An Unusual Case of Lynch Syndrome.

Lynch syndrome is the most common cause of hereditary colorectal cancer. It usually develops asymptomatically until symptoms related to colorectal carcinoma appear, such as gastrointestinal bleeding, abdominal pain, and changes in bowel habits and/or stool characteristics. Oftentime, when these clinical signs and symptoms are not present, the diagnosis becomes challenging. We present the clinical case of a 69-year-old woman, adopted, with no known previous history, who presented to the emergency department with low back pain, without irradiation, that had been going on for three days, associated with inflammatory signs in the right hip region. There were no urinary or sensory alterations and no recent trauma. She was initially discharged with antibiotherapy with the diagnosis of hip cellulitis. As the symptoms continued and the inflammation spread to the right lower limb, she returned to the emergency department. A CT scan revealed an abscess (17 cm) in the right buttock, complicated by necrotizing fasciitis due to fistulization from a tumor in the right colon. She underwent an exploratory laparotomy, which identified a neoplasm of the ascending colon, adherent to the abdominal wall, in the right lumbar region. Right hemicolectomy and drainage of the right buttock/thigh abscess were performed. The histology was compatible with invasive adenocarcinoma, with high-grade dysplasia but well differentiated, pT3G1N0. The immunohistochemistry was suggestive of Lynch syndrome.

Gene therapy: principles, challenges and use in clinical practice.

INTRODUCTION: Gene therapy is an emerging topic in medicine. The first products have already been licensed in the European Union for the treatment of immune deficiency, spinal muscular atrophy, hemophilia, retinal dystrophy, a rare neurotransmitter disorder and some hematological cancers, while many more are being assessed in preclinical and clinical trials. OBJECTIVE: The purpose of this review is to provide an overview of the core principles of gene therapy along with information on challenges and risks. Benefits, adverse effects and potential risks are illustrated based on the examples of hemophilia and spinal muscular atrophy. RESULTS: At present, in-vitro and in-vivo gene addition or gene augmentation is the most commonly established type of gene therapy. More recently, more sophisticated and precise approaches such as in situ gene editing have moved into focus. However, all types of gene therapy require long-term observation of treated patients to ensure safety, efficacy, predictability and durability. Important safety concerns include immune reactions to the vector, the foreign DNA or the new protein resulting from gene therapy, and a remaining low cancer risk based on insertional mutagenesis. Ethical and regulatory issues need to be addressed, and new reimbursement models are called for to ease the financial burden that this new treatment poses for the health care system. CONCLUSION: Gene therapy holds great promise for considerable improvement or even cure of genetic diseases with serious clinical consequences. However, a number of questions and issues need to be clarified to ensure broad accessibility of safe and efficacious products.

Clinical and Demographic Characteristics of Pyruvate Kinase Deficiency Patients: A Comprehensive Case Series Analysis.

Introduction Pyruvate kinase deficiency (PKD) is a rare autosomal recessive disorder characterized by mutations in the PKLR gene, causing impaired glycolysis in red blood cells and leading to diverse clinical manifestations. The prevalence of PKD in Saudi Arabia remains understudied, particularly in the context of consanguinity and non-specialized medical facilities. Methods We conducted a retrospective analysis of seven PKD patients of Arab ethnicity, focusing on demographics, medical history, clinical features, laboratory results, treatments, and outcomes. Results Our patient cohort comprised five males and two females, aged 10 to 38 years, of Arab ethnicity. Consanguinity was prevalent, and hereditary connections were identified in five patients. PKD exhibited varying clinical presentations, with early-onset symptoms including neonatal jaundice and symptomatic anemia. One patient experienced severe hepatic disease progression leading to multiorgan failure. Blood transfusions were universally required, indicating the severity of the disorder. Anemia severity varied among patients, with diverse hematological irregularities. Splenectomy was performed for most patients, improving hemoglobin levels and transfusion needs in some cases. Iron chelation was administered, although iron overload persisted. Thrombocytosis and venous thromboembolism were observed post splenectomy. Jaundice and gallstones were common, leading to cholecystectomy. Laboratory findings remained consistent, with heightened reticulocyte counts and altered enzyme levels. Discussion PKD is a rare disorder characterized by diverse clinical manifestations. Prevalence estimation is complex due to various factors, and its diagnosis is challenged by clinical similarities with other disorders. Our cohort exhibited a spectrum of complications, highlighting the necessity for tailored interventions. Iron overload remained a concern, necessitating continuous monitoring. Although endocrine disorders and osteoporosis were absent in our cohort, vigilance is essential due to the disease's progressive nature. Genetic factors were prominent, supporting the genetic basis of PKD. Splenectomy improved anemia but had a limited impact on gallstones. Iron overload management and bone health remain crucial considerations. Conclusion This study offers comprehensive insights into the clinical and demographic characteristics of PKD patients, illustrating the complex nature of the disorder. The findings underscore the need for personalized management strategies and vigilant monitoring to address the diverse clinical manifestations and challenges associated with PKD.

Diagnostic and therapeutic value of human serpin family proteins.

SERPIN (serine proteinase inhibitors) is an acronym for the superfamily of structurally similar proteins found in animals, plants, bacteria, viruses, and archaea. Over 1500 SERPINs are known in nature, while only 37 SERPINs are found in humans, which participate in inflammation, coagulation, angiogenesis, cell viability, and other pathophysiological processes. Both qualitative or quantitative deficiencies or overexpression and/or abnormal accumulation of SERPIN can lead to diseases commonly referred to as "serpinopathies". Hence, strategies involving SERPIN supplementation, elimination, or correction are utilized and/or under consideration. In this review, we discuss relationships between certain SERPINs and diseases as well as putative strategies for the clinical explorations of SERPINs.

[Early differential diagnosis and restorative treatment of cerebral palsy]. / Rannyaya differentsial'naya diagnostika i vosstanovitel'noe lechenie patsientov s detskim tserebral'nym paralichom.

The article is devoted to an urgent problem of modern neurology - early diagnosis and complex restorative treatment of cerebral palsy (cerebral palsy). Etiological factors and pathogenetic aspects of the formation of various forms of cerebral palsy are considered in detail, as well as modern possibilities of differential diagnosis in children of the first years of life of cerebral palsy and a wide range of pathological conditions (somatic, endocrine, hereditary-conditioned, including hereditary-metabolic and neuromuscular diseases). The leading directions of complex rehabilitation of cerebral palsy are widely presented, taking into account modern standards and clinical recommendations. The high efficacy of the drug Cortexin has been shown, due to its positive multimodal action (stimulation of the processes of neuropreparation, neuroprotection, neuroplasticity) in the treatment of motor, cognitive and autonomic disorders in children with perinatal lesions of the central nervous system and cerebral palsy.

Public perceptions of genomic studies and hereditary diseases in Aari community, South Omo Zone, Ethiopia.

BACKGROUND: Genetic and genomic research is revolutionizing precision medicine; however, addressing ethical and cultural aspects is crucial to ensure ethical conduct and respect for community values and beliefs. This study explored the beliefs, perceptions and concerns of the Aari community in South Ethiopia regarding genetic concepts, hereditary diseases and ethical research practices related to sample collection, storage and sharing. METHODS: In-depth interviews and focus group discussions were conducted with community elders, health officials, tuberculosis patients and apparently healthy individuals. Data were thematically analysed using MAXQDA software. RESULTS: Participants identified diseases such as podoconiosis, leprosy, goitre and epilepsy as hereditary and perceived some as 'curses' due to generational impact and social stigma. Disease susceptibility was attributed to divine intervention or factors such as malnutrition and sanitation. Although hereditary diseases were considered unavoidable, in some cases environmental factors were acknowledged. Participants shared personal examples to demonstrate inheritance concepts. Blood held cultural significance, and concerns about its potential misuse resulted in scepticism towards giving samples. CONCLUSIONS: This study emphasizes the significance of comprehending local beliefs and perceptions and stresses the need to establish effective communication, build trust and address underlying causes of hesitancy to improve recruitment and ensure ethical conduct.

Monitoring of recessive defects associated with low reproductive performance in dairy cattle in Uruguay.

Background: Most dairy cattle breeds originate show an average generational inbreeding rate of 1%, which favors the occurrence of recessive defects associated with low reproductive performance. Aim: The objective of this study was to monitor recessive defects associated with low reproductive performance in dairy cattle. Methods: To monitor bulls carrying the Holstein Friesian haplotype (HH) 1, HH3, and HH4 haplotypes, we analyzed the records of 3,028 national and imported Holstein Friesian bulls from the 2021 updated sires' catalog published by "Evaluaciones Genéticas Lecheras"; and to determine the presence of these mentioned haplotypes, as well as Jersey haplotype (JH) 1 and complex vertebral malformation (CVM), were genotype with the GeneTitan® 2,500 single nucleotide polymorphism (SNP) bovine chip, estimate their frequencies and evaluate their impact on the fertility of 100 Holstein Friesian cows and 70 Holstein Friesian-Jersey crosses belonging to an experimental dairy. Results: From a total of 1,468 (48.5%) bulls with genetic information from the sires' catalog for HH1 and 1,471 (48.6%) for HH3 and HH4, we found 90 (6.1%) carriers for HH1, 60 (4.1%) for HH3, and 6 (0.4%) for HH4, respectively. By genotyping with the chip, we calculated the herd frequency of the mutant alleles and herd prevalence of carriers for HH1 and CVM as q = 0.003 and 0.022; 0.59% and 4.3% (call rate >0.99), respectively. No mutant alleles were found for HH3, HH4, and JH1 in the analyzed population. We examined reproductive data by observing the presence of CVM and HH1 mutant alleles in repeat cows with an average of four services to achieve pregnancy. Conclusion: This study demonstrated the presence of recessive defects associated with low reproductive performance in the analyzed population, which can affect the health and productivity of dairy cattle. Therefore, cows and bulls should be closely monitored through genetic testing to lower the incidence of recessive defects in dairy cattle.

Genetic testing in focal segmental glomerulosclerosis: in whom and when?

Background: Genetic causes are increasingly recognized in patients with focal segmental glomerulosclerosis (FSGS), but it remains unclear which patients should undergo genetic study. Our objective was to determine the frequency and distribution of genetic variants in steroid-resistant nephrotic syndrome FSGS (SRNS-FSGS) and in FSGS of undetermined cause (FSGS-UC). Methods: We performed targeted exome sequencing of 84 genes associated with glomerulopathy in patients with adult-onset SRNS-FSGS or FSGS-UC after ruling out secondary causes. Results: Seventy-six patients met the study criteria; 24 presented with SRNS-FSGS and 52 with FSGS-UC. We detected FSGS-related disease-causing variants in 27/76 patients (35.5%). There were no differences between genetic and non-genetic causes in age, proteinuria, glomerular filtration rate, serum albumin, body mass index, hypertension, diabetes or family history. Hematuria was more prevalent among patients with genetic causes. We found 19 pathogenic variants in COL4A3-5 genes in 16 (29.3%) patients. NPHS2 mutations were identified in 6 (16.2%) patients. The remaining cases had variants affecting INF2, OCRL, ACTN4 genes or APOL1 high-risk alleles. FSGS-related genetic variants were more common in SRNS-FSGS than in FSGS-UC (41.7% vs 32.7%). Four SRNS-FSGS patients presented with NPHS2 disease-causing variants. COL4A variants were the most prevalent finding in FSGS-UC patients, with 12 patients carrying disease-causing variants in these genes. Conclusions: FSGS-related variants were detected in a substantial number of patients with SRNS-FSGS or FSGS-UC, regardless of age of onset of disease or the patient's family history. In our experience, genetic testing should be performed in routine clinical practice for the diagnosis of this group of patients.

Chinese experts' consensus guideline on preimplantation genetic testing of monogenic disorders.

Recent developments in molecular biological technologies and genetic diagnostic methods, accompanying with updates of relevant terminologies, have enabled the improvements of new strategies of preimplantation genetic testing for monogenic (single gene) disorders (PGT-M) to prevent the transmission of inherited diseases. However, there has been much in the way of published consensus on PGT-M. To properly regulate the application of PGT-M, Chinese experts in reproductive medicine and genetics have jointly developed this consensus statement. The consensus includes indications for patient selection, genetic and reproductive counseling, informed consent, diagnostic strategies, report generation, interpretation of results and patient follow-ups. This consensus statement serves to assist in establishment of evidence-based clinical and laboratory practices for PGT-M.

Cryptic splice mutation in the fumarate hydratase gene in patients with clinical manifestations of Hereditary Leiomyomatosis and Renal Cell Cancer.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant condition characterized by the development of cutaneous and uterine leiomyomas and risk for development of an aggressive form of papillary renal cell cancer. HLRCC is caused by germline inactivating pathogenic variants in the fumarate hydratase (FH) gene, which encodes the enzyme that catalyzes the interconversion of fumarate and L-malate. We utilized enzyme and protein mobility assays to evaluate the FH enzyme in a cohort of patients who showed clinical manifestations of HLRCC but were negative for known pathogenic FH gene variants. FH enzyme activity and protein levels were decreased by 50% or greater in three family members, despite normal FH mRNA expression levels as measured by quantitative PCR. Direct Nanopore RNA sequencing demonstrated 57 base pairs of retained intron sequence between exons 9 and 10 of polyadenylated FH mRNA in these patients, resulting in a truncated FH protein. Genomic sequencing revealed a heterozygous intronic alteration of the FH gene (chr1: 241498239 T/C) resulting in formation of a splice acceptor site near a polypyrimidine tract, and a uterine fibroid obtained from a patient showed loss of heterozygosity at this site. The same intronic FH variant was identified in an unrelated patient who also showed a clinical phenotype of HLRCC. These data demonstrate that careful clinical assessment as well as biochemical characterization of FH enzyme activity, protein expression, direct RNA sequencing, and genomic DNA sequencing of patient-derived cells can identify pathogenic variants outside of the protein coding regions of the FH gene.

Progress and challenges of multidrug resistance proteins in diseases.

Chemotherapy remains the first choice for patients with advanced cancers when other treatments are ineffective. Multidrug resistance (MDR) is an unavoidable factor that negatively affects the effectiveness of cancer chemotherapy drugs. Researchers are trying to reduce MDR, improve the effectiveness of chemotherapeutic drugs, and alleviate patient suffering to positively contribute to disease treatment. MDR also occurs in inflammation and genetic disorders, which increases the difficulty of clinically beneficial treatments. The ATP-binding cassette (ABC) is an active transporter that plays an important role in the barrier and secretory functions of many normal cells. As the C subfamily in the ABC family, multidrug resistance proteins (MRPs/ABCCs) export a variety of antitumour drugs and are expressed in a variety of cancers. The present review summarises the role of MRPs in cancer and other diseases and recent research progress of MRP inhibitors to better examine the mechanism and function of MRPs, and establish a good relationship with clinical treatment.

A Multi-Point View of Genetic Factors Affecting Hereditary Transmissibility of Asthma.

Asthma is a respiratory illness characterized by episodes of bronchial spasm that make breathing difficult. It often has an association with an allergic response or any hypersensitivity followed by inflammation and hypersensitivity of the airways. Asthma is a sophisticated, complicated, and diverse respiratory condition. Even while heredity is a chief hazard factor for developing asthma, environmental and inner exposures, as well as how they interact with genetic variables, also have a substantial impact on the disease's pathogenesis. In recent years, the field of asthma research has seen the emergence and deployment of high throughput omics techniques for the unbiased screening of biomarkers such as genes, transcripts, proteins, and metabolites. Better asthma risk profile has been achieved by utilizing large-scale studies that are illustrative of various population-based data and merging with clinical data. This allergic airway illness has a wide range of phenotypes and endotypes, many of which have not yet been fully defined. The diversity of phenotypes is reflected in similarly complicated etiologies, and it is thought that a number of genetic and environmental variables interrelate to promote the danger of asthma in both children and adults. In order to achieve this objective, significant efforts are necessary to describe different phenotypes, uncover fundamental mechanisms, and find associated biomarkers. It is clear that the analysis, monitoring, and treatment of asthma require a tailored strategy. The risk of developing a multifactorial ailment is characterized by the grade of genetic relationship between the individual and affected relative. Additionally, the risk is typically larger if the relative has a severe illness or was afflicted when they were young. The asthma phenotype is highly varied and expressed non-linearly in contrast to single gene illnesses. This makes it challenging to predict whether someone with a certain gene or set of genotypes would have asthma.

A Rare Phenotype of Inherited Cerebellar Ataxia.

Ataxia is a syndrome of imbalance and incoordination, categorized as hereditary ataxias, degenerative ataxias (non-hereditary), and acquired ataxias. Hereditary ataxia is further classified based on its mode of inheritance. Here, we have reported a case of early-onset autosomal recessive cerebellar ataxia with retained reflexes in a young male with positive family history. A young male presented with ten years history of tremors in both hands and head, aggravated with work and relieved with rest, and imbalance while walking, which has now progressed to the level where the patient cannot walk without support. The patient's younger brother also had a similar history. Central nervous system examination revealed cerebellar ataxia with retained reflexes. After ruling out other causes of ataxia in this age group by investigations, we could make the diagnosis of early-onset cerebellar ataxia with retained tendon reflexes (autosomal recessive). Presenting as a disease of variable presentation, the important diagnostic cues are classification and localization of ataxia. The investigations should be focusing on those cases of ataxias that are treatable. Family history is important to identify hereditary ataxias, as well as in genetic counselling of the affected patients.

Li-Fraumeni Syndrome: A Rare Genetic Disorder.

Li-Fraumeni syndrome (LFS) is an inherited genetic condition that makes individuals predisposed to specific types of cancer. As a result, cancer risk can be passed down from generation to generation. TP53 is the genetic blueprint for a protein called p53 and most commonly causes this condition by mutations or alterations in that gene. Mutations prevent the gene from functioning properly. LFS is associated with TP53 gene mutations in approximately 70% of families. Most patients with LFS have one normal copy of TP53 and one mutated copy of TP53, usually inherited from a parent with the condition. This is a case report of a 40-year-old female who underwent genetic testing to determine her p53 mutation status. Her mother was diagnosed with breast cancer at a young age, despite the fact that her brothers and sisters' genetic tests came out normal. The genetic testing showed her as a carrier for the TP53 gene mutation. Despite the fact that she had no signs or symptoms of any linked tumors associated with the condition, she was diagnosed with LFS.

A survey of protein interactions and posttranslational modifications that influence the polyglutamine diseases.

The presence and aggregation of misfolded proteins has deleterious effects in the nervous system. Among the various diseases caused by misfolded proteins is the family of the polyglutamine (polyQ) disorders. This family comprises nine members, all stemming from the same mutation-the abnormal elongation of a polyQ repeat in nine different proteins-which causes protein misfolding and aggregation, cellular dysfunction and disease. While it is the same type of mutation that causes them, each disease is distinct: it is influenced by regions and domains that surround the polyQ repeat; by proteins with which they interact; and by posttranslational modifications they receive. Here, we overview the role of non-polyQ regions that control the pathogenicity of the expanded polyQ repeat. We begin by introducing each polyQ disease, the genes affected, and the symptoms experienced by patients. Subsequently, we provide a survey of protein-protein interactions and posttranslational modifications that regulate polyQ toxicity. We conclude by discussing shared processes and pathways that bring some of the polyQ diseases together and may serve as common therapeutic entry points for this family of incurable disorders.

Corrigendum: Epidemiology of rare hereditary diseases in the European part of Russia: Point and cumulative prevalence.

[This corrects the article DOI: 10.3389/fgene.2021.678957.].

Epidemiology and Prevention of Renal Cell Carcinoma.

With 400,000 diagnosed and 180,000 deaths in 2020, renal cell carcinoma (RCC) accounts for 2.4% of all cancer diagnoses worldwide. The highest disease burden developed countries, primarily in Europe and North America. Incidence is projected to increase in the future as more countries shift to Western lifestyles. Risk factors for RCC include fixed factors such as gender, age, and hereditary diseases, as well as intervening factors such as smoking, obesity, hypertension, diabetes, diet and alcohol, and occupational exposure. Intervening factors in primary prevention, understanding of congenital risk factors and the establishment of early diagnostic tools are important for RCC. This review will discuss RCC epidemiology, risk factors, and biomarkers involved in reducing incidence and improving survival.

Preanalytical DNA assessment for downstream applications: How to optimize the management of human biospecimens to support molecular diagnosis-An experimental study.

BACKGROUND: The development of next-generation sequencing approaches has accelerated the diagnostic process, although at present, there is a lack of a clear consensus on efficient management of human samples for downstream applications. This study aims to investigate timeframe (in terms of short preservation), temperature, and additional preservation procedures (i.e., freeze and thaw cycles) for human biospecimens to implement the reliability and reproducibility of molecular investigations. METHODS: Overall, 45 whole peripheral bloods, 22 peripheral blood mononuclear cells samples, 15 saliva, and 15 buccal swab biospecimens (through the extracted DNA) were investigated, assessing yield, integrity, amplifiability, and sizing accuracy via the most common molecular techniques. RESULTS: Based on the overall evaluation criteria, the results indicate that DNA extracted from all samples, shortly preserved, have suitable quality and reliable reproducibility to be used in diagnostic activities and biomedical research, even if DNA from peripheral blood mononuclear cells is more affected by the experimental conditions. CONCLUSION: Our findings confirm the reliability of peripheral blood samples in almost all the experimental conditions. Saliva and buccal swabs are efficient almost as well, while peripheral blood mononuclear cells, albeit remain a primary source of DNA for molecular screenings, represent a less efficient source.

Nefronoptisis: reporte de un caso pediátrico / Nephronophthisis: a pediatric case report

La nefronoptisis es una enfermedad renal quística, de herencia autosómica recesiva, causada por mutaciones en genes que codifican proteínas involucradas en la función de cilios primarios, lo que resulta en enfermedad renal y manifestaciones extrarrenales como degeneración retiniana y fibrosis hepática. Según la edad de desarrollo de enfermedad renal crónica terminal, se describen tres formas clínicas de presentación: infantil, juvenil y adolescente. El diagnóstico se realiza por una prueba genética positiva o una biopsia de riñón que demuestre cambios tubulointersticiales crónicos con un engrosamiento de las membranas basales tubulares. No existe hasta la actualidad una terapia curativa, por lo que el trasplante renal oportuno es determinante en cuanto al pronóstico. Se presenta un paciente de 13 meses de edad con poliuria de 3 meses de evolución, insuficiencia renal, anemia y elevación de transaminasas. Con hallazgos histológicos compatibles en la biopsia renal, se arribó al diagnóstico de nefronoptisis infantil, con afectación hepática

Nephronophthisis is an autosomal recessive cystic kidney disease caused by mutations in genes that encode proteins involved in the primary cilia function, resulting in kidney disease and extrarenal manifestations such as retinal degeneration and liver fibrosis. According to the age of development of end-stage chronic kidney disease, three clinical forms of presentation are described: infantile, juvenile and adolescent. Diagnosis is made by a positive genetic test, or a kidney biopsy demonstrating chronic tubulointerstitial changes with thickening of the tubular basement membranes. At the moment there is no healing therapy, so early kidney transplant is a fundamental tool to improve prognosis.We present a 13-month old male patient with polyuria, kidney failure, anemia and elevated aminotransferases over three months. With compatible histological kidney biopsy, the diagnosis of infantile nephronophthisis with liver involvement was reached.