Molecular Genetic Data Research Articles

Eye-Transcriptome and Genome-Wide Sequencing for Scolecophidia: Implications for Inferring the Visual System of the Ancestral Snake.

Molecular genetic data have recently been incorporated in attempts to reconstruct the ecology of the ancestral snake, though this has been limited by a paucity of data for one of the two main extant snake taxa, the highly fossorial Scolecophidia. Here we present and analyze vision genes from the first eye-transcriptomic and genome-wide data for Scolecophidia, for Anilios bicolor, and A. bituberculatus, respectively. We also present immunohistochemistry data for retinal anatomy and visual opsin-gene expression in Anilios. Analyzed in the context of 19 lepidosaurian genomes and 12 eye transcriptomes, the new genome-wide and transcriptomic data provide evidence for a much more reduced visual system in Anilios than in non-scolecophidian (=alethinophidian) snakes and in lizards. In Anilios, there is no evidence of the presence of 7 of the 12 genes associated with alethinophidian photopic (cone) phototransduction. This indicates extensive gene loss and many of these candidate gene losses occur also in highly fossorial mammals with reduced vision. Although recent phylogenetic studies have found evidence for scolecophidian paraphyly, the loss in Anilios of visual genes that are present in alethinophidians implies that the ancestral snake had a better-developed visual system than is known for any extant scolecophidian.

Evaluation of gene flow and genetic diversity in rice accessions across Kurdistan region-iraq using SSR markers.

BackgroundIn recent years, farmers have complained that the only way to obtain seeds is to select plants that show good performance under local climate conditions in the region. This study aimed to investigate the diversity of rice accessions grown in the region to build a breeding program.Methods and resultsA total of 62 accessions of rice from farmers and research stations were collected from the Kurdistan region, including short-grain and long-grain types, for molecular genetics and diversity analysis. In this study, 37 polymorphic simple sequence repeat (SSR) markers were selected with several molecular genetics software programs. The results show that these SSR markers are very effective for this investigation, generating a total of 152 observed alleles (Na), 75.166 Effective number of alleles (Ne) and an average of 4.1 and 2.03 alleles per locus, respectively. The average polymorphic information content (PIC) per locus was recorded as 0.404. The research presented here confirms two subpopulations, japonica (C1 and C2) and indica (C3), based on molecular genetics data analysis. Analysis of molecular variance revealed that the 72% variance was due to the variation among populations and 28% within the population.ConclusionsAltogether, these results indicate that there is very low gene flow. These results show the importance of the study of genetic diversity and relationships for starting breeding and improvement programs for rice in the Kurdistan region.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11033-021-06920-x.

Prediction of Complete Remission and Survival in Acute Myeloid Leukemia Using Supervised Machine Learning

Prediction of Complete Remission and Survival in Acute Myeloid Leukemia Using Supervised Machine Learning

Impact of Peri-Transplant Molecular Mutations on Outcomes of AML Patients Undergoing Fludarabine/Melphalan Conditioned Allogeneic Stem Cell Transplant

Impact of Peri-Transplant Molecular Mutations on Outcomes of AML Patients Undergoing Fludarabine/Melphalan Conditioned Allogeneic Stem Cell Transplant

Two species of Leymus (Poaceae) are artificial as inferred from the molecular-genetic data

The results of studying taxonomic relationships between five species of the aggregate Leymus secalinus (Georgi) Tzvel. of the genus Leymus Hochst. are presented. The research is based on the study of the ITS1-5.8S-ITS2 region obtained by sequencing the nuclear ribosomal DNA internal transcribed spacers, and on the anatomical and morphological data. A molecular-genetic study of the L. secalinus aggregate has revealed that the two species L. ovatus and L. jenisseiensis are artificial.

Clinical, Genetic and Orthopedic Characteristics of Desbuquois Dysplasia

Introduction. Desbuquois dysplasia is a rare skeletal dysplasia with an autosomal recessive inheritance, resembling to the group of multiple joint dislocations. The disease is caused by mutations in the CANT1 and XYLT1 genes, the protein products of which are involved in the degradation of proteoglycans, which play an important role in endochondral ossification. The polymorphism of clinical and radiological characteristics and the genetic heterogeneity of Desbuquois dysplasia necessitate the description of the phenotypic characteristics of patients with various types of mutations, which optimize diagnosis. Objective description of the clinical and radiological characteristics of three Russian patients with Desbuquois dysplasia of types 1 and 2 with remarkable orthopedic manifestation, caused by mutations in the CANT1 and XYLT1 genes. Materials and Methods. Genealogical, clinical, radiographic and genetic data of three unrelated Russian patients aged 2 to 8 years was carried out. Genetic testing was carried out using clinical exome sequencing and methyl-sensitive PCR. Results. Two patients were diagnosed with type 1 disease due to a previously described homozygous mutation in the CANT1 gene: c.898CT (p.Arg300Cys), and one type 2 due to heterozygous mutations in the XYLT1 gene. One mutation: c.1651CT (p.Arg551Cys) was detected during exome sequencing, and the second mutation: expansion of GGC repeats in the promoter region of the gene, revealed by methyl-sensitive PCR of the first exon of the gene. The main clinical signs of the disease were micromelic dwarfism, hypermobility in the joints and specific facial dysmorphisms, radiographic analysis revealed characteristic monkey wrench appearance of the proximal femur in all 3 patients, additional ossification center of the second metacarpal, advanced bone age and multiple dislocations in the joints. The patients also had extra-skeletal manifestations (congenital glaucoma, obstructive bronchitis, renal hypoplasia and congenital heart malformations). Conclusion. Genetic heterogeneity and the presence of polymorphism of clinical manifestations make it possible to consider sequencing of the clinical exome as the optimal method for diagnosing Desbuquois dysplasia types 1 and 2. Analysis of the literature and the results of our molecular genetic data indicate the possibility of expansion of the GGC repeat in the XYLT1 gene in patients with clinical manifestations of type 2 Desbuquois dysplasia.

A new hip-pocket frog from mid-eastern Australia (Anura: Myobatrachidae: Assa).

The hip-pocket frog (Assa darlingtoni), a small terrestrial myobatrachid frog found in mid-eastern Australia, has a highly derived, unusual, reproductive mode involving a unique form of male parental care. Males have subcutaneous pouches that open near the hip, and the developing tadpoles are carried in these pouches to post metamorphosis. It is found on several isolated mountain ranges in closed forest habitats, associated with high rainfall and temperate or sub-tropical climates. We established genetic relationships among specimens sampled across the range using phylogenetic analyses of thousands of single nucleotide polymorphisms (SNPs) from the nuclear genome and mitochondrial ND2 gene nucleotide sequences. These analyses uncovered two lineages that are genetically distinct in both nDNA and mtDNA analyses and that have low levels of divergence in male advertisement calls and are morphologically cryptic. Our data support separate species status for each lineage, based on the molecular genetic data. The first, which we name as a new species, Assa wollumbin sp. nov., is restricted to a single mountain, Wollumbin (= Mount Warning), the eroded cone of an ancient shield volcanothe Tweed Volcano. The second, the nominal species A. darlingtoni, has a wider distribution in five geographically disjunct subpopulations along 430 km of the Great Dividing Range in south-eastern Queensland and north-eastern New South Wales. The distributions of the two species closely approach within 15 km of each other on the central plug and rim of the caldera of the Tweed Volcano. Assa wollumbin sp. nov. meets the conservation criteria for Critically Endangered [A3(e), B2(a,b)]. When all subpopulations of A. darlingtoni are combined the conservation assessment is Endangered [A3(e), B2(a,b)]. Because of the fragmented nature of the distribution of A. darlingtoni, combined with the genetic evidence of concordant sub-structuring, we also conducted a conservation assessment on the five subpopulations. Two were assessed as Critically Endangered (DAguilar Range and Conondale/Blackall Ranges), and the remainder as Endangered (Dorrigo Plateau, McPherson Ranges, and Gibraltar Ranges/Washpool).

Adolescent cannabis use and adult psychoticism: A longitudinal co-twin control analysis using data from two cohorts.

Observational studies have repeatedly linked cannabis use and increased risk of psychosis. We sought to clarify whether this association reflects a causal effect of cannabis exposure or residual confounding. We analyzed data from two cohorts of twins who completed repeated, prospective measures of cannabis use (N = 1544) and cannabis use disorder symptoms (N = 1458) in adolescence and a dimensional measure of psychosis-proneness (the Personality Inventory for DSM-5 Psychoticism scale) in adulthood. Twins also provided molecular genetic data, which were used to estimate polygenic risk of schizophrenia. Both cumulative adolescent cannabis use and use disorder were associated with higher Psychoticism scores in adulthood. However, we found no evidence of an effect of cannabis on Psychoticism or any of its facets in co-twin control models that compared the greater-cannabis-using twin to the lesser-using co-twin. We also observed no evidence of a differential effect of cannabis on Psychoticism by polygenic risk of schizophrenia. Although cannabis use and disorder are consistently associated with increased risk of psychosis, the present results suggest this association is likely attributable to familial confounds rather than a causal effect of cannabis exposure. Efforts to reduce the prevalence and burden of psychotic illnesses thus may benefit from greater focus on other therapeutic targets. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The subfamily Myoxocephalinae of cottid fishes (Cottidae): Genetic divergence and phylogenetic relationships.

A comprehensive study based on molecular marker and karyotype analyses has provided evidence for the monophyly of the subfamily Myoxocephalinae, which includes the genera Myoxocephalus, Megalocottus, Microcottus, Porocottus, Enophrys and Argyrocottus. In addition, the karyotype of the threadfoot sculpin Argyrocottus zanderi Herzenstein 1892 has been studied for the first time. Marker traits of karyotypes identified 13 species among six cottid genera. As the molecular genetic results confirmed, the subfamily is divided into two groups corresponding to Enophrys and Myoxocephalus. The molecular genetic data did not support the formation of tribes within the subfamily Myoxocephalinae, as proposed earlier based on morphological characters. Moreover, the genera Trichocottus and Taurocottus should be excluded from the Myoxocephalinae. The evolutionary transformations of karyotypes in cottid fish tended towards a reduction in the number of chromosomes and chromosome arms.

Are immigrants outbred and unrelated? Testing standard assumptions in a wild metapopulation.

Immigration into small recipient populations is expected to alleviate inbreeding and increase genetic variation, and hence facilitate population persistence through genetic and/or evolutionary rescue. Such expectations depend on three standard assumptions: that immigrants are outbred, unrelated to existing natives at arrival, and unrelated to each other. These assumptions are rarely explicitly verified, including in key field systems in evolutionary ecology. Yet, they could be violated due to non-random or repeated immigration from adjacent small populations. We combined molecular genetic marker data for 150-160microsatellite loci with comprehensive pedigree data to test the three assumptions for a song sparrow (Melospiza melodia) population that is a model system for quantifying effects of inbreeding and immigration in the wild. Immigrants were less homozygous than existing natives on average, with mean homozygosity that closely resembled outbred natives. Immigrants can therefore be considered outbred on the focal population scale. Comparisons of homozygosity of real or hypothetical offspring of immigrant-native, native-native and immigrant-immigrant pairings implied that immigrants were typically unrelated to existing natives and to each other. Indeed, immigrants' offspring would be even less homozygous than outbred individuals on the focal population scale. The three standard assumptions of population genetic and evolutionary theory were consequently largely validated. Yet, our analyses revealed some deviations that should be accounted for in future analyses of heterosis and inbreeding depression, implying that the three assumptions should be verified in other systems to probe patterns of non-random or repeated dispersal and facilitate precise and unbiased estimation of key evolutionary parameters.

Niemann\u2013Pick disease type C in Palestine: genotype and phenotype of sixteen patients and report of a novel mutation in the NPC1 gene

BackgroundNiemann–Pick disease type C (NPC) is an autosomal recessive, neurodegenerative disease caused by mutations in either the NPC1 or NPC2 genes. Mutations in these genes are associated with abnormal endosomal–lysosomal trafficking, resulting in the accumulation of tissue-specific lipids in lysosomes.MethodsWe described sixteen patients with NPC diagnosed between the age of 1 month and 30 years at two tertiary care centers in Palestine. The clinical phenotype, brain magnetic resonance imaging (MRI), and molecular genetic analysis data were reviewed.ResultsThe diagnosis was confirmed by molecular analysis in all patients. Fourteen out of sixteen patients were homozygous for the NPC1 p.G992W variant. Among them, most were categorized as having the late-infantile neurological form of disease onset. They predominantly manifested with early-onset visceral manifestations in the form of hepatosplenomegaly and prolonged neonatal jaundice, and late-onset neuropsychiatric manifestations in the form of vertical supranuclear gaze palsy (VSGP), ataxia, cognitive impairment and seizures. Brain MRI in 6 patients was normal in 5 or consistent with cerebellar hemisphere atrophy in 1 of them. Two other mutations were identified in the NPC1 gene, of which p.V845Cfs*24 was novel.ConclusionsOur results revealed phenotypic heterogeneity of NPC even within the same genotype, and add to the increasingly recognized evidence that cholestatic jaundice and hepatosplenomegaly during infancy, should alert the physician for the possibility of NPC. We reported a novel mutation in the NPC1 gene further expanding its genotype.

P14.87 Significance of clinical and molecular-genetic factors for prognosis in 574 adult patients with primary glioblastoma

Abstract BACKGROUND Despite advances in the characterization of genomic alterations in glioblastoma patient survival remains poor. The aim of this single center retrospective study was to estimate prognostic factors affecting to survival for optimizing personalized treatment strategy in glioblastoma patients. MATERIAL AND METHODS 574 consecutive patients with primary glioblastoma treated at the Burdenko National Medical Research Center of Neurosurgery from 2014 to 2019 were included in this study (314 male /260 female). Survival data was analyzed using Kaplan-Meier with log-rank tests to assess statistical significance. A linear regression model was built to predict overall survival. RESULTS Older patients (> 45 years) had the worse prognosis than patients ≤ 45 (p = 2.37 * 10^-6). Female patients had advantages in overall survival (p = 0.014). Time interval from surgery to the starting of radiotherapy longer than 4 weeks was associated with worse overall survival (p = 0.062). Patients with positive IDH1/2 and MGMT had better prognosis than patients with wild type and MGMT negative (p = 0.000841, p = 0.000138, respectively). We revealed that there were significant differences in overall survival between patients who had progression on the first (p = 0.000312), second (p = 0.001046) and third (p = 0.00223) follow-up MRI after radiotherapy. Median survival times (from the date of surgery) were 17, 20, 23 months, respectively. The feature importance in the linear regression model was patient’s age, IDH1/2 mutation, MGMT promoter methylation status, progression on the first follow-up MRI and sex. CONCLUSION Older patient’s age, prolonged time between surgery and RT starting, male sex, negative IDH1/2 and MGMT, progression on the first MRI were associated with poor overall survival in glioblastoma patients. Our results suggested additional clinical, radiomics and molecular-genetic data should be added to improve the overall survival prediction. The results have been obtained under the support of the RFBR grant 18-29-01054

Molecular Genetics, Clinical Characteristics, and Treatment Outcomes of KATP-Channel Neonatal Diabetes Mellitus in Vietnam National Children’s Hospital

BackgroundNeonatal diabetes mellitus (NDM) is defined as insulin-requiring persistent hyperglycemia occurring within the first 6 months of life, which can result from mutations in at least 25 different genes. Activating heterozygous mutations in genes encoding either of the subunits of the ATP-sensitive K+ channel (KATP channel; KCNJ11 or ABCC8) of the pancreatic beta cell are the most common cause of permanent NDM and the second most common cause of transient NDM. Patients with NDM caused by KATP channel mutations are sensitive to sulfonylurea (SU) treatment; therefore, their clinical management can be improved by replacing insulin with oral agents.Patients and MethodsSeventy patients were diagnosed with NDM between May 2008 and May 2021 at Vietnam National Children’s Hospital, and molecular genetic testing for all genes known to cause NDM was performed at the Exeter Genomic Laboratory, UK. Patients with ABCC8 or KCNJ11 mutations were transferred from insulin to oral SU. Clinical characteristics, molecular genetics, and annual data relating to glycemic control, SU dose, severe hypoglycemia, and side effects were collected. The main outcomes of interest were SU dose, SU failure (defined as permanent reintroduction of daily insulin), and glycemic control (HbA1c).ResultsFifty-four of 70 patients (77%) with NDM harbored a genetic mutation and of these; 27 (50%) had activating heterozygous mutations in ABCC8 or KCNJ11. A total of 21 pathogenic mutations were identified in the 27 patients, including 13 mutations in ABCC8 and 8 mutations in KCNJ11. Overall, 51% had low birth weight (below 3rd percentile), 23 (85%) were diagnosed before 3 months of age, and 23 (85%) presented with diabetic ketoacidosis. At diagnosis, clinical and biochemical findings (mean ± SD) were pH 7.16 ± 0.16; , 7.9 ± 7.4 mmol/L; BE, −17.9 ± 9.1 mmol/L; HbA1C, 7.98% ± 2.93%; blood glucose, 36.2 ± 12.3 mmol/L; and C-peptide median, 0.09 (range, 0–1.61 nmol/l). Twenty-six patients were successfully transferred from insulin to SU therapy. In the remaining case, remission of diabetes occurred prior to transfer. Glycemic control on SU treatment was better than on insulin treatment: HbA1c and blood glucose level decreased from 7.58% ± 4.63% and 19.04 ± 14.09 mmol/L when treated with insulin to 5.8 ± 0.94% and 6.87 ± 3.46 mmol/L when treated with SU, respectively.ConclusionsThis is the first case series of NDM patients with ABCC8/KCNJ11 mutations reported in Vietnam. SU is safe in the short term for these patients and more effective than insulin therapy, consistent with all studies to date. This is relevant for populations where access to and cost of insulin are problematic, reinforcing the importance of genetic testing for NDM.

The importance of molecular characters when morphological variability hinders diagnosability: systematics of the moon jellyfish genus Aurelia (Cnidaria: Scyphozoa).

Cryptic species have been detected across Metazoa, and while no apparent morphological features distinguish them, it should not impede taxonomists from formal descriptions. We accepted this challenge for the jellyfish genus Aurelia, which has a long and confusing taxonomic history. We demonstrate that morphological variability in Aurelia medusae overlaps across very distant geographic localities. Even though some morphological features seem responsible for most of the variation, regional geographic patterns of dissimilarities are lacking. This is further emphasized by morphological differences found when comparing lab-cultured Aurelia coerulea medusae with the diagnostic features in its recent redescription. Previous studies have also highlighted the difficulties in distinguishing Aurelia polyps and ephyrae, and their morphological plasticity. Therefore, mostly based on genetic data, we recognize 28 species of Aurelia, of which seven were already described, 10 are formally described herein, four are resurrected and seven remain undescribed. We present diagnostic genetic characters for all species and designate type materials for newly described and some resurrected species. Recognizing moon jellyfish diversity with formal names is vital for conservation efforts and other studies. This work clarifies the practical implications of molecular genetic data as diagnostic characters, and sheds light on the patterns and processes that generate crypsis.

Pantothenate kinase-associated neurodegeneration (Hallerworden–Spatze disease): clinical aspects, diagnosis, treatment (literature review and own data)

Aim. To analyze current data of scientific literature on the etiology, pathogenesis, approaches to the diagnosis and treatment of rare orphan disease – pantothenate kinase-associated neurodegeneration and to describe the clinical case of this disease. Pantothenate kinase-associated neurodegeneration (PKAN) is a rare inherited autosomal recessive disorder caused by mutations in the PANK2 gene, which is located at the chromosomal locus: 20p13-p12.3. The article presents a literature review and a case report of the diagnosis and treatment of 8-year-old girl with pantothenate kinase-associated neurodegeneration who suffered from progressive motor impairment. Among the dominant clinical manifestations is a growing extrapyramidal motor disorder, the so-called “dystonic storm”, which can range from severe sensorimotor motor deficits in infants and young children to mild parkinsonism in adults. MRI signs in the form of specific changes in the T2-weighted mode, which detects typical areas of hyperintensive signal in globus pallidus, surrounded by a border of hypointensive signal (“tiger’s eye”) are particular important. Neuroimaging data most likely make possible to suspect a correct diagnosis, reducing the time and cost of additional examinations. There is no pathogenetic treatment of this disease now. The main directions of currently available symptomatic drug therapy are described. Clinical trials of detoxifying drugs that reduce iron levels in the body (chelation) and surgical treatments are currently underway. Conclusions. The presented clinical observation once again confirms the complexity of the diagnostic search for orphan diseases of the nervous system. A key place in the diagnosis of pantothenate kinase-associated neurodegeneration belongs to the neuroimaging methods and molecular genetic testing data.

Genetic variation of myostatin MSTN gene and protein polymorphism in three goat populations

The aims of the present research are to analyze the polymorphism between three goat breeds Baladi, Hybrid (BaladiDamascus), and Damascus breeds by Biochemical and advanced molecular assay. A total of 15 samples from three goat breeds; Baladi (n=5), Hybrid (n=5), and Damascus breeds (n=5) were used. The accession no. of MW654246, MW654247, and MW654248, with Baladi, Hybrid, and Damascus goat breed, respectively. The deposited sequences of objects are part of intron 3, and exon 3 is fully sequenced with three breeds, according to the findings. The frequency of the Myostatin gene was the same in all three breeds. Also, the deletion of C and A in two SNPs of 259 and 260, respectively with all breeds were showed. While the convert case with Baladi breed from A to T in the SNP of 236 is the case in Hybrid breed. Damascus breeds the convert of T to C in the SNP with 248. These results agree with the molecular genetics data output the higher similarity values between the three goat breeds were found. The value of similarity between samples Baladi and Hybrid goat breed was 0.92%. And between Damascus and Hybrid goat breeds were 0.74%. Finally, the value of similarity was lowest between Baladi and Damascus goat breed of 0.62% using analysis of plasma. The three goat breeds investigated exhibited low variation in the Myostatin gene; these results suggest that the Baladi breed has a higher amount of genetic material (DNA) that will be passed down to future generations than the Damascus breed.

Molecular genetic data in terms of associative and population genetics

In studies on associative genetics of various multifactorial diseases, it is most often found that the minor allele’s frequency in the group of patients is higher than in the group of healthy people. Due to reduced adaptation, the minor allele manifests itself as a disease. In the group of patients, the number of homozygotes by major allele is reduced, the number of heterozygous carriers of the provocative allele is increased, and the frequency of homozygotes by the provocative allele is significantly increased. The aim of this article was to analyze the unusual result for SNP 1298A/C of the MTHFR gene in multiple sclerosis, previously obtained by one of the authors. The allele frequencies in the control group and in the group of multiple sclerosis do not differ, but the distribution of genotypes in the patients does not correspond to the Hardy–Weinberg ratio in compare to healthy people. Among patients, the number of heterozygotes is increased and the number of each homozygote is decreased. The increase in the proportion of heterozygotes can be explained by the presence of one provocative allele, but the large shortage of homozygotes for the minor allele is unclear. To explain this fact, the composition of the group of patients was analysed. The patients are of different ages, this group is heterogeneous in sex and form of multiple sclerosis, but none of these indicators has not be taken into account in the analysis of the distribution of genotypes. The age of the disease is a diagnostic sign and may depend on the genotype. The manifestation of multifactorial diseases depends on gender as well. Clinical forms of the disease usually have a different genetic basis. Due to the neglect of these conditions, a genetically heterogeneous group is formed, and any result, difficult for explanation, can be obtained. The lack of СС genotypes may be due to increased mortality, which reduces the probability of patients to be investigated in the sample. These facts once again indicate the need to form homogeneous groups for research on associative genetics.

Disease expression caused by different variants in the BEST1 gene: genotype and phenotype findings in bestrophinopathies.

Purpose:To analyse the spectrum of clinical features and molecular genetic data in a series of patients carrying likely disease-associated variants in the BEST1 gene.Methods:Retrospective observational analysis of clinical data extracted from the medical records of visual function, multimodal imaging and electrophysiology of 62 eyes of 31 patients. Molecular genetic analysis was performed by means of panel-based NGS or Sanger sequencing.Results:The spectrum of variants in the BEST1 gene comprised 19 different variants and three of which are novel. Fundus photographs and OCT images allowed categorization of 52 eyes as Best vitelliform macular dystrophy (BVMD) with stages 1 to 5 and 10 eyes with autosomal recessive bestrophinopathy (ARB), with more severe phenotype. One patient was shown to be heterozygous for a variant, which has so far been described only in ARB, but this patient had the BVMD phenotype. There was no significant progression of the visual acuity during the follow-up period of 5 years both in BVMD and ARB. The most prevalent pattern of fundus autofluorescence (FAF) in BVMD was ‘patchy’. There were diverse visual field defects in static automated perimetry (SAP) depending on the stage. The Arden ratio was significantly lower in ARB patients and in eyes with stage 5 of BVMD.Conclusions:The genotype does not always predict the phenotype in patients with BVMD and ARB; however, having two mutations in the BEST1 gene causes a more severephenotype. FAFhelped to distinguish ARB from BVMD. Most of the observed eyesdidnotprogressfunctionallyduringthefollow-up.ARBandtheatrophicstageof BVMD as the disease end-stage had the worst visual functions and EOG results.

Mevalonate kinase deficiency syndrome: Single center experience

The aimof this study was to analyze the clinical, laboratory and molecular genetic data of 26 patients (15 boys, 11 girls) diagnosed with mevalonate kinase deficiency syndrome (MKD).Subjects and methods. The age of MKD manifestation ranged from 0 to 30.0 months (M – 1.5 months). Clinical manifestations and their severity were extremely diverse: from symptoms resembling Marshall’s syndrome to severe systemic manifestations with respiratory failure, hepatosplenomegaly and pancytopenia.Results/Conclusion. All patients had homozygous/compound-heterozygous mutations in theMVKgene, including 10 newly described variants. In all 20 patients, who have been treated with IL-1 inhibitors long enough to assess the effect of the treatment, drastic improvement of the condition was noted, but only in 17/20 patients achieved full remission.

Molecular diagnostics in drug-resistant focal epilepsy define new disease entities.

Structural brain lesions, including the broad range of malformations of cortical development (MCD) and glioneuronal tumors, are among the most common causes of drug‐resistant focal epilepsy. Epilepsy surgery can provide a curative treatment option in respective patients. The currently available pre‐surgical multi‐modal diagnostic armamentarium includes high‐ and ultra‐high resolution magnetic resonance imaging (MRI) and intracerebral EEG to identify a focal structural brain lesion as epilepsy underlying etiology. However, specificity and accuracy in diagnosing the type of lesion have proven to be limited. Moreover, the diagnostic process does not stop with the decision for surgery. The neuropathological diagnosis remains the gold standard for disease classification and patient stratification, but is particularly complex with high inter‐observer variability. Here, the identification of lesion‐specific mosaic variants together with epigenetic profiling of lesional brain tissue became new tools to more reliably identify disease entities. In this review, we will discuss how the paradigm shifts from histopathology toward an integrated diagnostic approach in cancer and the more recent development of the DNA methylation‐based brain tumor classifier have started to influence epilepsy diagnostics. Some examples will be highlighted showing how the diagnosis and our mechanistic understanding of difficult to classify structural brain lesions associated with focal epilepsy has improved with molecular genetic data being considered in decision making.