Physiological studies in animals and human support an important role of circadian system in reproduction. The aim of this study was to investigate the potential association of CLOCK gene ...polymorphisms with idiopathic recurrent spontaneous abortion (IRSA). We performed a case-control study. The study group consisted of 268 women with a history of three or more idiopathic recurrent spontaneous abortions and 284 women with at least two live births and no history of pathologic pregnancies all from Slovenia and Serbia. Two SNPs in the CLOCK gene were chosen and genotyped. The results showed a statistically significant difference in genotype distribution between the two groups in the CLOCK gene for rs6850524 and rs11932595. Our analysis showed that G allele under dominant model (GG+GC/CC) for rs6850524 (p = 2∙10-4, OR = 2.28, 95%CI = 1.46-3.56) as well as G allele under dominant model (GA+AA/AA) for rs11932595 (p = 0.04, OR = 1.47, 95%CI = 1.01-2.04) might be risk factors against IRSA. Our data suggest that genetic variability in the CLOCK gene is associated with IRSA warranting further confirmation and mechanistic investigations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The role of rare genetic variation and the innate immune system in the etiology of multiple sclerosis (MS) is being increasingly recognized. Recently, we described several rare variants in the NLRP1 ...gene, presumably conveying an increased risk for familial MS. In the present study we aimed to assess rare genetic variation in the inflammasome regulatory network. We performed whole exome sequencing of 319 probands, comprising patients with familial MS, sporadic MS and control subjects. 62 genes involved in the NLRP1/NLRP3 inflammasome regulation were screened for potentially pathogenic rare genetic variation. Aggregate mutational burden was analyzed, considering the variants' predicted pathogenicity and frequency in the general population. We demonstrate an increased (p = 0.00004) variant burden among MS patients which was most pronounced for the exceedingly rare variants with high predicted pathogenicity. These variants were found in inflammasome genes (NLRP1/3, CASP1), genes mediating inflammasome inactivation via auto and mitophagy (RIPK2, MEFV), and genes involved in response to infection with DNA viruses (POLR3A, DHX58, IFIH1) and to type-1 interferons (TYK2, PTPRC). In conclusion, we present new evidence supporting the importance of rare genetic variation in the inflammasome signaling pathway and its regulation via autophagy and interferon-β to the etiology of MS.
Novel GATOR1 variants in focal epilepsy Kovačević, Maša; Janković, Milena; Branković, Marija ...
Epilepsy & behavior,
April 2023, 2023-04-00, 20230401, Letnik:
141
Journal Article
Recenzirano
•Variants in GATOR1 complex genes are a frequent finding in patients with focal epilepsy.•Patients carrying GATOR1 gene variants exhibit a broad spectrum of clinical phenotypes.•GATOR1 gene variants ...can frequently be found in sporadic epilepsy.•NPRL2 variants can be associated with temporal lobe epilepsy with hippocampal sclerosis.
Variants in GATOR1 genes are well established in focal epilepsy syndromes. A strong association of GATOR1 variants with drug-resistant epilepsy as well as an increased risk of sudden unexplained death in epilepsy warrants developing strategies to facilitate the identification of patients who could potentially benefit from genetic testing and precision medicine. We aimed to determine the yield of GATOR1 gene sequencing in patients with focal epilepsy typically referred for genetic testing, establish novel GATOR1 variants and determine clinical, electroencephalographic, and radiological characteristics of variant carriers.
Ninety-six patients with clinical suspicion of genetic focal epilepsy with previous comprehensive diagnostic epilepsy evaluation in The Neurology Clinic, University Clinical Center of Serbia, were included in the study. Sequencing was performed using a custom gene panel encompassing DEPDC5, NPRL2, and NPRL3. Variants of interest (VOI) were classified according to criteria proposed by the American College of Medical Genetics and the Association for Molecular Pathology.
Four previously unreported VOI in 4/96 (4.2%) patients were found in our cohort. Three likely pathogenic variants were determined in 3/96 (3.1%) patients, one frameshift variant in DEPDC5 in a patient with nonlesional frontal lobe epilepsy, one splicogenic DEPDC5 variant in a patient with nonlesional posterior quadrant epilepsy, and one frameshift variant in NPRL2 in a patient with temporal lobe epilepsy associated with hippocampal sclerosis. Only one VOI, a missense variant in NPRL3, found in 1/96 (1.1%) patients, was classified as a variant of unknown significance.
GATOR1 gene sequencing was diagnostic in 3.1% of our cohort and revealed three novel likely pathogenic variants, including a previously unreported association of temporal lobe epilepsy with hippocampal sclerosis with an NPRL2 variant. Further research is essential for a better understanding of the clinical scope of GATOR1 gene-associated epilepsy.
•Variants in DEPDC5, SCN1A, PCDH19 and GRIN2A are a frequent finding in patients with focal epilepsy.•SCN1A and PCDH19 gene null variants can be found in patients with focal epilepsy and normal ...intellectual function.•Targeted genetic sequencing with small tailored gene panels could be a viable diagnostic option for epilepsy centers with limited resources.
Next generation sequencing (NGS) has greatly expanded our understanding of genetic contributors in multiple epilepsy syndromes, including focal epilepsy. Describing the genetic architecture of common syndromes promises to facilitate the diagnostic process as well as aid in the identification of patients who stand to benefit from genetic testing, but most studies to date have been limited to examining children or adults with intellectual disability. Our aim was to determine the yield of targeted sequencing of 5 established epilepsy genes (DEPDC5, LGI1, SCN1A, GRIN2A, and PCHD19) in an extensively phenotyped cohort of focal epilepsy patients with normal intellectual function or mild intellectual disability, as well as describe novel variants and determine the characteristics of variant carriers.
Targeted panel sequencing was performed on 96 patients with a strong clinical suspicion of genetic focal epilepsy. Patients had previously gone through a comprehensive diagnostic epilepsy evaluation in The Neurology Clinic, University Clinical Center of Serbia. Variants of interest (VOI) were classified using the American College of Medical Genetics and the Association for Molecular Pathology criteria.
Six VOI in eight (8/96, 8.3%) patients were found in our cohort. Four likely pathogenic VOI were determined in six (6/96, 6.2%) patients, two DEPDC5 variants in two patients, one SCN1A variant in two patients and one PCDH19 variant in two patients. One variant of unknown significance (VUS) was found in GRIN2A in one (1/96, 1.0%) patient. Only one VOI in GRIN2A was classified as likely benign. No VOI were detected in LGI1.
Sequencing of only five known epilepsy genes yielded a diagnostic result in 6.2% of our cohort and revealed multiple novel variants. Further research is necessary for a better understanding of the genetic basis in common epilepsy syndromes in patients with normal intellectual function or mild intellectual disability.
Most of the heritability in frontotemporal dementia (FTD) is accounted for by autosomal dominant hexanucleotide expansion in the chromosome 9 open reading frame 72 (C9orf72), pathogenic/likely ...pathogenic variants in progranulin (GRN), and microtubule-associated protein tau (MAPT) genes. Until now, there has been no systematic analysis of these genes in the Serbian population. Herein, we assessed the frequency of the C9orf72 expansion, pathogenic/likely pathogenic variants in GRN and MAPT in a well-characterized group of 472 subjects (FTD, Alzheimer's disease - AD, mild cognitive impairment - MCI, and unspecified dementia - UnD), recruited in the Memory Center, Neurology Clinic, University Clinical Center of Serbia. The C9orf72 repeat expansion was detected in 6.98% of FTD cases (13.46% familial; 2.6% sporadic). In the UnD subgroup, C9orf72 repeat expansions were detected in 4.08% (8% familial) individuals. Pathogenic variants in the GRN were found in 2.85% of familial FTD cases. Interestingly, no MAPT pathogenic/likely pathogenic variants were detected, suggesting possible geographical specificity. Our findings highlight the importance of wider implementation of genetic testing in neurological and psychiatric practice managing patients with cognitive-behavioral and motor symptoms.
The circadian system has a major role in maintaining homeostasis and proper body functions including reproductive capacity. The aim of this study was to examine whether there is an association ...between genetic variability in the primary clock genes CLOCK and ARNTL and male infertility in humans.
We performed a case-control study, where we searched for an association between polymorphisms of CLOCK and ARNTL genes and male infertility in 961 Slovenian and Serbian Caucasian men. The study group consisted of 517 patients with idiopathic infertility and a control group of 444 fertile men. A statistically significant difference was found in genotype distribution between the two groups in the CLOCK gene: rs11932595 (p = 6·10(-5), q = 4·10(-4), OR equaled 1.9 with 95% CI 1.4-2.7), rs6811520 (p = 2·10(-3), q = 8·10(-3), OR = 1.7 with 95% CI 1.2-2.2) and rs6850524 (p = 0.01, q = 0.02, OR = 1.4 with 95% CI 1.1-1.9). Further analyses of haplotypes were consistent with genotyping results.
We provide evidence that genetic variability in the CLOCK gene might be associated with male infertility warranting further confirmation and mechanistic investigations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Incontinentia pigmenti (IP) is a rare skin disease combined with anomalies of the teeth, eyes, and central nervous system (CNS). Mutations of the
gene are responsible for IP. Among the most frequent ...CNS abnormalities found in IP using magnetic resonance imaging (MRI) are corpus callosum (CC) abnormalities. The aim of the study was to determine the presence of CC abnormalities, their relationship with the
mutations, and the possible presence of mutations of other genes. A group of seven IP patients was examined. Analyses of the
gene and the X-chromosome inactivation pattern were performed, as well as MRI and whole exome sequencing (WES) with the focus on the genes relevant for neurodegeneration. WES analysis showed
mutation in all examined patients. A patient who had a mutation of a gene other than
was excluded from further study. Four of the seven patients had clinically diagnosed CNS anomalies; two out of four had MRI-diagnosed CC anomalies. The simultaneous presence of
mutation and CC abnormalities and the absence of other mutations indicate that
may be the cause of CC abnormalities and should be included in the list of genes responsible for CC abnormalities.
In this study we aimed to perform the first research on the current state of compulsory basic and clinical courses in genetics for medical students offered at medical faculties in six Balkan ...countries with Slavic languages (Bosnia and Herzegovina, Croatia, Montenegro, North Macedonia, Serbia, and Slovenia).
The study was conducted from June to September 2021. One representative from each country was invited to collect and interpret the data for all medical faculties in their respective country. All representatives filled a questionnaire, which consisted of two sets of questions. The first set of questions was factual and contained specific questions about medical faculties and design of compulsory courses, whereas the second set of questions was more subjective and inquired the opinion of the representatives about mandatory education in clinical medical genetics in their countries and internationally. In addition, full course syllabi were analysed for course aims, learning outcomes, course content, methods for student evaluation and literature.
Detailed analysis was performed for a total of 22 medical faculties in Bosnia and Herzegovina (6), Croatia (4), Montenegro (1), North Macedonia (3), Serbia (6), and Slovenia (2). All but the two medical faculties in Slovenia offer either compulsory courses in basic education in human genetics (16 faculties/courses) or clinical education in medical genetics (3 faculties/courses). On the other hand, only the medical faculty in Montenegro offers both types of education, including one course in basic education in human genetics and one in clinical education in medical genetics. Most of the basic courses in human genetics have similar aims, learning outcomes and content. Conversely, clinical courses in medical genetics are similar concerning study year position, number of contact hours, ECTS (European Credit Transfer and Accumulation System) and contents, but vary considerably regarding aims, learning outcomes, ratio of types of classes, teaching methods and student evaluation.
Our results emphasise the need for future collaboration in reaching a consensus on medical genetics education in Balkan countries with Slavic languages. Further research warrants the analysis of performance of basic courses, as well as introducing clinical courses in medical genetics to higher years of study across Balkan countries.
Introduction: Parkinson's disease (PD) belongs to neurodegenerative diseases, and since the prevalence is 1% to 2% in people older than 65 years and over 4% in people older than 85 years, it is the ...second most common disease in this group. The cause of PD is the death of dopaminergic neurons in the CNS, primarily in the basal ganglia and the substantia nigra. The LRRK2/PARK8 gene is located on the short arm of chromosome 12. There are many variants in this gene associated with PD, and the most common of which is mutation c.6055G>A (p.Gly2019Ser), also referred to as rs34637584. Aim: The aim of this study was to determine the frequency of the c.6055G>A (rs34637584) mutation in the LRRK2 gene in a group of patients with PD from Serbia. Material and methods: The study included a group of 127 patients with PD from tertiary healthcare institutions in Serbia, as well as an appropriate control group without neurological diseases. Molecular genetic analysis was performed by real-time PCR, using a commercial TaqMan assay. Results: Mutation c.6055G>A ie. rs34637584 variant was detected in 1 of 127 examinees with PD (0.7%). That patient was without a previous family history of PD. This mutation was not found in the control group. Conclusion: The results obtained align with findings of previous studies for the European, especially the southern European population. If these results would be confirmed in a larger patient sample, testing of LRRK2 mutation c.6055G>A (rs34637584) should become part of the PD test protocol.
A disturbed iron metabolism may damage brain and trigger disorders known as neurodegeneration with brain iron accumulation (NBIA). NBIAs are rare, inherited disorders in which responsible mutations ...affect the function of proteins that participate in tissue iron homeostasis. Accumulated iron, which may be recognized as a low signal intensity on T2-weighted MRI images, oftentimes points to a diagnosis. Recent genetic discoveries confirm that NBIA is not a homogenous group of diseases. Fifteen different NBIAs have been described to date; among these, autosomal recessive inheritance was reported in 13, and autosmal dominant and X-linked dominant inheritance in one disease, respectively. Among NBIAs, the most common is pantothenate kinase-associated neurodegeneration (PKAN-NBIA 1) (30%-50% of all NBIA cases), that occurrs as a consequence of the autosomal recessive mutation in PANK2 gene, followed by phospholipase 2-associated neurodegeneration (PLAN, NBIA 2), due to mutation in PLA2G6 gene, and mitochondrial membrane protein-associated neurodegeneration (MPAN) with the underlying C19orf12 mutation Table 1. NBIAs are characterized by complex motor presentations from early-onset degeneration and premature fatality to adult-onset parkinsonism and dystonia. Epileptic seizures, pyramidal signs, visual disorders, and cognitive deterioration can develop. NBIAs are often refractory to therapeutical strategies, although certain interventions may provide significant symptomatic relief in selected patients. In this review, we discuss the expanding clinical spectrum of these complex and rare syndromes, their genetic and imaging features, and potential therapeutical targets and strategies.{Table 1}
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
PDF
