants, followed by Sanger sequencing confirmation in probands and other 10 family members., Results: Homozygous pathogenic variant c.92G>C (p.(Gly31Ala)) in the Exosome Component 3 (EXOSC3) gene was found in all 3 probands, thus confirming the diagnosis of a severe form of PCH1B. The parents and six siblings were carriers, while one sibling was homozygous for a reference allele. This variant is frequent in the Czech Roma population, where it is considered a founder mutation. Haplotype analysis in this largest reported PCH1B family showed that our patients inherited from their father (of Roma origin) a haplotype identical to that found in the Czech Roma population, thus indicating these alleles have a common origin., Conclusion: This EXOSC3 variant is rare among the general population but most likely frequent also among Roma people in Slovakia. PCH1B should be considered for a differential diagnosis in infants manifesting SMA-like phenotype, especially if of Roma origin (Tab. 1, Fig. 1, Ref. 22). Text in PDF www.elis.sk Keywords: pontocerebellar hypoplasia, PCH1B, EXOSC3, SMA plus syndromes, pathogenic sequence variant.

Objectives: For the first time we used targeted next-generation sequencing to detect candidate pathogenic variants in Slovak cardiomyopathy patients., Background: Targeted next-generation sequencing is considered to be the best practice in genetic diagnostics of cardiomyopathies. However, in Slovakia, with high cardiomyopathies prevalence of 1/440, the current diagnostic tests are still based on Sanger sequencing of a few genes. Consequently, little is known about the exact contribution of pathogenic variants in known cardiomyopathy genes in Slovak patients., Methods: We used a panel of 46 known cardiomyopathy-associated genes to detect genetic variants in 16 Slovak cardiomyopathy patients (6 dilated, 8 hypertrophic, 2 non-compaction subtypes)., Results: We identified candidate pathogenic variants in 11 of 16 patients (69 %). Genes with higher count of candidate pathogenic variants were MYBPC3, MYH and TTN, each with 3 different variants. Seven variants ACTC1 (c.329C>T), ANKRD1 (c.683G>T), MYH7 (c.1025C>T), PKP2 (c.2003delA), TTN (c.51655C>T, c.84841G>T, c.101874_101881delAGAATTTG) have been detected for the first time and might represent Slovak-specific genetic cause., Conclusions: We have performed genetic testing of previously untested Slovak cardiomyopathy patients using next-generation sequencing cardiomyopathy gene panel. Given the high percentage of candidate pathogenic variants it should be recommended to implement this method into routine genetic diagnostic practice in Slovakia (Tab. 4, Ref. 39).

Background and Aims: The thiopurine drugs, azathioprine (AZA) and 6-mercaptopurine, are established in the treatment of inflammatory bowel diseases (IBD). Polymorphisms in thiopurine S-methyltransferase (TPMT) gene have been associated with adverse drug reactions (ADRs) to AZA., Methods: The aim of this study was to evaluate TPMT polymorphisms and AZA-related toxicity in a Slovak cohort of 220 IBD patients treated with AZA. In every patient, the dose and duration of AZA therapy, concomitant 5-aminosalicylate (5-ASA) medication, frequency, type, time to onset, dose of ADR and concomitant 5-ASA at the onset of ADR were recorded. Each patient was also genotyped for the presence of variant TPMT alleles (*2,*3A,*3B,*3C). Frequency, type and circumstances of ADRs were compared according to TPMT status., Results: Of the 220 patients, 205 (93.2 %) were wild-type (TPMT*1/*1), one (0.5%) carried a TPMT*1/*3C allele, 13 (5.9 %) carried TPMT *1/*3A allele and one was homozygous for TMPT *3A allele. No TPMT *2 mutation was found. The incidence of adverse drug reactions was 62/205 (30.2 %) in the wild-type group as compared to 13/15 (86.7 %) in the TPMT mutation group, p=2.10-5. Leukopenia (WBC< 3.0*10^9/L) occurred in 21/205 (10.2 %) patients with wild type TPMT versus 11/15 (73.3 %) patients with TPMT mutations, p=0.000001. There was no significant difference between TMPT groups in gastrointestinal or other ADRs. No impact of 5-ASA on the incidence and severity of AZA adverse drug reactions was observed., Conclusion: The incidence of leukopenia in TPMT mutant patients was significantly higher and more severe as compared to TPMT wild type patients. We observed no impact of concomitant 5-ASA therapy on AZA induced toxicity (Tab. 4, Fig. 2, Ref. 37).

Background: Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism of thiopurines. It has been suggested that TPMT genetic polymorphisms lead to dose-related hematopoietic toxicity. Since there are major ethnic differences in the prevalence of particular TPMT variants, it is important for each country to study their own prevalence in order to estimate the role of TPMT variants-related thiopurines toxicity in population suffering from particular inflammatory bowel disease (IBD)., Aims: The aim of this study was to determine the frequency of the four most common allelic variants of TPMT gene in the population of Slovak IBD patients., Methods: TPMT genetic polymorphisms (TPMT*2, TPMT*3A, TPMT*3B, TPMT*3C) were amplified using PCR and consequently genotyped with genetic analyzer. The allele frequencies of particular allelic variants were calculated and compared with other Caucasian populations reported so far., Results: Three hundred and thirty IBD patients were included; 196/132/2 cases of Crohn´s disease/ulcerative colitis/unclassified colitis; 180 (55 %) males. Ninety-three percent of patients were homozygous for wild-type TPMT variant. Heterozygous genotype of any of the studied polymorphisms was present in 6 % of patients while only one patient was homozygous for TPMT*3A allele (0.3 %). The most prevalent mutant allele was that of TPMT*3A (3.2 %). The distribution of most common allelic variants of TPMT gene among Slovak IBD patients was in accordance with previously reported prevalence in Caucasian populations., Conclusion: This study shows the prevalence of TPMT genetic polymorphisms in population of Slovak IBD patients. As in other Caucasian populations, the most common mutant allelic variant is that of TPMT*3A while the prevalence of homozygosity is relatively low (Tab. 3, Ref. 22).

Background: Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism of thiopurines. It has been suggested that TPMT genetic polymorphisms lead to dose-related hematopoetic toxicity. Since there are major ethnic differences in the prevalence of particular TPMT variants, it is important for each country to study their own prevalence in order to estimate the role of TPMT variants-related thiopurines toxicity in the particular inflammatory bowel disease (IBD) population., Aims: The aim of this study was to determine the frequency of the four most common allelic variants of TPMT gene in the population of Slovak IBD patients., Methods: TPMT genetic polymorphisms (TPMT*2, TPMT*3A, TPMT*3B, TPMT*3C) were amplified using PCR and consequently genotyped on genetic analyzer. The allele frequencies of particular allelic variants were calculated and compared with other Caucasian populations reported so far., Results: Three hundred and thirty IBD patients were included; 196/132/2 Crohn´s disease/ulcerative colitis/unclassified colitis, 180 (55 %) males. Ninety-three percent of patients were homozygous for wild type TPMT variant. Heterozygous genotype of any of the studied polymorphisms was present in 6 % of patients, only one patient was homozygous for TPMT*3A allele (0.3 %). The most prevalent mutant allele was TPMT*3A (3.2 %). The distribution of the most common allelic variants of TPMT gene among Slovak IBD patients were in accordance with previously reported prevalence in Caucasian populations., Conclusion: This study shows the prevalence of TPMT genetic polymorphisms in the Slovak IBD patient`s population. As in other Caucasian populations, the most common mutant allelic variant is TPMT*3A, and the prevalence of homozygosity is relatively low (Tab. 3, Ref. 16).