Journal of Biochemical and Clinical Genetics

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: Sensorineural hearing loss is among the most common sensory defects worldwide. Nonsyndromic hearing loss (NSHL) accounts for 70% of inherited hearing loss. The genetic causes of NSHL 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 NSHL 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 the American College of Medical Genetics and Genomics guidelines, it is classified as a pathogenic variant.

Conclusion: A novel biallelic frameshift variant in MYO15A causes NSHL 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.

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.

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.

Background: The cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction is linked to gastrointestinal inflammation and has been implicated in early-onset malignancies. However, its role in gastric cancer remains poorly understood.

Aims: To investigate the CFTR interactome and assess its potential functional involvement across different subtypes of gastric cancer.

Methods: We conducted a system-level in silico analysis using data from the Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD). CFTR expression and co-expression profiles were examined across molecular and histological subtypes of gastric cancer, including signet-ring cell carcinoma (Lauren’s classification). Differential gene expression (DGE) and co-expression analyses were integrated with protein-protein interaction networks, pathway enrichment, and gene ontology (GO) analysis to delineate CFTR’s functional associations.

Results: CFTR did not exhibit significant differential expression across gastric cancer subtypes. However, co-expression analysis identified CFTR as a key hub gene with a distinct interaction network, especially prominent in the signet-ring cell carcinoma subtype. Enrichment analyses revealed that CFTR's interactome is involved in regulatory pathways related to cellular homeostasis, ion transport, and immune modulation, suggesting a noncanonical yet critical role in tumor biology.

Conclusion: While CFTR expression remains stable across gastric cancer subtypes, its interactome reveals significant regulatory roles, particularly in signet-ring cell carcinoma. These findings highlight the potential contribution of CFTR to gastric cancer pathogenesis through its involvement in broader molecular networks rather than through expression changes alone.

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.

Inborn errors of metabolism (IEMs) caused by a deficit of some specific metabolic pathways are phenotypically heterogeneous complex disorders. Although in recent years metabolomics has helped in understanding the pathophysiology of IEMs, its challenges and limitations such as false positives and negatives result in delayed diagnosis and postponed treatment. This leaves the physician with a large list of differential diagnosis among IEMs. Early and accurate diagnosis in case of suspicious IEMs can be lifesaving, especially for conditions those are treatable. Recently, next-generation sequencing (NGS)-based whole-exome sequencing proved to be an efficient technology in enhancing the accuracy of diagnosis of metabolic disorders, especially for complex disorders. It offers a broader range of disorders diagnosed at an affordable cost compared to metabolomics. The aim of this article is to provide insights into bridging metabolomics and NGS-based genomics to improve diagnostic yield in complex IEMs, while also emphasizing the role of genetic counselling in empowering families and improving patient quality life.

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 is imperative 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.

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: Developmental and epileptic encephalopathies (DEEs) are severe disorders marked by refractory seizures and developmental delay. Pathogenic variants in the syntaxin-binding protein 1 (STXBP1) gene are among the top five genetic causes of DEE and impair neurotransmitter release, especially in GABAergic interneurons. The clinical presentation is highly variable, and diagnosis depends on molecular genetic testing. Precision medicine is key for diagnosis, treatment, follow-up, prognosis, and hereditary risk reduction.

Case Presentation: We present a male patient with drug-resistant epilepsy, polypharmacy, and cognitive impairment, without significant family or perinatal risk factors. Given the clinical complexity and strong suspicion of genetic cause, a molecular study using next-generation sequencing of epilepsy-related genes and copy number variation analysis was performed. A heterozygous pathogenic variant in STXBP1, c.1652G>A (p.Arg551His), was identified, associated with early infantile epileptic encephalopathy type type 4, also known as STXBP1-DEE (MONDO:0012812 - orphanet identifier (ORPHA):599373], with autosomal dominant inheritance.

Conclusion: STXBP1-DEE represents a heterogeneous spectrum of neurodevelopmental disorders with refractory epilepsy, developmental delay, and intellectual disability. Diagnosis requires clinical suspicion, imaging, laboratory tests, and molecular confirmation. While current treatments are limited, promising approaches are under investigation. The lack of genotype-phenotype correlation and wide phenotypic variability complicate management, but advances in precision medicine support more individualized treatment strategies. Although most variants are de novo, genetic counseling remains crucial to assess recurrence risk. Preclinical studies show potential for novel therapies, yet clinical trials are needed to confirm their efficacy in affected individuals.