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Background: Sensorineural hearing loss is among the most common sensory defects worldwide. Nonsyndromic hearing loss accounts for 70% of inherited hearing loss. The genetic causes of nonsyndromic hearing loss are considered heterogeneous. The high rate of consanguineous marriages in Saudi Arabia increases the population's prevalence of autosomal recessive inheritance patterns. 

Objective: To discover a novel variant for nonsyndromic hearing loss patients.

 
Methods: A family with two hearing-impaired children was recruited. Targeted exome sequencing, the Twist Exome 2.0 kit (Twist Bioscience) using the Novaseq X plus platform, was used to identify the variant. Sanger sequencing was carried out to confirm the finding and perform segregation analysis. MutationTaster tool was used to determine the pathogenicity effect on the protein structure.

Results: A homozygous two-bp duplication variant on the (c.8813_8814dup) MYO15A gene was identified in a Saudi family of two hearing-impaired children. Sanger sequencing confirmed the variant in the affected children and their parents. The prediction tool indicated the frameshift effect on the protein level, which leads to protein function disruption. Based on ACMG guidelines, it’s classified as a pathogenic variant. 

Conclusion: A novel biallelic frameshift variant in MYO15A causes nonsyndromic hearing loss in a Saudi family. This variant is considered rare and isolated to the Saudi population. Expanded genotype-phenotype correlations for hearing loss patients are likely to confirm the findings and reveal novel variants.

Background: Transaldolase deficiency (TALDO-D, Eyaid syndrome) is a rare autosomal recessive disorder of the
pentose phosphate pathway. It can present prenatally with intrauterine growth restriction or oligohydramnios; neonatally with dysmorphic features, cardiovascular defects, hepatosplenomegaly, anemia, and thrombocytopenia; or later with a milder phenotype. The present case report aimed at enhancing the effectiveness and confidence in treating patients with rare metabolic disorders that are further complicated by complex presentation.

Case Presentation: We present a rare case of a 14-year-old girl diagnosed with Eyaid Syndrome - TALDO-D based on clinical and molecular findings of a homozygous pathogenic variant in the TALDO1 gene, c.793del,p.(Gln265Argfs*56). She developed type 1 diabetes around the age of nine and was found to have a baseline non-anion gap metabolic acidosis that persisted despite adequate diabetes management. An extensive workup for possible renal causes, given that they are part of her primary syndrome, revealed proximal renal tubular acidosis. During an emergency department visit, she presented with abdominal pain, vomiting, diarrhea, and lethargy. Laboratories showed severe metabolic acidosis (pH of 6.93, HCO3–of 3.3), marking the beginning of her challenging management approach.

Conclusion: The patient in this case report has shown an excellent response to sodium bicarbonate in a well monitored clinical and biochemical setting. However, given the rarity and complexity of such cases, it isimperative to conduct a comprehensive literature review involving all relevant subspecialties and report similar challenging cases to establish evidence-based clinical practices for the high-quality management of this rare patient population.

Premarital genetic screening (PGS) refers to the procedure whereby couples are tested for genetic abnormalities before marriage in order to determine the likelihood that their future children may inherit certain genetic conditions. This screening can lower the prevalence of genetic illnesses and assist potential parents in making educated reproductive decisions.

Background: Lipoprotein lipase deficiency (LPLD) is an exceedingly rare autosomal recessive disorder characterized by severe hypertriglyceridemia and significant clinical complications, notably recurrent acute pancreatitis.

Case Presentation: We present the detailed case of a Saudi girl who initially exhibited severe hypertriglyceridemia at 3 months old and received a genetic diagnosis at 8 months, confirming homozygous LPL deficiency (variant c.765_766del). Despite rigorous dietary management and medium-chain triglyceride supplementation, she experienced multiple episodes of necrotizing pancreatitis.

Conclusion: This report underscores the essential role of early genetic confirmation, rigorous dietary management, multidisciplinary care, and explores emerging treatment strategies for LPLD.

Background: This retrospective study aims to present the clinical and genetic data of patients diagnosed with immunodeficiency through genetic diagnostic methods. It is essential to investigate the impact of genetic risk factors,
such as consanguinity, on immunodeficiency, identify the underlying genetic variants, and assess potential risks. Identifying genetic defects in patients with unknown etiology is critical for accurate diagnosis and effective treatment.

Methodology: Patient histories were evaluated, and detailed clinical findings were recorded. Genetic analyses were performed, identifying eight different variants consistent with autosomal recessive inheritance. The American College of Medical Genetics and Genomics classification criteria were utilized to assess several pathogenic and likely pathogenic variants associated with various immunodeficiency disorders.

Results: Several pathogenic and likely pathogenic variants were identified, related to immunodeficiency disorders such as severe combined ımmunodeficiency due to ADA deficiency and LIG4 syndrome. A significant proportion of patients had a history of consanguinity. The clinical variability observed emphasizes the importance of comprehensive genetic evaluation. Whole exome sequencing (WES) proved effective in uncovering the genetic causes of unexplained immunodeficiency symptoms.

Conclusion: This study highlights the critical role of genetic testing in diagnosing immunodeficiency disorders. WES and next-generation sequencing technologies were particularly useful in identifying the genetic basis of immunodeficiency in patients with unexplained symptoms. Genetic evaluation enables personalized treatment strategies, improving patient management and outcomes. Comprehensive genetic assessments are especially important in populations with high consanguinity rates.

The SWItch/Sucrose Non-Fermentable chromatin remodeling complex, particularly the SMARCA5 gene and its product circSMARCA5, holds significant implications for understanding nucleosomal transformations, gene regulation, and cancer development. Additionally, the concept of cancer stem cells (CSCs) and their role in malignancies sheds light on the complex nature of cancer progression and the potential for targeted therapeutic interventions. The circSMARCA5 expression showed a significant and opposite association with its parent gene in breast cancer, indicating its potential as a therapeutic target for breast cancer treatment. CSCs in breast cancer share similarities with normal stem cells and exhibit disrupted signaling pathways, emphasizing the importance of identifying CSCs for understanding disease biology and developing targeted therapies. Additionally, research revealed circSMARCA5 expression is reduced in nonsmall cell lung cancer (NSCLC), and its overexpression impedes the proliferation, migration, and invasion of NSCLC, indicating its potential as a prognostic indicator for lung cancer patients. The CSCs have been identified in small cell lung cancer, contributing to tumor development, treatment resistance, and potential metastasis through the process of epithelial-mesenchymal transition, and are characterized by the overexpression of specific signaling pathways and cell surface markers. The current understanding of circSMARCA5's role in breast and lung malignancy highlights its significant contribution to tumor development and potential clinical applications, paving the way for promising therapeutic interventions in cancer treatment. This opens new avenues for personalized medicine and novel strategies for cancer management in the future.

Objectives: Our objective was to identify the genetic cause in a patient with intellectual disability and bilateral cataracts.

Methods: The genetic, neurological, and ophthalmological evaluations were performed. DNA samples were provided from the patient, parents, and unaffected sibs to perform whole exome sequencing (WES) and Sanger confirmation. Biochemical testing on the serum sample was performed to ascertain the clinical significance of the WES finding.

Results: The proband presented with intellectual disability, subtle dysmorphic features, and bilateral cataracts. WES and segregation studies using Sanger sequencing revealed a homozygous missense variant of uncertain significance (VUS) in SRD5A3 and a de novo pathogenic frameshift variant in PITX3 in the proband. Biochemical analysis of serum carbohydrate-deficient-transferrin (CDT) to ascertain the significance of the VUS in SRD5A3 was consistent with a glycosylation defect and confirmed type 1, N-glycosylation defect.

Conclusion: This case has a dual molecular diagnosis. The SRD5A3 variant with confirmed biochemical abnormality accounts for intellectual disability and subtle dysmorphic features, whereas the de novo pathogenic PITX3 variant accounts for bilateral cataracts. This case expands the severity spectrum of SRD5A3 disorder and represents a milder form. It also highlights the importance of clinical correlation and reverse phenotyping.