scholarly journals Molecular testing for imprinting disorders

2020 ◽  
Vol 32 (4) ◽  
pp. 305-319
Author(s):  
Jasmin Beygo ◽  
Deniz Kanber ◽  
Thomas Eggermann ◽  
Matthias Begemann
Keyword(s):  
New Technologies ◽  
Molecular Genetic ◽  
Gene Clusters ◽  
Recurrence Risk ◽  
Imprinted Genes ◽  
Molecular Testing ◽  
Imprinting Disorders ◽  
Genetic Causes ◽  
Phenotypic Spectrum ◽  
Or Gene

Abstract Imprinting disorders are a group of rare diseases with a broad phenotypic spectrum caused by a wide variety of genetic and epigenetic disturbances of imprinted genes or gene clusters. The molecular genetic causes and their respective frequencies vary between the different imprinting disorders so that each has its unique requirements for the diagnostic workflow, making it challenging. To add even more complexity to this field, new molecular genetic causes have been identified over time and new technologies have enhanced the detectability e. g. of mosaic disturbances. The precise identification of the underlying molecular genetic cause is of utmost importance in regard to recurrence risk in the families, tumour risk, clinical management and conventional and in the future therapeutic managements. Here we give an overview of the imprinting disorders, their specific requirements for the diagnostic workup and the most common techniques used and point out possible pitfalls.

scholarly journals Role of Imprinting Disorders in Short Children Born SGA and Silver-Russell Syndrome Spectrum

2020 ◽  
Author(s):  
Tomoko Fuke ◽  
Akie Nakamura ◽  
Takanobu Inoue ◽  
Sayaka Kawashima ◽  
Kaori Isono Hara ◽  
...  
Keyword(s):  
Genetic Disorders ◽  
Uniparental Disomy ◽  
Clinical Analysis ◽  
Comparative Genomic ◽  
Imprinting Disorders ◽  
Genetic Causes ◽  
Phenotypic Spectrum ◽  
Short Children ◽  
Clinical Scoring ◽  
Silver Russell Syndrome

Abstract Background (Epi)genetic disorders associated with small-for-gestational-age with short stature (SGA-SS) include imprinting disorders (IDs). Silver-Russell syndrome (SRS) is a representative ID in SGA-SS and has heterogenous (epi)genetic causes. Subjects and Methods To clarify the contribution of IDs to SGA-SS and the molecular and phenotypic spectrum of SRS, we recruited 269 patients with SGA-SS, consisting of 103 and 166 patients referred to us for genetic testing for SGA-SS and SRS, respectively. After excluding 20 patients with structural abnormalities detected by comparative genomic hybridization analysis using catalog array, 249 patients were classified into 3 subgroups based on the Netchine-Harbison clinical scoring system (NH-CSS), SRS diagnostic criteria. We screened various IDs by methylation analysis for differentially methylated regions (DMRs) related to known IDs. We also performed clinical analysis. Results These 249 patients with SGA-SS were classified into the “SRS-compatible group” (n = 148), the “non-SRS with normocephaly or relative macrocephaly at birth group” (non-SRS group) (n = 94), or the “non-SRS with relative microcephaly at birth group” (non-SRS with microcephaly group) (n = 7). The 44.6% of patients in the “SRS-compatible group,” 21.3% of patients in the “non-SRS group,” and 14.3% in the “non-SRS with microcephaly group” had various IDs. Loss of methylation of the H19/IGF2:intergenic-DMR and uniparental disomy chromosome 7, being major genetic causes of SRS, was detected in 30.4% of patients in the “SRS-compatible group” and in 13.8% of patients in the “non-SRS group.” Conclusion We clarified the contribution of IDs as (epi)genetic causes of SGA-SS and the molecular and phenotypic spectrum of SRS. Various IDs constitute underlying factors for SGA-SS, including SRS.

scholarly journals Paternal Uniparental Isodisomy of Chromosome 2 in a Patient with CNGA3-Associated Autosomal Recessive Achromatopsia

2021 ◽  
Vol 22 (15) ◽  
pp. 7842
Author(s):  
Susanne Kohl ◽  
Britta Baumann ◽  
Francesca Dassie ◽  
Anja K. Mayer ◽  
Maria Solaki ◽  
...  
Keyword(s):  
Segregation Analysis ◽  
Molecular Genetic ◽  
Retinal Disease ◽  
Underlying Mechanism ◽  
Recurrence Risk ◽  
Molecular Genetic Analysis ◽  
Recessive Mutation ◽  
Chromosome 2 ◽  
Inherited Retinal Disease ◽  
Uniparental Isodisomy

Achromatopsia (ACHM) is a rare autosomal recessively inherited retinal disease characterized by congenital photophobia, nystagmus, low visual acuity, and absence of color vision. ACHM is genetically heterogeneous and can be caused by biallelic mutations in the genes CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, or ATF6. We undertook molecular genetic analysis in a single female patient with a clinical diagnosis of ACHM and identified the homozygous variant c.778G>C;p.(D260H) in the CNGA3 gene. While segregation analysis in the father, as expected, identified the CNGA3 variant in a heterozygous state, it could not be displayed in the mother. Microsatellite marker analysis provided evidence that the homozygosity of the CNGA3 variant is due to partial or complete paternal uniparental isodisomy (UPD) of chromosome 2 in the patient. Apart from the ACHM phenotype, the patient was clinically unsuspicious and healthy. This is one of few examples proving UPD as the underlying mechanism for the clinical manifestation of a recessive mutation in a patient with inherited retinal disease. It also highlights the importance of segregation analysis in both parents of a given patient or especially in cases of homozygous recessive mutations, as UPD has significant implications for genetic counseling with a very low recurrence risk assessment in such families.

Future directions for the discovery of antibiotics from actinomycete bacteria

2017 ◽  
Vol 1 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Rebecca Devine ◽  
Matthew I. Hutchings ◽  
Neil A. Holmes
Keyword(s):  
New Technologies ◽  
Gene Clusters ◽  
Biosynthetic Gene Clusters ◽  
Future Directions ◽  
Streptomyces Species ◽  
Genus Streptomyces ◽  
New Antibiotics ◽  
The Uk ◽  
Almost All ◽  
New Generation

Antimicrobial resistance (AMR) is a growing societal problem, and without new anti-infective drugs, the UK government-commissioned O'Neil report has predicted that infectious disease will claim the lives of an additional 10 million people a year worldwide by 2050. Almost all the antibiotics currently in clinical use are derived from the secondary metabolites of a group of filamentous soil bacteria called actinomycetes, most notably in the genus Streptomyces. Unfortunately, the discovery of these strains and their natural products (NPs) peaked in the 1950s and was then largely abandoned, partly due to the repeated rediscovery of known strains and compounds. Attention turned instead to rational target-based drug design, but this was largely unsuccessful and few new antibiotics have made it to clinic in the last 60 years. In the early 2000s, however, genome sequencing of the first Streptomyces species reinvigorated interest in NP discovery because it revealed the presence of numerous cryptic NP biosynthetic gene clusters that are not expressed in the laboratory. Here, we describe how the use of new technologies, including improved culture-dependent and -independent techniques, combined with searching underexplored environments, promises to identify a new generation of NP antibiotics from actinomycete bacteria.

scholarly journals Genetics, Diagnosis, and Management of Hürthle Cell Thyroid Neoplasms

2021 ◽  
Vol 12 ◽  
Author(s):  
David G. McFadden ◽  
Peter M. Sadow
Keyword(s):  
Molecular Genetic ◽  
Thyroid Neoplasms ◽  
Invasive Disease ◽  
Thyroid Tumor ◽  
Molecular Testing ◽  
Cell Adenoma ◽  
Tumor Subtypes ◽  
Hürthle Cell ◽  
Hürthle Cell Tumors ◽  
Widely Invasive

Hürthle cell lesions have been a diagnostic conundrum in pathology since they were first recognized over a century ago. Controversy as to the name of the cell, the origin of the cell, and even which cells in particular may be designated as such still challenge pathologists and confound those treating patients with a diagnosis of “Hürthle cell” anything within the diagnosis, especially if that anything is a sizable mass lesion. The diagnosis of Hürthle cell adenoma (HCA) or Hürthle cell carcinoma (HCC) has typically relied on a judgement call by pathologists as to the presence or absence of capsular and/or vascular invasion of the adjacent thyroid parenchyma, easy to note in widely invasive disease and a somewhat subjective diagnosis for minimally invasive or borderline invasive disease. Diagnostic specificity, which has incorporated a sharp increase in molecular genetic studies of thyroid tumor subtypes and the integration of molecular testing into preoperative management protocols, continues to be challenged by Hürthle cell neoplasia. Here, we provide the improving yet still murky state of what is known about Hürthle cell tumor genetics, clinical management, and based upon what we are learning about the genetics of other thyroid tumors, how to manage expectations, by pathologists, clinicians, and patients, for more actionable, precise classifications of Hürthle cell tumors of the thyroid.

DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR IN CHILDREN: MR CHARACTERISTICS, CLINICAL FEATURES AND OUTCOME. FOUR CLINICAL CASES

2021 ◽  
Vol 20 (1) ◽  
pp. 42-55
Author(s):  
A. F. Valiakhmetova ◽  
L. I. Papusha ◽  
A. V. Artemov ◽  
G. V. Tereshchenko ◽  
E. A. Sal’nikova ◽  
...  
Keyword(s):  
Fusion Gene ◽  
Molecular Genetic ◽  
Complete Response ◽  
Mek Inhibitor ◽  
Braf V600e ◽  
Glioneuronal Tumor ◽  
Molecular Testing ◽  
Genetic Characteristics ◽  
Diffuse Leptomeningeal Glioneuronal Tumor ◽  
Braf Fusion

Background. Diffuse leptomeningeal glioneuronal tumor (DLGNT) is an extremely rare entity first officially recognized in 2016 WHO classification of tumors of the central nervous system. Magnetic resonance imaging (MRI) of this tumor usually visualizes diffuse meningeal infiltration with contrast enhancement, with the presence of multiple small contrast‑negative cysts, visible mainly in the T2 images. The main molecular markers of DLGNTs include the KIAA1549-BRAF fusion gene, BRAF V600E substitution is less common.The aim of this work is to describe the manifestation of DLGNT, its neuroimaging and molecular genetic characteristics, the experience of using anti‑BRAF and anti‑MEK therapy.Materials and methods. In this article are described four cases of DLGNT. The first patient with the presence of the KIAA1549-BRAF fusion in the tumor tissue received a full course of SIOP‑LGG / 2004 chemotherapy (carbo‑ platin and vincristine), the stabilization of the disease on the MRI remains for 4 years after completion of treatment. Second patient with KIAA1549-BRAF fusion gene in tumour tissue received MEK inhibitor trametinib as first line of treatment with the stabilization of the disease on control MRI which last for 2 years. A third patient with a mutation in the BRAF V600E gene. After disease progression on standard chemotherapy (carboplatin and vincristine) according to the SIOP‑LGG / 2004 protocol, anti‑BRAF therapy with vemurafenib was prescribed. After 10 months on MRI a complete response was recorded, which persists during the drug intake for 2.5 years. In the fourth patient, no molecular genetic aberrations were detected; a refractory / progressive course of the dis‑ ease was noted. To date, the stabilization of the disease is recorded on the fourth line of chemotherapy (everoli‑ mus and temozolomide).Conclusion. Given the rarity of this tumor and the lack of consensus about therapy, despite the limited number of observations, our experience allows us to recommend molecular testing of DLGNT to detect activating events in the BRAF gene, as well as consideration of anti‑BRAF / MEK therapy if either the BRAF V600E mutation is de‑ tected or KIAA1549-BRAF fusion.

Endophenotypes

2018 ◽  
pp. 103-106
Author(s):  
David C. Glahn ◽  
Laura Almasy ◽  
John Blangero
Keyword(s):  
Mental Illness ◽  
Genetic Variation ◽  
Psychiatric Disorders ◽  
Genetic Locus ◽  
Molecular Genetic ◽  
Gene Discovery ◽  
Psychiatric Diagnoses ◽  
Behavioral Syndrome ◽  
Molecular Genetic Variation ◽  
Or Gene

Endophenotypes are traits that, while genetically related to an illness, are not used for diagnoses (e.g., a symptom). It is unlikely that specific genes directly code for any of our current psychiatric diagnoses. Rather, genes influence neurobiological processes that either increase or decrease risk for mental illness. One use of an endophenotype is to help characterize a genetic locus or gene previously identified as conferring risk for a particular illness. In this context, endophenotypes help to bridge the gap between a behavioral syndrome and molecular genetic variation. Alternately, endophenotypes can be used for novel locus or gene discovery, particularly when used in multivariate analyses. In this chapter, we define endophenotypes and describe different ways they have been applied to aid our understanding of the genetic architecture of psychiatric disorders.

Molecular Genetic Causes and Clinical Description of Branchio-Oto-renal Syndrome

2019 ◽  
Vol 55 (5) ◽  
pp. 630-638 ◽  
Author(s):  
O. L. Mironovich ◽  
E. A. Bliznetz ◽  
T. G. Markova ◽  
N. N. Alekseeva ◽  
T. I. Golybeva ◽  
...  
Keyword(s):  
Molecular Genetic ◽  
Genetic Causes ◽  
Clinical Description

scholarly journals Bioinformatics Discovery of Putative Enhancers within Mouse Odorant Receptor Gene Clusters

2019 ◽  
Vol 44 (9) ◽  
pp. 705-720
Author(s):  
James E Farber ◽  
Robert P Lane
Keyword(s):  
Odorant Receptor ◽  
Receptor Gene ◽  
Gene Clusters ◽  
Small Subset ◽  
Histone 3 ◽  
Large Size ◽  
Dnase Hypersensitivity ◽  
Or Gene ◽  
Or Genes ◽  
Flanking Regions

Abstract Olfactory neuronal function depends on the expression and proper regulation of odorant receptor (OR) genes. Previous studies have identified 54 putative intergenic enhancers within or flanking 40 mouse OR clusters. At least 2 of these putative enhancers have been shown to regulate the expression of a small subset of proximal OR genes. In recognition of the large size of the mouse OR gene family (~1400 OR genes distributed across multiple chromosomal loci), it is likely that there remain many additional not-as-yet discovered OR enhancers. We utilized 23 of the previously identified enhancers as a training set (TS) and designed an algorithm that combines a broad range of epigenetic criteria (histone-3-lysine-4 monomethylation, histone-3-lysine-79 trimethylation, histone-3-lysine-27 acetylation, and DNase hypersensitivity) and genetic criteria (cross-species sequence conservation and transcription-factor binding site enrichment) to more broadly search OR gene clusters for additional candidates. We identified 181 new candidate enhancers located at 58 (of 68) mouse OR loci, including 25 new candidates identified by stringent search criteria whose signal strengths are not significantly different from the 23 previously characterized OR enhancers used as the TS. Additionally, we compared OR enhancer versus generic enhancer features in order to evaluate likelihoods that new enhancer candidates specifically function in OR regulation. We found that features distinguishing OR-specific function are significantly more evident for enhancer candidates located within OR clusters as compared with those in flanking regions.

Hereditary Hemochromatosis Since Discovery of the HFE Gene

2001 ◽  
Vol 47 (7) ◽  
pp. 1147-1156 ◽  
Author(s):  
Elaine Lyon ◽  
Elizabeth L Frank
Keyword(s):  
Molecular Genetic ◽  
Hereditary Hemochromatosis ◽  
Phenotypic Expression ◽  
Protein Product ◽  
Population Screening ◽  
The Body ◽  
Hfe Gene ◽  
Molecular Testing ◽  
Disease Mechanism ◽  
Biochemical Tests

Abstract Background: Hereditary hemochromatosis is an inherited disorder of iron metabolism that is characterized by excessive iron deposition in major organs of the body. Chronic increased iron absorption leads to multiorgan dysfunction. Since the discovery of the gene responsible for the majority of cases, research has progressed rapidly to identify the gene product, the effects of mutations, and the implications for different populations. The protein product of the HFE gene is a transmembrane glycoprotein, termed HFE, that modulates iron uptake. Mutations in the HFE protein compromise its function and produce disease symptoms. Two mutations, C282Y and H63D, have been linked to the majority of disease cases. Approach: We reviewed the recent literature for the molecular basis of hereditary hemochromatosis. Genotypic information was combined with biochemical and clinical phenotypic information to achieve a better understanding of the disease mechanism. Content: This review provides a comprehensive discussion of known mutations in the HFE gene and their phenotypic expression. Diagnostic criteria using molecular genetic techniques in conjunction with traditional biochemical tests are provided. Current methods and limitations of molecular testing are examined in detail. A strategy for population screening and an algorithm for diagnosis that incorporates molecular testing are presented. Treatment by therapeutic phlebotomy and the use of blood obtained from hemochromatosis patients are discussed. Summary: Although the disease mechanism has not been completely elucidated, phenotypic and penetrance data are becoming available. Controversy still exists concerning the role of genetic testing in diagnosis and population screening.

scholarly journals Population Genomic Evidence Reveals Subtle Patterns of Differentiation in the Trophically Polymorphic Cuatro Ciénegas Cichlid, Herichthys minckleyi

2019 ◽  
Vol 110 (3) ◽  
pp. 361-369 ◽  
Author(s):  
Katherine L Bell ◽  
Chris C Nice ◽  
Darrin Hulsey
Keyword(s):  
Gene Flow ◽  
Biological Diversity ◽  
Molecular Genetic ◽  
Molecular Ecology ◽  
Cichlid Fish ◽  
Genome Wide ◽  
A Genome ◽  
The Face ◽  
Or Gene ◽  
Herichthys Minckleyi

Abstract In recent decades, an increased understanding of molecular ecology has led to a reinterpretation of the role of gene flow during the evolution of reproductive isolation and biological novelty. For example, even in the face of ongoing gene flow strong selection may maintain divergent polymorphisms, or gene flow may introduce novel biological diversity via hybridization and introgression from a divergent species. Herein, we elucidate the evolutionary history and genomic basis of a trophically polymorphic trait in a species of cichlid fish, Herichthys minckleyi. We explored genetic variation at 3 hierarchical levels; between H. minckleyi (n = 69) and a closely related species Herichthys cyanoguttatus (n = 10), between H. minckleyi individuals from 2 geographic locations, and finally between individuals with alternate morphotypes at both a genome-wide and locus-specific scale. We found limited support for the hypothesis that the H. minckleyi polymorphism is the result of ongoing hybridization between the 2 species. Within H. minckleyi we found evidence of geographic genetic structure, and using traditional population genetic analyses found that individuals of alternate morphotypes within a pool appear to be panmictic. However, when we used a locus-specific approach to examine the relationship between multi-locus genotype, tooth size, and geographic sampling, we found the first evidence for molecular genetic differences between the H. minckleyi morphotypes.

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