Year 2023, Volume 6 - Issue 1

Background: Accurate diagnosis benefits patients and their families by directing clinical management; predicting recurrence risks; providing prognosis; and preventing the invasive, time-consuming, and costly diagnostic odyssey. The present study aimed at evaluating the usefulness and clinical utility of supplementary testing (deletion/duplication, targeted genome methylation analysis, and whole mitochondrial genome testing) after inconclusive or negative exome results and the outcome of the supplementary testing. Methods: A total of 3,505 clinical exome sequencing results were evaluated, and cases with supplementary testing were analyzed for the accuracy and validity of the supplementary testing. Results: The present study cohort comprised 26 cases where supplementary testing was ordered (12 inconclusive results and 14 negative results). Out of the 12 inconclusive results, only one case was positive for supplementary testing (1/12) and none of the negative cases (0/14). Conclusion: For most cases, supplementary testing to negative exome sequencing failed to identify any possible explanation of the disorder, concluding that supplementary testing has limited clinical utility.

Background: A definite anemia [hemoglobin (HB) 10-12 g/dl] or the need for significantly higher Erythropoietin (EPO) dosages of epoetin alfa are symptoms of EPO resistance, respectively. The recommended restorative goal is to maintain HB levels between 11 and 12 g/dl. Fe deficiency, concurrent inflammation, inadequate dialysis, hyperparathyroidism, hemolysis, vitamin B12, and folate deficiency are the main causes of EPO resistance. The objective of this study was to evaluate patients who receive frequent hemodialysis for EPO resistance. Methods: This study was performed at Sohag University Hospital on 50 hemodialysis patients compared to 40 healthy adult subjects from June 2021 to January 2022. Serum EPO was analyzed by enzyme-linked immunosorbent assay and Angiotensin Converting Enzyme (ACE) rs1799752 polymorphism was assessed using the Genomic TaqMan genotyping test. Results: This study found insignificant relation between EPO Resistance Index (ERI) and diverse ACE genotype groups and para thyroid hormone. A further significant direct proportional relationship was found between ERI and Ferritin. EPO and parathyroid hormone did not show any significant relationship. Conclusion: Considering the non-critical connection between ERI and our components, it is vital to enhance the treatment of anemic patients with chronic kidney diseases to recognize the potential causes of resistance and ponder other variables for resistance before proposing an expanded EPO-stimulating agent administration.

Background: Glycosylphosphatidylinositol (GPI) is a glycolipid containing phosphatidylinositol related to the protein surfaces by covalent attachment. Inherited GPI deficiencies have various phenotypic chrematistics, which range from intellectual disability to dysmorphic features, epilepsy, and other severe anomalies. Methods: Molecular diagnosis was performed using whole exome sequencing (WES) followed by Sanger sequencing. Results: WES revealed a novel homozygous nonsense variant (c.250C>T; p.Gln84Ter) in the exon 2 of the phosphatidylinositol glycan anchor biosynthesis class Ogene that might explain the disease phenotype in the patient. Conclusion: This study will help in proper genetic counselling of the family and help in genotype-phenotype correlation in the future.

Background: Polydactyly or hexadactyly is a familiar limb defect that either occurs as an isolated entity (non-syndromic) or is associated with severe (syndromic) morphological phenotypes. Generally, it appears due to a defect in the anteroposterior patterning during limb development. Methods: Here, we present a proband having non-syndromic post-axial polydactyly (PAP) evaluated using whole exome sequencing followed by Sanger sequencing. Furthermore, 3D protein modeling was executed for the normal and mutated IQ domain-containing protein E (IQCE) gene. Results: WES analysis revealed an already reported bi-allelic variant (c.395-1 G>A) in the IQCE gene, previously associated with PAP 7. Furthermore, 3D modeling revealed significant fluctuations in the IQCE protein secondary structure, thus affecting downstream signaling. Conclusion: The work presented validated the significant role of the IQCE gene in the development and patterning of human limbs.

Background: Preimplantation genetic testing (PGT) is used to identify a pathogenic variant in embryos created through in vitro fertilization. A "variant of uncertain significance" (VOUS) is a genetic variant discovered through genetic testing but with unknown clinical significance. The primary goal is to gauge geneticists' perspectives on performing PGT-M for VOUS in Saudi Arabia, which results in the development of recommendations from higher authorities regarding the criteria of PGT-M in clinical practice. Methods: After reviewing the literature, a cross-sectional study was conducted employing questionnaire developed using survey monkey. The reliability of the questionnaire was assessed in terms of internal consistency and Cronbach's alpha-assessed test-retest. Results: In particular, a total of 96 Saudis and non-Saudis, male and female geneticists, agreed to participate in the study. Out of the 96 geneticists, 56 (59.6%) were female. Most participants were of Saudi origin, with a percentage of (76.6%). The most important finding of this study is that 64% of geneticists opposed performing PGT-M for VOUS. The outcome that 94.5% of geneticists concurred that PGT-M is poorly understood was another noteworthy finding. Conclusion: Future research with a larger sample size is required for performing PGT-M for VOUS, which will help in developing guidelines for PGT-M in Saudi Arabia.

Acid sphingomyelinase deficiency (ASMD) is an autosomal-recessive progressive multiorgan metabolic disorder due to pathogenic variants in the sphingomyelin phosphodiesterase 1 gene. It can lead to death in early childhood in its most severe form. According to previous registries, the birth prevalence of ASMD is nearly 0.4-0.6 per 100,000 live births. The diagnosis of ASMD is usually delayed or missed due to the wide variability of clinical manifestations of the disease. Until recently, the management of ASMD patients was based on symptomatic treatments and supportive care; however, the introduction of enzyme replacement therapy (ERT) has revolutionized the management landscape of ASMD. ERT with a recombinant human Acid Sphingomyelinase Enzyme administered intravenously demonstrated a significant improvement in the non-neuronopathic type of ASMD in phase 2/3 trials. In June 2022, the European Medical Agency granted the ERT, olipudase alfa, marketing authorization. The prevalence of inherited metabolic disorders, including lysosomal storage diseases, is relatively higher in the Arab world than in the rest of the world due to the high consanguinity rate. In this study, we aim to review the current landscape of ASMD in the Gulf Cooperation Council countries and gather insights from experts regarding the roadmap to diagnosis, prevalence, and management approaches of ASMD in the region.

Genetic skeletal disorders (GSDs) are a large group of rare heterogeneous disorders characterized by abnormal development, remodeling, and growth of the human skeleton's cartilage and bones. GSDs have a high spectrum of phenotypes that range from disproportionate short stature (dwarfism) in childhood to osteoarthritis in old age. According to the latest nosology classification of skeletal dysplasias, 461 disorders under 42 groups are classified according to specific radiographic, clinical, and molecular standards. In addition, correct molecular diagnosis for these rare GSDs is important for genetic and psychological counseling and treatment. GSDs are also associated with many syndromic forms that affect other parts such as hearing, vision, neurological, pulmonary, renal, or cardiac function. This review highlights the importance of GSDs and details a few selected disorders and their management strategies.

Background: The genetic basis of dilated cardiomyopathy (DCM) is highly diverse, with over 100 known genes and several possibilities described. Nebulin-related-anchoring protein (NRAP) is an action-binding cytoskeletal protein that has a role in the myofibrillar assembly in the embryonic heart. It is primarily generated in striated and cardiac muscles. Case Presentation: We described three cases of DCM that were related to NRAP gene mutations [NM_001261463.1: c.3568G > T; p. (Glu1190*)]. Conclusion: Our data imply that biallelic nonsense mutations in the NRAP might be a genetic risk factor with limited penetrance and induce DCM at various ages.

Background: Anterior segment dysgenesis (ASD) is a developmental condition that affects the frontal part of the eyes. Genetic mutations in FORKHEAD BOX E3 can lead to a variety of ASD conditions. Case Presentation: Here, we report a 2-year-old female patient with ASD type 2 autosomal recessive linked disease. Whole exome sequencing test was conducted and resulted in a missense mutation at position 120 altering arginine to proline. To our knowledge, this is the first case reported in Oman. Conclusion: For patients with ASD, it is crucial to take the full family history and genetic work up to aid in the diagnosis and long-term management of the condition.

Background: Atopic dermatitis (AD) is one of the most common diseases encountered in pediatric practice. Genetic factors play a role in the development of this condition. Topical corticosteroids are the cornerstone of AD management, but with potentially serious adverse events. Misuse of these medications is not uncommon. Case Presentation: We describe a case of severe AD with inadvertent overuse of topical steroids. The patient presented with multisystem involvement and a cushingoid appearance. Laboratory tests showed thrombocytosis and abnormal liver function test, among other findings. A whole exome test showed mutations in two genes, a homozygous pathogenic variant c.317C>T p.(Pro106Leu) in the protooncogene, thrombopoietin receptor (MPL) gene (NM_005373.2) inherited from both parents and a de novo heterozygous c.139C>T p.(Arg- 47Cys) in the CARD11 gene (NM_001324281.1), that explain her combined presentation. Conclusion: The aim of this report is to share our experience with the diagnosis and treatment of a challenging case. This report also shows the association between the MPL, CARD11 genes, and severe AD. In addition, this case is consistent with the published literature on systemic involvement in severe AD and variable response to routine management.

Background: Progressive pseudorheumatoid dysplasia (PPRD) is an inherited autosomal recessive musculoskeletal condition caused by mutations in the Cellular Communication Network Factor 6 (CCN6) gene. This causes a variety of clinical features such as short stature, genu varum, etc. Case Presentation: This study reported cases of three patients from the same family who exhibited the clinical features of PPRD, and the condition was diagnosed through confirmatory genetic testing. The whole exome sequencing test results for the 15-year-old and 3-year-old males revealed a class-5 pathogenic homozygous mutation in the CCN6 gene, resulting in both individuals being diagnosed with autosomal recessive PPRD. The results for the third patient had not come out yet. Conclusion: For patients with PPRD, it is necessary to take the full family history and genetic testing that might help in the diagnosis and treatment of the condition.