Search

Large international consortia examining the genomic architecture of the epilepsies focus on large diagnostic subgroupings such as "all focal epilepsy" and "all genetic generalized epilepsy". In addition, phenotypic data are generally entered into these large discovery databases in a unidirectional manner at one point in time only. However, there are many smaller phenotypic subgroupings in epilepsy, many of which may have unique genomic risk factors. Such a subgrouping or "microphenotype" may be defined as an uncommon or rare phenotype that is well recognized by epileptologists and the epilepsy community, and which may or may not be formally recognized within the International League Against Epilepsy classification system. Here we examine the genetic structure of a number of such microphenotypes and report in particular on two interesting clinical phenotypes, Jeavons syndrome and pediatric status epilepticus. Although no single gene reached exome-wide statistical significance to be associated with any of the diagnostic categories, we observe enrichment of rare damaging variants in established epilepsy genes among Landau-Kleffner patients (GRIN2A) and pediatric status epilepticus patients (MECP2, SCN1A, SCN2A, SCN8A).

In recent decades, some monogenic forms of arterial hypertension have been identified. They were caused by specific pathways due to rare disruptive mutations in individual genes that determined an early and severe hypertension phenotype. At least 37 genes are known, the disruption of which is clearly accompanied by a dysfunction of the blood pressure regulation. This knowledge improves our understanding of both the mechanisms of development and treatment of hypertension. The genetic causes of secondary hypertension are usually due to a single gene disorder. The discovery of genes responsible for monogenic forms of hypertension revealed the role of the kidneys and adrenal glands as important players in the regulation of blood pressure. Most of these syndromes are caused by mutations that lead to increased of the function or its loss, which in turn leads to changes in the content of mineralocorticoids, glucocorticoids or sympathetic pathway activation. Monogenic forms of hypertension often lead to severe forms of hypertension, electrolyte and hormonal disorders, accompanied by drug resistance, and often cause a higher risk of cardiovascular events and premature death. The lecture provides recommendations for genetic testing in hypertension, an algorithm for diagnostic examination of a patient with suspected monogenic form of hypertension, as well as features of the clinical course and treatment of the main known forms of monogenic hypertension.

Vicieae tribe, Leguminosae family (Fabaceae), has been extensively studied. In particular, the study of lectins. The purification, physicochemical and structural characterizations of the various purified lectins and the analysis of their relevant biological activities are ongoing. In this review, several works already published about Vicieae lectins are addressed. Initially, we presented the purification protocols and the physicochemical aspects, such as specificity for carbohydrates, optimal activity in the face of variations in temperature and pH, as well metals-dependence. Following, structural characterization studies are highlighted and, finally, various biological activities already reported are summarized. Studies on lectins in almost all genera (Lathyrus, Lens, Pisum and Vicia) are considered, with the exception of Vavilovia which studies of lectins have not yet been reported. Like other leguminous lectins, Vicieae lectins present heterogeneous profiles of agglutination profiles for erythrocytes and other cells of the immune system, and glycoproteins. Most Vicieae lectins consist of two subunits, α and β, products of a single precursor protein derived from a single gene. The differences between the isoforms result from varying degrees of proteolytic processing. Along with the identification of these molecules and their characteristics, biological activities become very relevant and robust for both basic and applied research.

Alternative splicing (AS) is a method of increasing the number of proteins that the genome is capable of coding for, by altering the pre-mRNA during its maturation. This process provides the ability of a broad range of proteins to arise from a single gene. AS events are known to occur in up to 94% of human genes. Cumulative data have shown that aberrant AS functionality is a major factor in human diseases. This review focuses on the contribution made by aberrant AS functionality in the development and progression of esophageal cancer. The changes in the pattern of expression of alternately spliced isoforms in esophageal cancer can be used as diagnostic or prognostic biomarkers. Additionally, these can be used as targets for the development of new treatments for esophageal cancer.

Rice grain quality is of paramount importance in the consumer preference for rice varieties and therefore the development of rice varieties should match to the consumer preference. Assessment of segregating population of breeding material in rice for quality parameter made it possible by the use of simple sequence repeat(SSR) marker. The F2 mapping population of a cross between a long slender rice genotype VDN 1137-1-1 and a short slender rice landrace Badshabhog was studied for the inheritance of grain length and to identify the marker associated with grain type. The F2 population showed 3:1 ration for long slender to short slender grain type. This segregating population was assessed by 24 SSR markers using bulk segregant analysis. Among these 24 SSR Markers, a marker RM 147 reported polymorphism between the long slender and short slender parents and respective bulks. Genetic analysis indicated goodness of fit for single gene model indicating the association of RM147 with grain length gene in the segregating population. Therefore, SSR marker RM 147 is of immense value in the assessment of grain quality parameter in rice during the development of rice varieties.

Congenital bronchopulmonary malformations are relatively common and arise during various periods of morphogenesis. Although some are isolated or sporadic occurrences, others may result from single gene mutations or cytogenetic imbalances. Single gene mutations have been identified, which are etiologically related to primary pulmonary hypoplasia, lung segmentation defects as well as pulmonary vascular and lymphatic lesions. Functional defects in cystic fibrosis, primary ciliary dyskinesias, alpha-1-antitrypsin deficiency, and surfactant proteins caused by gene mutations may result in progressive pulmonary disease. This article provides an overview of pediatric pulmonary disease from a genetic perspective.

PurposePredictive diagnostics play an increasingly important role in personalized medicine for cancer treatment. Whole genome sequencing (WGS) based treatment selection is expected to rapidly increase worldwide. Detailed and comparative cost analyses of diagnostic techniques are an essential element in decision-making. This study aimed to calculate and compare the total cost of currently used diagnostic techniques and of WGS in treatment of non-small cell lung carcinoma (NSCLC), melanoma, colorectal cancer (CRC) and gastrointestinal stromal tumor (GIST) in the Netherlands.MethodsThe activity-based costing (ABC) method was conducted to calculate the total cost of included diagnostic techniques based on data provided by Dutch pathology laboratories and the Dutch centralized cancer WGS facility. Costs were allocated to four categories: capital costs, maintenance costs, software costs and operational costs. Outcome measures were total cost per cancer patient per included technique, and the total cost per cancer patient per most commonly applied technique (combination) for each cancer type.ResultsThe total cost per cancer patient per technique varied from € 58 (Sanger sequencing, 3 amplicons) to € 4738 (paired tumor-normal WGS). The operational costs accounted for the vast majority over 90 % of the total per cancer patient technique costs. The most important operational cost drivers were consumables followed by personnel (for sample preparation and primary data analysis).ConclusionThis study outlined in detail all costing aspects and cost prices of current and new diagnostic modalities used in treatment of NSCLC, melanoma, CRC and GIST in the Netherlands. Detailed cost differences and value comparisons between these diagnostic techniques enable future economic evaluations to support decision-making on implementation of WGS and other diagnostic modalities in routine clinical practice.

Eight F2 populations of crosses carried out between the resistant cultivar Amigo and 8 susceptible bread wheat cultivars were evaluated to study the inheritance of resistance to powdery mildew (Pm) caused byBlumeria. graminis f.sp . tritici and also to estimate the number and action of genes related to adult plant resistance. The response to powdery mildew disease was studied in a conditioned glasshouse and natural infection in the open field. Individual plants were scored and classified as resistant or susceptible according to a specific scale. The tested local wheat cultivars showed susceptible responses at both seedling and adult stages, while the Amigo cultivar was susceptible at seedling stage and resistant at adult stage. The F2 plants of all tested crosses were susceptible at seedling stage and resistant at the adult stage. Obtained results revealed that the inheritance of resistance is ruled by a single gene in the crosses Amigo/Sids12 and Amigo/Misr2; and by two recessive genes in Amigo/Gemmeiza11 cross. The inheritance of resistance in F2 populations of Amigo/Sakha95, and Amigo/Giza171 crosses is controlled by two dominant genes, while in Amigo/Gemmeiza12, Amigo/Sakha94 and Amigo/Misr1 crosses is conditioned by two incompatible dominant genes. Sakha 95 and Giza171 wheat cultivars were the best and suitable for transferring the adult plant resistance gene Pm17.

A two-dimensional nanoparticle–single-stranded DNA (ssDNA) array has been assembled for the detection of bacterial species using machine-learning (ML) algorithms. Out of 60 unknowns prepared from bacterial lysates, 54 unknowns were predicted correctly. Furthermore, the nanosensor array, supported by ML algorithms, was able to distinguish wild-type Escherichia coli from its mutant by a single gene difference. In addition, the nanosensor array was able to distinguish untreated wild-type E. coli from those treated with antimicrobial drugs. This work demonstrates the potential of nanoparticle–ssDNA arrays and ML algorithms for the discrimination and identification of complex biological matrixes.

Background Next-generation sequencing (NGS) has been implemented in clinical oncology to analyze multiple genes and to guide targeted therapy; however, little is known about the performance of the Oncomine Dx Target Test compared with conventional single gene tests for detecting EGFR mutations. The objective of this study was to evaluate the performance of the Oncomine Dx Target Test compared with a PNA-LNA PCR clamp test to detect EGFR mutations. Methods We retrospectively reviewed consecutive patients with non-small cell lung cancer (NSCLC) from whom FFPE samples were simultaneously submitted for the Oncomine Dx Target Test, and a PNA-LNA PCR clamp test using the same specimen. We subsequently compared the analysis success rates and detection rates between the two tests. Results A total of 116 samples were identified. The success rates and detection rates of EGFR mutations in the total number of samples were 90% and 28%, respectively for the Oncomine Dx Target Test, and 100% and 35% for the PNA-LNA PCR clamp test. The Oncomine Dx Target Test was unable to analyze three samples (2%) due to the samples not passing the nucleic acid concentration threshold, and nine (8%) samples had invalid results. The exon 19 deletion was not detected by the Oncomine Dx Target Test in four cases (4%). Conclusions The analytical performance of the Oncomine Dx Target Test analysis for EGFR mutations may not be comparable with conventional single gene tests due to both invalid and false-negative results. Key points Significant findings of the study The success rate of the Oncomine Dx Target Test was significantly lower than the PNA-LNA PCR clamp test. Among the samples successfully analyzed, four exon 19 deletions were not detected by the Oncomine Dx Target Test. What this study adds The analytical performance of the Oncomine Dx Target Test may not be comparable with conventional single gene tests. We should revise the sampling procedures, and review the sample quality assessment methods, to improve the analytical performance.

Please cite 10.7554/eLife.59683 if you use this protocol. Note; our eLife publication used Version 2 of this protocol. Later version are subsequent improvements/simplifications. Get in touch for questions/suggestions twitter –@francois_kroll email –francois@kroll.be

Summary Albino cavefish sleep less than their pigmented siblings. A recent study used CRISPR–Cas9-directed mutation to establish unambiguously that loss of function of a single gene, ocular and cutaneous albinism2, underlies both phenotypes, one morphological, the other behavioral.

Marla Sokolowski's scientific achievements established her as an internationally recognized leader in behavioural genetics. As a graduate student, she made a significant discovery while observing natural populations of the fruit fly, Drosophila melanogaster: the larvae exhibited a behavioural polymorphism which she traced to alleles of a single gene. Some larvae were 'sitters' which fed in a restricted location, while others were 'rovers' which ranged more widely in feeding. The gene in question, foraging, codes for a cyclic GMP kinase which is expressed in numerous locations throughout larval and adult Drosophila. Building on this foundation, she and her students have elucidated the genetic and environmental factors that account for individual differences in behaviour. In this article, I review significant stages of her scientific career.

Pseudoxanthoma elasticum (PXE) is a rare genetic disorder characterised by elastic tissue alterations and caused by mutations in a single gene, ABCC6, on chromosome 16p that includes manifestations that are predominantly cutaneous, ocular and cardiovascular. PXE-like lesions in association with β-thalassemia have previously been reported in the literature in patients with β-thalassaemia intermediate and major, being clinically indistinguishable from classic PXE. The case is presented of a 10-year-old boy with β-thalassaemia minor and characteristic lesions of PXE. It is worth noting the benefit of multimodal imaging in the diagnosis and monitoring of the lesions.

Author(s): Chitre, Apurva S; Polesskaya, Oksana; Holl, Katie; Gao, Jianjun; Cheng, Riyan; Bimschleger, Hannah; Garcia Martinez, Angel; George, Tony; Gileta, Alexander F; Han, Wenyan; Horvath, Aidan; Hughson, Alesa; Ishiwari, Keita; King, Christopher P; Lamparelli, Alexander; Versaggi, Cassandra L; Martin, Connor; St Pierre, Celine L; Tripi, Jordan A; Wang, Tengfei; Chen, Hao; Flagel, Shelly B; Meyer, Paul; Richards, Jerry; Robinson, Terry E; Palmer, Abraham A; Solberg Woods, Leah C | Abstract: ObjectiveObesity is influenced by genetic and environmental factors. Despite the success of human genome-wide association studies, the specific genes that confer obesity remain largely unknown. The objective of this study was to use outbred rats to identify the genetic loci underlying obesity and related morphometric and metabolic traits.MethodsThis study measured obesity-relevant traits, including body weight, body length, BMI, fasting glucose, and retroperitoneal, epididymal, and parametrial fat pad weight in 3,173 male and female adult N/NIH heterogeneous stock (HS) rats across three institutions, providing data for the largest rat genome-wide association study to date. Genetic loci were identified using a linear mixed model to account for the complex family relationships of the HS and using covariates to account for differences among the three phenotyping centers.ResultsThis study identified 32 independent loci, several of which contained only a single gene (e.g., Epha5, Nrg1, Klhl14) or obvious candidate genes (e.g., Adcy3, Prlhr). There were strong phenotypic and genetic correlations among obesity-related traits, and there was extensive pleiotropy at individual loci.ConclusionsThis study demonstrates the utility of HS rats for investigating the genetics of obesity-related traits across institutions and identify several candidate genes for future functional testing.

During mRNA translation, the genetic information stored in mRNA is translated into a protein sequence. It is imperative that the genetic information is translated with high precision. Surprisingly, however, recent experimental evidence has demonstrated that translation can be highly heterogeneous, even among different mRNA molecules derived from a single gene in an individual cell; multiple different polypeptides can be produced from a single mRNA molecule and the rate of translation can vary in both space and time. However, whether translational heterogeneity serves an important cellular function, or rather predominantly represents gene expression 'noise' remains an open question. In this review, we discuss the molecular basis and potential functions of such translational heterogeneity.

Higher temperatures associated with climate change often increase the severity of plant diseases. An understanding of how plants respond to pathogens during high temperature stress is required for crop improvement, but the molecular mechanisms underlying this response are largely unknown. Mechanistic research has primarily focused on plant responses during either single stresses or heat-induced loss of single gene resistance. Transcriptome analyses of plant responses to a single stress compared to combined-stresses reveal significant differences showing that single-stress response studies are inadequate for determining the mechanisms of high temperature-induced disease susceptibility. To combat plant disease in light of climate change, future research will require comprehensive study designs and analyses.

The assembly of protein machines in cells is precise, rapid, and coupled to protein synthesis with regulation in space and time. The assembly of natural and synthetic nanomachines could be similarly controlled by genetic programming outside the cell. Here, we present quasi-two-dimensional (2D) silicon compartments that enable programming of protein assembly lines by local synthesis from surface-immobilized DNA brushes. Using this platform, we studied the autonomous synthesis and assembly of a structural complex from a bacteriophage and a bacterial RNA-synthesizing machine. Local synthesis and surface capture of complexes provided high assembly yield and sensitive detection of spatially resolved assembly intermediates, with the 3D geometry of the compartment and the 2D pattern of brushes dictating the yield and mode of assembly steps. Localized synthesis of proteins in a single gene brush enhances their interactions, and displacement of their genes in separated brushes leads to step-by-step surface assembly. This methodology enables spatial regulation of protein synthesis, and deciphering, reconstruction and design of biological machine assembly lines.

There have been significant advancements in precision medicine and approaches to medication selection based on pharmacogenetic results. With the availability of direct-to-consumer genetic testing and growing awareness of genetic interindividual variability, patient demand for more precise, individually tailored drug regimens is increasing. The University of Florida (UF) Health Precision Medicine Program (PMP) was established in 2011 to improve integration of genomic data into clinical practice. In the ensuing years, the UF Health PMP has successfully implemented several single-gene tests to optimize the precision of medication prescribing across a variety of clinical settings. Most recently, the UF Health PMP launched a custom-designed pharmacogenetic panel, including pharmacogenes relevant to supportive care medications commonly prescribed to patients undergoing chemotherapy treatment, referred to as "GatorPGx." This tutorial provides guidance and information to institutions on how to transition from the implementation of single-gene pharmacogenetic testing to a preemptive panel-based testing approach. Here, we demonstrate application of the preemptive panel in the setting of an adult solid tumor oncology clinic. Importantly, the information included herein can be applied to other clinical practice settings.

SUMMARYThere is considerable work being carried out in neuroscientific laboratories to delineate the mechanisms underlying single-gene disorders, particularly those related to intellectual disability and autism spectrum disorder. Many clinicians will have little if any direct experience of this type of work and so find the procedures and terminology difficult to understand. This article describes some of the laboratory techniques used and their increasing relevance to clinical practice. It is pitched for clinicians with little or no laboratory science background.

In this essay, I recount and examine my response to a genetic diagnosis of my disabled daughter. My daughter was forty-nine before the diagnosis came. All her disabilities were traceable to a de novo single gene variant on the PURA gene that was discovered only in 2014. I speak of the jolt and the recalibration that this discovery engendered, concluding that, while it seemed that everything had changed, nothing had changed. But my family did discover a community in which Sesha joins other PURA-perfect sons and daughters and where we as a family acquire a "horizontal identity" marked by a genetic variant.

Rearrangement is one of the most studied features in the animal mitochondrial genomes. The progress in high-throughput sequencing and comparative genomics has brought opportunities for systematic studies of mitochondrial genome rearrangements. However, there are few reports on globally examining mitogenome rearrangement and distinguishing the rearrangement frequency of each gene, which could contribute to a better understanding of its models and evolution. We presented qMGR, a new approach for large-scale quantifying mitogenome rearrangements considering a single gene as a structural unit. Compared to a reference arrangement, qMGR accumulates the changes of two nearest neighbor genes to calculate rearrangement score (RS) and rearrangement frequency (RF) of each single gene in the mitogenomes of a given taxonomic group. By accumulating RS of all genes in one genome, qMGR was developed to calculate each mitogenome rearrangement score, which can be used as a quantitative feature of the mitogenome rearrangement. Based on the frequency of rearrangement of each gene, qMGR can further detect the conserved gene set and high frequency rearrangement segments within the taxon. They may facilitate the assessment of rearrangement distances and understanding rearrangement mechanisms. qMGR web service is freely available at http://qmgr.hnnu.edu.cn/. The source code is available under GNU GPL at https://github.com/zhanglab2019/qMGR.

Metabolic resistances to atrazine (atz-R) and mesotrione (meso-R) occur in several waterhemp [Amaranthus tuberculatus (Moq.) Sauer] populations in the United States. Interestingly, although metabolic atz-R but mesotrione-sensitive A. tuberculatus populations have been reported, an Amaranthus population has not been confirmed as meso-R but atrazine-sensitive, implying an association between these traits. Experiments were designed to investigate whether the single gene conferring metabolic atz-R plays a role in meso-R. An F2 population was generated from a multiple herbicide–resistant A. tuberculatus population from McLean County, IL (MCR). A cross was made between a known meso-R male clone (MCR-6) and a herbicide-sensitive female clone from Wayne County, IL (WCS-2) to develop an F1 population. Survival of MCR-6 plants following atrazine POST treatment (14.4 kg ha−1) indicated the male parent was homozygous atz-R. F1 plants were intermated to obtain a segregating pseudo-F2 population. Dose–response and metabolic studies conducted with mesotrione using F1 plants indicated intermediate biomass reductions and metabolic rates compared with MCR-6 and WCS. F2 plants were initially treated with either mesotrione (260 g ha−1) or atrazine (2 kg ha−1) POST, and after 21 d of recovery, vegetative clones from surviving resistant plants were subsequently treated with the other herbicide. When mesotrione was applied first, the meso-R frequency was 8.2%, and when atrazine was applied first, the atz-R frequency was 75%. However, the meso-R frequency increased to 16.5% following preselection for atz-R, and 100% of surviving meso-R plants were atz-R. Our findings indicate that the gene conferring metabolic atz-R is also involved with the meso-R trait within the population tested.

Prion disease is a rare, fatal, and exceptionally rapid neurodegenerative disease. Although incurable, prion disease follows a clear pathogenic mechanism, in which a single gene gives rise to a single prion protein (PrP) capable of converting into the sole causal disease agent, the misfolded prion. As efforts progress to leverage this mechanistic knowledge toward rational therapies, a principal challenge will be the design of clinical trials. Previous trials in prion disease have been done in symptomatic patients who are often profoundly debilitated at enrolment. About 15% of prion disease cases are genetic, creating an opportunity for early therapeutic intervention to delay or prevent disease. Highly variable age of onset and absence of established prodromal biomarkers might render infeasible existing models for testing drugs before disease onset. Advancement of near-term targeted therapeutics could crucially depend on thoughtful design of rigorous presymptomatic trials.

Preimplantation genetic testing for monogenic conditions (PGT-M) has become a valued reproductive option for couples at risk of having a child with a single gene condition. In line with developments in molecular genetics, there has been an overall trend toward laboratory techniques with higher accuracy in comparison to earlier PGT-M techniques. The recommendation for confirmatory prenatal diagnostic testing has remained a standard component of PGT-M counseling, reflecting the inherent difficulties of testing the limited number of cells obtained from embryo biopsy, as well as recognition of the biological and human factors that may lead to misdiagnosis in a PGT-M cycle. Reported misdiagnosis rates are less than 1 in 200 pregnancies following PGT-M, although updated data regarding newer methods of PGT-M are required. There is limited evidence available regarding clinician and patient behavior in pregnancies resulting from PGT-M cycles. It remains essential that clinicians involved in the care of patients undergoing PGT-M provide appropriate counseling regarding the risks of misdiagnosis and the importance of confirmatory prenatal diagnosis. The nature of PGT-M test design lends itself to cell-free DNA-based noninvasive prenatal testing for monogenic conditions (NIPT-M), which is likely to become a popular method in the near future.

Background: Current prognostic signatures are based on measurements of numerous targets and require specialized equipment and complex calculations. While the overall prognostic capabilities of the tests may be comparable in ER+/HER2- breast cancer, side by side comparisons of different tests have shown that results differ on the individual patient level (Bartlett et al., JNCI, 2016). Here we determined risk scores and classifications in 160 tumors to the following commercial and academic prognostic tests using a custom gene panel for which the publically available algorithms were trained against the actual commercial test scores: Mammaprint®, Oncotype DX®, Prosigna® including PAM50 subtyping; and academic risk scores: IHC4-like, 95-gene score and the Genomic Grade Index. These trained risk classifiers were compared to the results of the MammaTyper® IVD-kit. Methods: RNA was extracted from FFPE tissue sections and analyzed on the Nanostring nCounter® using a probe set containing all targets and reference genes used in the original signatures (N=199). Nanostring measurements and calculations of simulated risk classifiers were carried out as described previously (Bayani et al., npj Breast Cancer, 2017) and retrained against actual commercial test scores (Bartlett et al., in prep.). MammaTyper® RT-qPCR of ERBB2, ESR1, PGR and MKI67 (normalized to CALM2) was carried out on a separate aliquot of the same RNA sample. St. Gallen surrogate subtypes were assigned based on binary mRNA expression according to pre-defined cutoffs. For calculating pairwise agreements between test categorizations, simulated test results with ternary classification were transformed to binary classifications (IHC4-like: low + int vs. high, Oncotype DX-trained: RS≤25 vs. RS>25, Prosigna-trained ROR-P: low vs. int + high). Comparison of MammaTyper® with simulated risk scores was done on the level of surrogate subtypes and on the level of continuous MKI67 and LRP score values. The MammaTyper® LRP score is a previously developed signature to predict RS ≤25 results with high specificity. Results: Marker positivity rate by RT-qPCR was 83% for ESR1, 72% for PGR, 9% for ERBB2 and 58% for MKI67 based on the pre-specified MammaTyper® cutoffs. The highest rate of low risk results was found for binary RS classification with 68.1% of RS ≤25 samples. MammaTyper® Luminal A-like result was found in 30.6% of samples a rate similar to ROR-P, Genomic Grade Index or MammaPrint-trained low risk results (35.0%, 38.1% and 38.8% respectively). The highest agreement between the simulated risk classifications was observed between binary OncotypeDX-trained RS and IHC4-like classifications with 93.1%. Prosigna-trained (ROR-P) and IHC4-like score had the lowest pairwise agreement with only 65.0% agreement. Oncotype DX-trained and the 95 gene score had the highest concordance to MammaTyper® Luminal A-like subtype with 100% and 96% of Luminal A-like samples classified as RS ≤25 and low risk also by these signatures, respectively. ROC analyses of MammaTyper®MKI67 against binary 95-gene score risk classifier resulted in an AUC of 0.949. The lowest AUC for MKI67 was achieved against simulated MammaPrint-trained classification (AUC=0.874). When applying the LRP score to ROC analysis, almost identical AUCs were achieved for IHC4-like and binary Oncotype DX-trained classifications with AUCs of 0.976 and 0.969 respectively. Conclusion: Low cost local RT-qPCR measurements by MammaTyper® show a high agreement with the scores generated by our Oncotype DX-trained scores. The academic and well validated 95-gene signature agrees well with MammaTyper®MKI67 single gene measurement. Therefore, the locally performed MammaTyper® test may serve as cost effective surrogate for complex prognostic signatures or at least enables a pre-screening for molecularly “obviously” low risk samples. Citation Format: Mark Laible, Sebastian Aulmann, Alfred Etzrodt, Marcus Schmidt, Cheryl Crozier, Ralph Wirtz, Jane Bayani, Ugur Sahin, John MS Bartlett. Comparison of MammaTyper® RT-qPCR based subtyping with simulated breast cancer prognostic signatures [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-07-08.

Epistaza jest to zjawisko interakcji pomiędzy genami, w której fenotyp jednego genu jest zależny od obecności innego genu/genów. Epistaza powoduje, że określenie fenotypu na podstawie pojedynczych mutacji staje się niemożliwe, na skutek nieliniowego współdziałania genów. W poniższym artykule opisujemy rodzaje epistazy, metody jej badania oraz jej znaczenie dla procesów ewolucyjnych. Przybliżamy czytelnikom pojęcie epistazy wyższego rzędu (pomiędzy więcej niż dwoma genami) oraz pokrótce wprowadzamy zagadnienie praktycznego znaczenia epistazy dla człowieka.

Hereditary spastic paraplegia (HSP) is a heterogeneous inherited disorder that manifests with lower extremity weakness and spasticity. HSP can be inherited by autosomal dominant, autosomal recessive, and X-linked inheritance patterns. Recent studies have shown that, although rare, mutations in a single gene can lead to multiple patterns of inheritance of HSP. We enrolled the HSP family showing autosomal dominant inheritance and performed genetic study to find the cause of phenotype in this family. We recruited five members of a Korean family as study participants. Four of the five family members had pure HSP. Part of the family members underwent whole-exome sequencing (WES) to identify the causative mutation. As the result of WES and Sanger sequencing analysis, a novel missense mutation (c.452 C > T, p.Ala151Val) of ERLIN2 gene was identified as the cause of the autosomal dominant HSP in the family. Our study suggests that the ERLIN2 gene leads to both autosomal recessive and autosomal dominant patterns of inheritance in HSP. Moreover, autosomal dominant HSP caused by ERLIN2 appears to cause pure HSP in contrast to autosomal recessive ERLIN2 related complicated HSP (SPG18).

Hemoglobinopathies are the most common single gene disorders (monogenic disorders) in the world population. Due to specific position of Iran and the presence of multi-ethnic groups in the country, there are many varieties in the molecular genetics and clinical features of hemoglobinopathies in Iran. Hemoglobinopathies include structural variants, thalassemias, and hereditary persistence of fetal hemoglobin. In this review, we look at the common structural variants in various parts of the country along with their hematological and clinical characteristics. Also, we discuss about the burden of the thalassemias in the country, different types, complications, molecular defects and therapy.

Human genome contains ca. 20,000 protein-coding genes that could be translated into millions of unique protein species (proteoforms). Proteoforms coded by a. single gene often have different functions, which implies different protein partners. By interacting with each other, proteoforms create a. network reflecting the dynamics of cellular processes in an organism. Perturbations of protein-protein interactions change the network topology, which often triggers pathological processes. Studying proteoforms is a. relatively new research area in proteomics, and this is why there are comparatively few experimental studies on the interaction of proteoforms. Bioinformatics tools can facilitate such studies by providing valuable complementary information to the experimental data and, in particular, expanding the possibilities of the studies of proteoform interactions.

The advent of RNA-seq technologies has switched the paradigm of genetic analysis from a genome to a transcriptome-based perspective. Alternative splicing generates functional diversity in genes, but the precise functions of many individual isoforms are yet to be elucidated. Gene Ontology was developed to annotate gene products according to their biological processes, molecular functions and cellular components. Despite a single gene may have several gene products, most annotations are not isoform-specific and do not distinguish the functions of the different proteins originated from a single gene. Several approaches have tried to automatically annotate ontologies at the isoform level, but this has shown to be a daunting task. We have developed ISOGO (ISOform + GO function imputation), a novel algorithm to predict the function of coding isoforms based on their protein domains and their correlation of expression along 11,373 cancer patients. Combining these two sources of information outperforms previous approaches: it provides an area under precision-recall curve (AUPRC) five times larger than previous attempts and the median AUROC of assigned functions to genes is 0.82. We tested ISOGO predictions on some genes with isoform-specific functions (BRCA1, MADD,VAMP7 and ITSN1) and they were coherent with the literature. Besides, we examined whether the main isoform of each gene -as predicted by APPRIS- was the most likely to have the annotated gene functions and it occurs in 99.4% of the genes. We also evaluated the predictions for isoform-specific functions provided by the CAFA3 challenge and results were also convincing. To make these results available to the scientific community, we have deployed a web application to consult ISOGO predictions (https://biotecnun.unav.es/app/isogo). Initial data, website link, isoform-specific GO function predictions and R code is available at https://gitlab.com/icassol/isogo.

Highlights: • Generation of transcriptomes from three new Pirsoniales species for the first time. • Generation of transcriptomes from four new Developea species, enriching the clade. • Phylogenomic recovery of a monophyletic Bigyromonadea: Pirsoniales and Developea. • Bigyormonads’ ability to aggregate and form pseudopod resembles oomycete zoospores. • Report of the first case of eukaryovory in the flagellated stages of Pirsoniales. Stramenopiles are a diverse but relatively well-studied eukaryotic supergroup with considerable genomic information available (Sibbald and Archibald, 2017). Nevertheless, the relationships between major stramenopile subgroups remain unresolved, in part due to a lack of data from small nanoflagellates that make up a lot of the genetic diversity of the group. This is most obvious in Bigyromonadea, which is one of four major stramenopile subgroups but represented by a single transcriptome. To examine the diversity of Bigyromonadea and how the lack of data affects the tree, we generated transcriptomes from seven novel bigyromonada species described in this study: Develocauda condao n. gen. n. sp., Develocanicus komovi n. gen. n. sp., Develocanicus vyazemskyi n. sp., Cubaremonas variflagellatum n. gen. n. sp., Pirsonia chemainus nom. prov., Feodosia pseudopoda nom. prov., and Koktebelia satura nom. prov. Both maximum likelihood and Bayesian phylogenomic trees based on a 247 genematrix recovered a monophyletic Bigyromonadea that includes two diverse subgroups, Developea and Pirsoniales, that were not previously related based on single gene trees. Maximum likelihood analyses show Bigyromonadea related to oomycetes, whereas Bayesian analyses and topology testing were inconclusive. We observed similarities between the novel bigyromonad species and motile zoospores of oomycetes in morphology and the ability to self-aggregate. Rare formation of pseudopods and fused cells were also observed, traits that are also found in members of labyrinthulomycetes, another osmotrophic stramenopiles. Furthermore, we report the first case of eukaryovory in the flagellated stages of Pirsoniales. These analyses reveal new diversity of Bigyromonadea, and altogether suggest their monophyly with oomycetes, collectively known as Pseudofungi, is the most likely topology of the stramenopile tree.

Helsmoortel Van der Aa syndrome also known as ADNP syndrome is a neurological disorder which is caused by genetic changes in the ADNP gene. These genetic mutations occur impulsively in most patients, showing that there has been no family history of the disorder. These mutations mostly affect the intellectual abilities of the person, delays motor planning, and also may lead to autism or autism spectrum disorder. In 2014 ADNP disorder was discovered, and it is found that ADNP gene was one of the most consistent single gene causes of autism. Although several researchers have discovered a clear view with characteristics of the "core" effects associated with several mutations in the ADNP gene, a lot of things about the disorder is still unknown. Detecting ADNP syndrome in a person can be challenging as it is developed spontaneously without a long development curve. For this research of predicting the ADNP syndrome, a dataset comprising the details of 150 children, where 23 were diagnosed with ADNP syndrome and 127 were typically developing (TD) children was taken. The dataset comprises features such as a person's age, sex, whether he/she has been treated with jaundice, and their family history with ADNP and some other additional features.

Multiplexed detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rather than detection targeting a single gene is crucial to ensure more accurate coronavirus disease 2019 (COVID-19) diagnostics. Here, we develop a monolithic, 3D-printed, lab-on-disc platform for multiplexed molecular detection of SARS-CoV-2. The centrifugal lab-on-disc is fabricated in one step using simple 3D printing technology, circumventing the need for aligning and binding multiple layers. By combining isothermal amplification technology, this lab-on-disc platform is capable of simultaneously detecting the nucleoprotein and envelope genes of SARS-CoV-2 as well as an internal control of the human POP7 gene. Within a 50-minute incubation period, 100 copies SARS-CoV-2 RNA can be detected through visual detection according to color and fluorescence changes in the disc. Further, we clinically validated the lab-on-disc platform by testing 20 nasopharyngeal swab samples and demonstrated a sensitivity of 100% and an accuracy of 95%. Therefore, the monolithic, 3D-printed, lab-on-disc platform provides simple, rapid, disposable, sensitive, reliable, and multiplexed molecular detection of SARS-CoV-2, holding promise for COVID-19 diagnostics at the point of care., Graphical abstract