BACKGROUND: The highest mortality and morbidity worldwide is associated with atherosclerotic cardiovascular disease (ASCVD), which has in background both environmental and genetic risk factors. Apolipoprotein L1 (APOL1) variability influences the risk of ASCVD in Africans, but little is known about the APOL1 and ASCVD in other ethnic groups. METHODS: To investigate the role of APOL1 and ASCVD, we have genotyped four (rs13056427, rs136147, rs10854688 and rs9610473) APOL1 polymorphisms in a group of 1541 male patients with acute coronary syndrome (ACS) and 1338 male controls. RESULTS: Individual APOL1 polymorphisms were not associated with traditional CVD risk factors such as smoking, hypertension or diabetes prevalence, with BMI values or plasma lipid levels. Neither individual polymorphisms nor haplotypes were associated with an increased risk of ACS nor did they predict total or cardiovascular mortality over the 10.2 ± 3.9 years of follow-up. CONCLUSIONS: We conclude that APOL1 genetic variability has no major effect on risk of ACS in Caucasians.
- Klíčová slova
- Caucasians, apolipoprotein L1, cardiovascular disease, mortality, polymorphism,
- MeSH
- akutní koronární syndrom * genetika MeSH
- apolipoprotein L1 * genetika MeSH
- apolipoproteiny genetika MeSH
- běloši genetika MeSH
- genetická predispozice k nemoci MeSH
- haplotypy MeSH
- jednonukleotidový polymorfismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- lipoproteiny HDL genetika MeSH
- rizikové faktory MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
- Názvy látek
- APOL1 protein, human MeSH Prohlížeč
- apolipoprotein L1 * MeSH
- apolipoproteiny MeSH
- lipoproteiny HDL MeSH
INTRODUCTION AND METHODS: We report two series of individuals with DDX3X variations, one (48 individuals) from physicians and one (44 individuals) from caregivers. RESULTS: These two series include several symptoms in common, with fairly similar distribution, which suggests that caregivers' data are close to physicians' data. For example, both series identified early childhood symptoms that were not previously described: feeding difficulties, mean walking age, and age at first words. DISCUSSION: Each of the two datasets provides complementary knowledge. We confirmed that symptoms are similar to those in the literature and provides more details on feeding difficulties. Caregivers considered that the symptom attention-deficit/hyperactivity disorder were most worrisome. Both series also reported sleep disturbance. Recently, anxiety has been reported in individuals with DDX3X variants. We strongly suggest that attention-deficit/hyperactivity disorder, anxiety, and sleep disorders need to be treated.
- Klíčová slova
- DDX3X, ADHD, caregivers, developmental milestones,
- MeSH
- DEAD-box RNA-helikasy MeSH
- hyperkinetická porucha * genetika terapie MeSH
- kojenec MeSH
- lidé MeSH
- osoby pečující o pacienty * MeSH
- předškolní dítě MeSH
- zpráva o sobě MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- DDX3X protein, human MeSH Prohlížeč
- DEAD-box RNA-helikasy MeSH
BACKGROUND: Congenital myasthenic syndromes (CMSs) are characterized by hypotonia, episodic apnea, muscle weakness, ptosis and generalized fatigability. CMS type 20 (CMS20) is a rare disorder caused by variants in SLC5A7. In contrast to most other CMSs, CMS20 is also associated with neurodevelopmental disorders (NDDs). Only 19 patients from 14 families have been reported so far. METHODS: We studied a 12-year-old boy with symptoms manifested at six weeks of age. Later, he also showed speech delay, moderate intellectual disability and autism. Analysis of CMS genes known at the time of clinical diagnosis yielded no results. Trio exome sequencing (ES) was performed. RESULTS: ES revealed compound heterozygosity for two SLC5A7 variants, p.(Asn431Lys) and p.(Ile291Thr). While the first variant was absent from all databases, the second variant has already been described in one patient. In silico analysis of known pathogenic SLC5A7 variants showed that variants with a higher predicted deleteriousness may be associated with earlier onset and increased severity of neuromuscular manifestations. CONCLUSION: Our patient confirms that CMS20 can be associated with NDDs. The study illustrates the strength of ES in deciphering the genetic basis of rare diseases, contributes to characterization of CMS20 and suggests trends in genotype-phenotype correlation in CMS20.
- Klíčová slova
- SLC5A7, congenital myasthenic syndrome type 20, exome sequencing, neurodevelopmental disorders,
- MeSH
- genetické asociační studie MeSH
- heterozygot MeSH
- kongenitální myastenické syndromy * genetika diagnóza MeSH
- lidé MeSH
- mentální retardace * komplikace MeSH
- missense mutace MeSH
- symportéry * genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Názvy látek
- SLC5A7 protein, human MeSH Prohlížeč
- symportéry * MeSH
BACKGROUND: Cardiac-urogenital syndrome [MIM # 618280] is a newly described very rare syndrome associated with pathogenic variants in the myelin regulatory factor (MYRF) gene that leads to loss of protein function. MYRF is a transcription factor previously associated only with the control of myelin-related gene expression. However, it is also highly expressed in other tissues and associated with various organ anomalies. The clinical picture is primarily dominated by complex congenital cardiac developmental defects, pulmonary hypoplasia, congenital diaphragmatic hernia, and urogenital malformations. CASE PRESENTATION: We present case reports of two siblings of unrelated parents in whom whole-exome sequencing was indicated due to familial occurrence of extensive developmental defects. A new, previously undescribed splicing pathogenic variant c.1388+2T>G in the MYRF gene has been identified in both patients. Both parents are unaffected, tested negative, and have another healthy daughter. The identical de novo event in siblings suggests gonadal mosaicism, which can mimic recessive inheritance. CONCLUSIONS: To our knowledge, this is the first published case of familial cardiac-urogenital syndrome indicating gonadal mosaicism.
- Klíčová slova
- MYRF gene, Scimitar syndrome, cardiac-urogenital syndrome, familiar occurrence, whole-exome sequencing,
- MeSH
- lidé MeSH
- mozaicismus * MeSH
- sekvenování exomu MeSH
- sourozenci * MeSH
- syndrom MeSH
- transkripční faktory genetika MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Názvy látek
- Myrf protein, human MeSH Prohlížeč
- transkripční faktory MeSH
INTRODUCTION: This study presents a novel molecular parameter potentially co-defining tumor biology-the total tumor suppressor gene (TSG) count at chromosomal loci harboring genes rearranged in fusion-defined tumors. It belongs to the family of molecular parameters created using a black-box approach. METHOD: It is based on a public curated Texas TSG database. Its data are regrouped based on individual genes loci using another public database (Genecards). The total TSG count for NTRK (NTRK1; OMIM: 191315; NTRK2; OMIM: 600456; NTRK3; OMIM: 191316), NRG1 (OMIM: 142445), and RET (OMIM: 164761) rearranged tumors in patients treated with a theranostic approach is calculated using the results of recently published studies. RESULTS: Altogether 138 loci containing at least three TSGs are identified. These include 21 "extremely hot" spots, with 10 to 28 TSGs mapping to a given locus. However, the study falls short of finding a correlation between tumor regression or patient survival and the TSG count owing to a low number of cases meeting the study criteria. CONCLUSION: The total TSG count alone cannot predict the biology of translocation-defined tumors. The addition of other parameters, including microsatellite instability (MSI), tumor mutation burden (TMB), homologous recombination repair deficiency (HRD), and copy number heterogeneity (CNH), might be helpful. Thus a multi-modal data integration is advocated. We believe that large scale studies should evaluate the significance and value of the total TSG count.
- Klíčová slova
- artificial intelligence, cancer, chromosomal instability, chromothripsis, copy number heterogeneity, gene, gene rearrangement, homologous recombination repair, microsatellite instability, translocation, tumor mutation burden, tumor suppressor gene,
- MeSH
- fúze genů MeSH
- genomika MeSH
- lidé MeSH
- mutace MeSH
- nádorové biomarkery genetika MeSH
- nádory * genetika patologie MeSH
- translokace genetická MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- nádorové biomarkery MeSH
BACKGROUND: Family genetic testing of patients newly diagnosed with a rare genetic disease can improve early diagnosis of family members, allowing patients to receive disease-specific therapies when available. Fabry disease, an X-linked lysosomal storage disorder caused by pathogenic variants in GLA, can lead to end-stage renal disease, cardiac arrhythmias, and stroke. Diagnostic delays are common due to the rarity of the disease and non-specificity of early symptoms. Newborn screening and screening of at-risk populations, (e.g., patients with hypertrophic cardiomyopathy or undiagnosed nephropathies) can identify individuals with Fabry disease. Subsequent cascade genotyping of family members may disclose a greater number of affected individuals, often at younger age than they would have been diagnosed otherwise. METHODS: We conducted a literature search to identify all published data on family genetic testing for Fabry disease, and discussed these data, experts' own experiences with family genetic testing, and the barriers to this type of screening that are present in their respective countries. RESULTS: There are potential barriers that make implementation of family genetic testing challenging in some countries. These include associated costs and low awareness of its importance, and cultural and societal issues. Regionally, there are barriers associated with population educational levels, national geography and infrastructures, and a lack of medical geneticists. CONCLUSION: In this review, the worldwide experience of an international group of experts of Fabry disease highlights the issues faced in the family genetic testing of patients affected with rare genetic diseases.
- Klíčová slova
- Fabry disease, at-risk populations screening, cascade genotyping, early diagnosis, family genetic testing, pedigree drawing, rare disease,
- MeSH
- Fabryho nemoc diagnóza genetika MeSH
- genetické testování metody normy MeSH
- lidé MeSH
- rodokmen MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND: Recent studies suggest that duplication of the 9p24.3 chromosomal locus, which includes the DOCK8 and KANK1 genes, is associated with autism spectrum disorders (ASD), intellectual disability/developmental delay (ID/DD), learning problems, language disorders, hyperactivity, and epilepsy. Correlation between this duplication and the carrier phenotype needs further discussion. METHODS: In this study, three unrelated patients with ID/DD and ASD underwent SNP aCGH and MLPA testing. Similarities in the phenotypes of patients with 9p24.3, 15q11.2, and 16p11.2 duplications were also observed. RESULTS: All patients with ID/DD and ASD carried the 9p24.3 duplication and showed intragenic duplication of DOCK8. Additionally, two patients had ADHD, one was hearing impaired and obese, and one had macrocephaly. Inheritance of the 9p24.3 duplication was confirmed in one patient and his sibling. In one patient KANK1 was duplicated along with DOCK8. Carriers of 9p24.3, 15q11.2, and 16p11.2 duplications showed several phenotypic similarities, with ID/DD more strongly associated with duplication of 9p24.3 than of 15q11.2 and 16p11.2. CONCLUSION: We concluded that 9p24.3 is a likely cause of ASD and ID/DD, especially in cases of DOCK8 intragenic duplication. DOCK8 is a likely causative gene, and KANK1 aberrations a modulator, of the clinical phenotype observed. Other modulators were not excluded.
- Klíčová slova
- 15q11.2 duplication, 16p11.2 duplication, 9p24.3 duplication, developmental delay,
- MeSH
- adaptorové proteiny signální transdukční genetika MeSH
- chromozomální poruchy genetika patologie MeSH
- cytoskeletální proteiny genetika MeSH
- dítě MeSH
- duplikace chromozomů * MeSH
- fenotyp * MeSH
- lidé MeSH
- lidské chromozomy, pár 9 genetika MeSH
- předškolní dítě MeSH
- výměnné faktory guaninnukleotidů genetika MeSH
- vývojové poruchy u dětí genetika patologie MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- adaptorové proteiny signální transdukční MeSH
- cytoskeletální proteiny MeSH
- DOCK8 protein, human MeSH Prohlížeč
- KANK1 protein, human MeSH Prohlížeč
- výměnné faktory guaninnukleotidů MeSH
BACKGROUND: The Czech governmental study suggests up to a 25% higher prevalence of type 2 diabetes mellitus (T2DM) in the Roma population than within the majority population. It is not known whether and to what extent these differences have a genetic background. METHODS: To analyze whether the frequencies of the alleles/genotypes of the FTO, TCF7L2, CDKN2A/2B, MAEA, TLE4, IGF2BP2, ARAP1, and KCNJ11 genes differ between the two major ethnic groups in the Czech Republic, we examined them in DNA samples from 302 Roma individuals and 298 Czech individuals. RESULTS: Compared to the majority population, Roma are more likely to carry risk alleles in the FTO (26% vs. 16% GG homozygotes, p < .01), IGF2BP2 (22% vs. 10% TT homozygotes, p < .0001), ARAP1 (98% vs. 95% of A allele carriers, p < .005), and CDKN2A/2B (81% vs. 66% of TT homozygotes, p < .001) genes; however, less frequently they are carriers of the TCF7L2 risk allele (34% vs. 48% of the T allele p < .0005). Finally, we found significant accumulation of T2DM-associated alleles between the Roma population in comparison with the majority population (25.4% vs. 15.2% of the carriers of at least 12 risk alleles; p < .0001). CONCLUSION: The increased prevalence of T2DM in the Roma population may have a background in different frequencies of the risk alleles of genes associated with T2DM development.
- Klíčová slova
- Czech population, Roma population, T2DM, gene score, polymorphism,
- MeSH
- adipozita MeSH
- cholesterol krev MeSH
- diabetes mellitus 2. typu krev etnologie genetika MeSH
- dospělí MeSH
- frekvence genu * MeSH
- genetické lokusy * MeSH
- krevní glukóza analýza MeSH
- lidé středního věku MeSH
- lidé MeSH
- polymorfismus genetický MeSH
- Romové genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
- Názvy látek
- cholesterol MeSH
- krevní glukóza MeSH
BACKGROUND: Chorea-acanthocytosis (ChAc; OMIM #200150) is a rare autosomal recessive condition with onset in early adulthood that is caused by mutations in the vacuolar protein sorting 13A (VPS13A) gene encoding chorein. Several diagnostic genomic DNA (gDNA) sequencing approaches are widely used. However, their limitations appear not to be acknowledged thoroughly enough. METHODS: Clinically, we deployed magnetic resonance imaging, blood smear analysis, and clinical chemistry for the index patient's characterization. The molecular analysis of the index patient next to his parents covered genomic DNA (gDNA) sequencing approaches, RNA/cDNA sequencing, and chorein specific Western blot. RESULTS: We report a 33-year-old male patient without functional protein due to compound heterozygosity for two VPS13A large deletions of 1168 and 1823 base pairs (bp) affecting, respectively, exons 8 and 9, and exon 13. To our knowledge, this represents the first ChAc case with two compound heterozygous large deletions identified so far. Of note, standard genomic DNA (gDNA) Sanger sequencing approaches alone yielded false negative findings. CONCLUSION: Our case demonstrates the need to carry out detection of chorein in patients suspected of having ChAc as a helpful and potentially decisive tool to establish diagnosis. Furthermore, the course of the molecular analysis in this case discloses diagnostic pitfalls in detecting some variations, such as deletions, using only standard genomic DNA (gDNA) Sanger sequencing approaches and exemplifies alternative methods, such as RNA/cDNA sequencing or qRT-PCR analysis, necessary to avoid false negative results.
- Klíčová slova
- VPS13A, chorea-acanthocytosis, chorein, compound heterozygosity, deletion,
- MeSH
- choreoakantocytóza diagnóza genetika MeSH
- delece genu * MeSH
- dospělí MeSH
- genetické testování metody MeSH
- heterozygot MeSH
- kvantitativní polymerázová řetězová reakce metody MeSH
- lidé MeSH
- vezikulární transportní proteiny genetika metabolismus MeSH
- western blotting metody MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Názvy látek
- vezikulární transportní proteiny MeSH
- VPS13A protein, human MeSH Prohlížeč
