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1.
GLOBAL ENDOCRINOLOGY: Geographical variation in the profile of RET variants in patients with medullary thyroid cancer: a comprehensive review.
Maciel, RMB, Maia, AL
European journal of endocrinology. 2021;(1):R15-R30
Abstract
Genetic variability in humans is influenced by many factors, such as natural selection, mutations, genetic drift, and migrations. Molecular epidemiology evaluates the contribution of genetic risk factors in the etiology, diagnosis, and prevention of a particular disease. Few areas of medicine have been so clearly affected by genetic diagnosis and management as multiple neoplasia type 2 (MEN2), in which activating pathogenic variants in the RET gene results in the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism in nearly 98, 50, and 25% of gene carriers, respectively. Here, we aimed to collect RET genotyping data worldwide to analyze the distribution and frequency of RET variants from a global perspective. We show that the mutational spectrum of RET is observed worldwide. The codon 634 variants seem to be the most prevalent, but there are differences in the type of amino acid exchanges among countries and in the frequencies of the other RET codon variants. Most interestingly, studies using haplotype analysis or pedigree linkage have demonstrated that some pathogenic RET variants have been transmitted to offspring for centuries, explaining some local prevalence due to a founder effect. Unfortunately, after almost three decades after the causative role of the germline RET variants has been reported in hereditary MTC, comprehensive genotyping data remain limited to a few countries. The heterogeneity of RET variants justifies the need for a global effort to describe epidemiological data of families with MEN2 to further understand the genetic background and environmental circumstances that affect disease presentation.
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2.
A novel de novo heterozygous pathogenic variant in the SDHA gene results in childhood onset bilateral optic atrophy and cognitive impairment.
Zehavi, Y, Saada, A, Jabaly-Habib, H, Dessau, M, Shaag, A, Elpeleg, O, Spiegel, R
Metabolic brain disease. 2021;(4):581-588
Abstract
Isolated defects in the mitochondrial respiratory chain complex II (CII; succinate-ubiquinone oxidoreductase) are extremely rare and mainly result from bi-allelic mutations in one of the nuclear encoded subunits: SDHA, SDHB and SDHD, which comprise CII and the assembly CII factor SDHAF1. We report an adolescent female who presented with global developmental delay, intellectual disability and childhood onset progressive bilateral optic atrophy. Whole exome sequencing of the patient and her unaffected parents identified the novel heterozygous de novo variant c.1984C > T [NM_004168.4] in the SDHA gene. Biochemical assessment of CII in the patient's derived fibroblasts and lymphocytes displayed considerably decreased CII residual activity compared with normal controls, when normalized to the integral mitochondrial enzyme citrate synthase. Protein modeling of the consequent p.Arg662Cys variant [NP-004159.2] suggested that this substitution will compromise the structural integrity of the FAD-binding protein at the C-terminus that will ultimately impair the FAD binding to SDHA, thus decreasing the entire CII activity. Our study emphasizes the role of certain heterozygous SDHA mutations in a distinct clinical phenotype dominated by optic atrophy and neurological impairment. This is the second mutation that has been reported to cause this phenotype. Furthermore, it adds developmental delay and cognitive disability to the expanding spectrum of the disorder. We propose to add SDHA to next generation sequencing gene panels of optic atrophy.
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3.
Lessons learned from 40 novel PIGA patients and a review of the literature.
Bayat, A, Knaus, A, Pendziwiat, M, Afenjar, A, Barakat, TS, Bosch, F, Callewaert, B, Calvas, P, Ceulemans, B, Chassaing, N, et al
Epilepsia. 2020;(6):1142-1155
Abstract
OBJECTIVE To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations. METHODS Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches. RESULTS Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein. SIGNIFICANCE Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA.
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4.
Population Genetics in the Human Microbiome.
Garud, NR, Pollard, KS
Trends in genetics : TIG. 2020;(1):53-67
Abstract
While the human microbiome's structure and function have been extensively studied, its within-species genetic diversity is less well understood. However, genetic mutations in the microbiome can confer biomedically relevant traits, such as the ability to extract nutrients from food, metabolize drugs, evade antibiotics, and communicate with the host immune system. The population genetic processes by which these traits evolve are complex, in part due to interacting ecological and evolutionary forces in the microbiome. Advances in metagenomic sequencing, coupled with bioinformatics tools and population genetic models, facilitate quantification of microbiome genetic variation and inferences about how this diversity arises, evolves, and correlates with traits of both microbes and hosts. In this review, we explore the population genetic forces (mutation, recombination, drift, and selection) that shape microbiome genetic diversity within and between hosts, as well as efforts towards predictive models that leverage microbiome genetics.
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5.
Colletotrichum: species complexes, lifestyle, and peculiarities of some sources of genetic variability.
da Silva, LL, Moreno, HLA, Correia, HLN, Santana, MF, de Queiroz, MV
Applied microbiology and biotechnology. 2020;(5):1891-1904
Abstract
The genus Colletotrichum comprises species with different lifestyles but is mainly known for phytopathogenic species that infect crops of agronomic relevance causing considerable losses. The fungi of the genus Colletotrichum are distributed in species complexes and within each complex some species have particularities regarding their lifestyle. The most commonly found and described lifestyles in Colletotrichum are endophytic and hemibiotrophic phytopathogenic. Several of these phytopathogenic species show wide genetic variability, which makes long-term maintenance of resistance in plants difficult. Different mechanisms may play an important role in the emergence of genetic variants but are not yet fully understood in this genus. These mechanisms include heterokaryosis, a parasexual cycle, sexual cycle, transposable element activity, and repeat-induced point mutations. This review provides an overview of the genus Colletotrichum, the species complexes described so far and the most common lifestyles in the genus, with a special emphasis on the mechanisms that may be responsible, at least in part, for the emergence of new genotypes under field conditions.
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6.
Beyond the One Gene-One Disease Paradigm: Complex Genetics and Pleiotropy in Inheritable Cardiac Disorders.
Cerrone, M, Remme, CA, Tadros, R, Bezzina, CR, Delmar, M
Circulation. 2019;(7):595-610
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Abstract
Inheritable cardiac disorders, which may be associated with cardiomyopathic changes, are often associated with increased risk of sudden death in the young. Early linkage analysis studies in Mendelian forms of these diseases, such as hypertrophic cardiomyopathy and long-QT syndrome, uncovered large-effect genetic variants that contribute to the phenotype. In more recent years, through genotype-phenotype studies and methodological advances in genetics, it has become evident that most inheritable cardiac disorders are not monogenic but, rather, have a complex genetic basis wherein multiple genetic variants contribute (oligogenic or polygenic inheritance). Conversely, studies on genes underlying these disorders uncovered pleiotropic effects, with a single gene affecting multiple and apparently unrelated phenotypes. In this review, we explore these 2 phenomena: on the one hand, the evidence that variants in multiple genes converge to generate one clinical phenotype, and, on the other, the evidence that variants in one gene can lead to apparently unrelated phenotypes. Although multiple conditions are addressed to illustrate these concepts, the experience obtained in the study of long-QT syndrome, Brugada syndrome, and arrhythmogenic cardiomyopathy, and in the study of functions related to SCN5A (the gene coding for the α-subunit of the most abundant sodium channel in the heart) and PKP2 (the gene coding for the desmosomal protein plakophilin-2), as well, is discussed in more detail.
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Salinity stress response and 'omics' approaches for improving salinity stress tolerance in major grain legumes.
Jha, UC, Bohra, A, Jha, R, Parida, SK
Plant cell reports. 2019;(3):255-277
Abstract
Sustaining yield gains of grain legume crops under growing salt-stressed conditions demands a thorough understanding of plant salinity response and more efficient breeding techniques that effectively integrate modern omics knowledge. Grain legume crops are important to global food security being an affordable source of dietary protein and essential mineral nutrients to human population, especially in the developing countries. The global productivity of grain legume crops is severely challenged by the salinity stress particularly in the face of changing climates coupled with injudicious use of irrigation water and improper agricultural land management. Plants adapt to sustain under salinity-challenged conditions through evoking complex molecular mechanisms. Elucidating the underlying complex mechanisms remains pivotal to our knowledge about plant salinity response. Improving salinity tolerance of plants demand enriching cultivated gene pool of grain legume crops through capitalizing on 'adaptive traits' that contribute to salinity stress tolerance. Here, we review the current progress in understanding the genetic makeup of salinity tolerance and highlight the role of germplasm resources and omics advances in improving salt tolerance of grain legumes. In parallel, scope of next generation phenotyping platforms that efficiently bridge the phenotyping-genotyping gap and latest research advances including epigenetics is also discussed in context to salt stress tolerance. Breeding salt-tolerant cultivars of grain legumes will require an integrated "omics-assisted" approach enabling accelerated improvement of salt-tolerance traits in crop breeding programs.
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Clonazepam improves the symptoms of two siblings with novel variants in the SYNJ1 gene.
Hong, D, Cong, L, Zhong, S, He, Y, Xin, L, Gao, X, Zhang, J
Parkinsonism & related disorders. 2019;:221-225
Abstract
BACKGROUND Mutations in the SYNJ1 gene have been associated with early-onset of atypical Parkinson's disease or severe neurodegeneration with intractable seizures. Due to the rarity of the disease, there were limitations in the quality of available treatment options for SYNJ1-related diseases. METHODS Two affected siblings from a non-consanguineous family were evaluated through a set of clinical and laboratory tests. The genetic screening was performed through exome next generation sequencing. SYNJ1 mutant transcripts were purified and cloned into the vectors for Sanger sequence of single-stranded DNA. Relative level of the SYNJ1 transcript was measured by quantitative PCR. RESULTS The clinical features were characterized by a triad of symptomatic progression including diplopia, dystonia, and Parkinsonism. The dystonic symptoms were outstanding in the siblings, which preceded the Parkinsonism symptoms and became the main symptoms. Clonazepam resolved the clinical symptoms, especially the severe trunk dystonia and dystonic postures of limbs. Compound heterozygous variants (c.2579-2A > G; p.A860Gfs*5 and c.3845C > A; p.P1282L) were identified in the SYNJ1 gene co-segregating in this family. The proline residue is highly conserved across species and predicted to be damaging by several in silico tools. The splice site variant caused a skip of exon 20 and a significant reduction of the SYNJ1 transcript expression. CONCLUSIONS Our study expanded the clinical and genetic spectrums of the SYNJ1-related diseases. Although our study was a preliminary observation, it indicated that clonazepam could improve the dystonic symptoms caused by mutations in the SYNJ1 gene.
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9.
An Update on Genetic Modification of Chickpea for Increased Yield and Stress Tolerance.
Kumar, M, Yusuf, MA, Nigam, M, Kumar, M
Molecular biotechnology. 2018;(8):651-663
Abstract
Chickpea is a highly nutritious grain legume crop, widely appreciated as a health food, especially in the Indian subcontinent. The major constraints on chickpea production are biotic (Helicoverpa, bruchid, aphid, ascochyta) and abiotic (drought, heat, salt, cold) stresses, which reduce the yield by up to 90%. Various strategies like conventional breeding, molecular breeding, and modern plant breeding have been used to overcome these problems. Conventionally, breeding programs aim at development of varieties that combine maximum number of traits through inter-specific hybridization, wide hybridization, and hybridization involving more than two parents. Breeding is difficult in this crop because of its self-pollinating nature and limited genetic variation. Recent advances in in vitro culture and gene technologies offer unique opportunities to realize the full potential of chickpea production. However, as of date, no transgenic chickpea variety has been approved for cultivation in the world. In this review, we provide an update on the development of genetically modified chickpea plants, including those resistant to Helicoverpa armigera, Callosobruchus maculatus, Aphis craccivora, as well as to drought and salt stress. The genes utilized for development of resistance against pod borer, bruchid, aphid, drought, and salt tolerance, namely, Bt, alpha amylase inhibitor, ASAL, P5CSF129A, and P5CS, respectively, are discussed.
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The role of metabolic syndrome variant in the malignant tumors progression.
Yunusova, NV, Kondakova, IV, Kolomiets, LA, Afanas'ev, SG, Kishkina, AY, Spirina, LV
Diabetes & metabolic syndrome. 2018;(5):807-812
Abstract
Metabolic syndrome (MS) is one of the leading risk factors for the development of some common cancers (endometrial cancer, postmenopausal breast cancer, colorectal cancer). Currently, a drug-induced metabolic syndrome related with androgen deprivation therapy in patients with prostate cancer represents a serious medical problem. Not only MS, or its individual components, but MS variants with different levels of leptin, adiponectin, visfatin, resistin are associated with tumor invasion, metastasis and survival rates in patients with MS-associated malignancies.