Aetiology of MDS: With a Focus on Hereditary Predisposition

Myelodysplastic syndromes affect an older age group with a median age at onset in the eighth decade of life. As such, there is a relationship between the pathogenesis of MDS and age-related processes affecting haematopoietic stem/progenitor cells and/or the bone marrow microenvironment. MDS with an onset in younger people may be associated with recognised hereditary myeloid malignancy syndromes, and ‘forme fruste’ presentations of inherited syndromes in later life are now increasingly recognised such as germline mutations in DDX41. The considerable clinical and research interest in hereditary disorders is reflected in the relative emphasis within our manuscript. Prior chemo/radiotherapy is a clear cause of MDS but the predisposition factors for therapy-related MDS remain unclear. Clonal haematopoiesis is common in older people and may evolve to MDS, although once again, the biological factors driving this evolution are largely unknown. Finally, environmental exposure to genotoxic agents is likely to play only a minor role in the contemporary occupational/recreational setting.

Overview on Pediatric Myelodysplastic Syndrome: A Review

Myelodysplastic syndrome (MDS) is a set of clonal bone marrow diseases in children that are characterised by peripheral cytopenia, dysplastic alterations in the bone marrow, and inefficient hematopoiesis. MDS is uncommon in children, with just 1-4 occurrences per million children afflicted. Adults, particularly the elderly, are more susceptible to the disease. Some hereditary disorders, such as Fanconi's anaemia, Shwachman's, and Down's syndromes, are known to predispose children to developing MDS. JCML and monosomy 7 syndrome are the two most frequent paediatric MDS types, both of which affect children in their early years. Approximately 20% of juvenile myelodysplastic syndrome (MDS) cases are discovered by chance during normal laboratory testing or during the course of a suspected hereditary bone marrow failure (IBMF). Differentiating MDS with low blast numbers from aplastic anaemia (AA) and MDS with excess blasts from AML are the two key diagnostic issues in this condition. Bone marrow transplantation and stem cell transplantation is the treatment of choice in most cases. In this article we discuss the disease epidemiology, diagnosis, and treatment.

The Possible Role of Herpesviruses in the Pathogenesis of Coronary Atherosclerosis

Cardiovascular diseases are still the dominant cause of death worldwide. Coronary artery disease (CAD) is the most common type of heart disease and the leading cause of death for both men and women. Coronary atherosclerosis underlies multiple clinical manifestations ranging from asymptomatic to stable angina, acute coronary syndrome, MI, heart failure, and sudden cardiac death. The prerequisites for a closer study of the pathogenesis of the atherosclerotic process were the development of atherosclerotic vascular lesions at a younger age and the rapid progression of the process. Currently, it is generally accepted that CAD is a multifactorial disease. Attention is drawn to hereditary disorders of the receptor apparatus, endothelial dysfunction, and lipid metabolism disorders. In addition, latent viral infections are one of the etiopathogenetic factors in the development of atherosclerosis. A number of scientific studies have confirmed the relationship between infectious agents and the development of atherosclerotic vascular lesions. The viral etiology of the development and progression of atherosclerosis is the subject of debate among scientists around the world.

Prime Editing for Inherited Retinal Diseases

Inherited retinal diseases (IRDs) are chronic, hereditary disorders that lead to progressive degeneration of the retina. Disease etiology originates from a genetic mutation—inherited or de novo—with a majority of IRDs resulting from point mutations. Given the plethora of IRDs, to date, mutations that cause these dystrophies have been found in approximately 280 genes. However, there is currently only one FDA-approved gene augmentation therapy, Luxturna (voretigene neparvovec-rzyl), available to patients with RPE65-mediated retinitis pigmentosa (RP). Although clinical trials for other genes are underway, these techniques typically involve gene augmentation rather than genome surgery. While gene augmentation therapy delivers a healthy copy of DNA to the cells of the retina, genome surgery uses clustered regularly interspaced short palindromic repeats (CRISPR)-based technology to correct a specific genetic mutation within the endogenous genome sequence. A new technique known as prime editing (PE) applies a CRISPR-based technology that possesses the potential to correct all twelve possible transition and transversion mutations as well as small insertions and deletions. EDIT-101, a CRISPR-based therapy that is currently in clinical trials, uses double-strand breaks and nonhomologous end joining to remove the IVS26 mutation in the CEP290 gene. Preferably, PE does not cause double-strand breaks nor does it require any donor DNA repair template, highlighting its unparalleled efficiency. Instead, PE uses reverse transcriptase and Cas9 nickase to repair mutations in the genome. While this technique is still developing, with several challenges yet to be addressed, it offers promising implications for the future of IRD treatment.

Phenotypic Variability of MEGF10 Variants Causing Congenital Myopathy: Report of Two Unrelated Patients from a Highly Consanguineous Population

Congenital myopathies are rare neuromuscular hereditary disorders that manifest at birth or during infancy and usually appear with muscle weakness and hypotonia. One of such disorders, early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD, OMIM: 614399, MIM: 612453), is a rare autosomal recessive disorder caused by biallelic mutations (at homozygous or compound heterozygous status) in MEGF10 (multiple epidermal growth factor-like domains protein family). Here, we report two unrelated patients, who were born to consanguineous parents, having two novel MEGF10 deleterious variants. Interestingly, the presence of MEGF10 associated EMARDD has not been reported in Saudi Arabia, a highly consanguineous population. Moreover, both variants lead to a different phenotypic onset of mild and severe types. Our work expands phenotypic features of the disease and provides an opportunity for genetic counseling to the inflicted families.

Guidelines for pre-analytical conditions for assessing the methylation of circulating cell-free DNA

Methylation analysis of circulating cell-free DNA (cirDNA), as a liquid biopsy, has a significant potential to advance the detection, prognosis, and treatment of cancer, as well as many genetic disorders. The role of epigenetics in disease development has been reported in several hereditary disorders, and epigenetic modifications are regarded as one of the earliest and most significant genomic aberrations that arise during carcinogenesis. Liquid biopsy can be employed for the detection of these epigenetic biomarkers. It consists of isolation (pre-analytical) and detection (analytical) phases. The choice of pre-analytical variables comprising cirDNA extraction and bisulfite conversion methods can affect the identification of cirDNA methylation. Indeed, different techniques give a different return of cirDNA, which confirms the importance of pre-analytical procedures in clinical diagnostics. Although novel techniques have been developed for the simplification of methylation analysis, the process remains complex, as the steps of DNA extraction, bisulfite treatment, and methylation detection are each carried out separately. Recent studies have noted the absence of any standard method for the pre-analytical processing of methylated cirDNA. We have therefore conducted a comprehensive and systematic review of the important pre-analytical and analytical variables and the patient-related factors which form the basis of our guidelines for analyzing methylated cirDNA in liquid biopsy.

CDKN2A-Mutated Pancreatic Ductal Organoids from Induced Pluripotent Stem Cells to Model a Cancer Predisposition Syndrome

Patient-derived induced pluripotent stem cells (iPSCs) provide a unique platform to study hereditary disorders and predisposition syndromes by resembling germline mutations of affected individuals and by their potential to differentiate into nearly every cell type of the human body. We employed plucked human hair from two siblings with a family history of cancer carrying a pathogenic CDKN2A variant, P16-p.G101W/P14-p.R115L, to generate patient-specific iPSCs in a cancer-prone ancestry for downstream analytics. The differentiation capacity to pancreatic progenitors and to pancreatic duct-like organoids (PDLOs) according to a recently developed protocol remained unaffected. Upon inducible expression of KRASG12Dusing a piggyBac transposon system in CDKN2A-mutated PDLOs, we revealed structural and molecular changes in vitro, including disturbed polarity and epithelial-to-mesenchymal (EMT) transition. CDKN2A-mutated KRASG12DPDLO xenotransplants formed either a high-grade precancer lesion or a partially dedifferentiated PDAC-like tumor. Intriguingly, P14/P53/P21 and P16/RB cell-cycle checkpoint controls have been only partly overcome in these grafts, thereby still restricting the tumorous growth. Hereby, we provide a model for hereditary human pancreatic cancer that enables dissection of tumor initiation and early development starting from patient-specific CDKN2A-mutated pluripotent stem cells.

Osteoarticular system in children with bad posture on the background of hereditary disorders of connective tissue development

The authors of the presented article analyze the pathological manifestations of the osteoarticular system against the background of an existing hereditary disorder of the development of connective tissue. In addition, other changes in the internal organs and the hematopoietic system have been studied. On the basis of the city children's polyclinic, 125 children were registered with a diagnosis of bad posture in the frontal plane against the background of hereditary disorders of the development of connective tissue. They were included in the main group. 30 children of the same age and gender presented a comparison group with a diagnosis of bad posture in the frontal plane without hereditary impairment of connective tissue development. The dynamic observation involved 30 healthy children as a control group. Changes were observed among children of preschool age at preventive examinations in kindergartens, scheduled outpatient visits. Hypotension of the muscles that straighten the spine and bad posture was diagnosed.