Search Results (259)

This systematic review and meta-analysis aims to determine the diagnostic yield of whole-exome and targeted-panel sequencing in children with hearing loss. We searched PubMed, Google Scholar, and the Cochrane Library to identify studies describing cohorts of >50 families undergoing whole exome or targeted panel sequencing. Studies were excluded if they pre-screened for common deafness genes without including the data in final analyses, focused on syndromic hearing loss, or lacked diagnostic yield information. Meta-analysis employed a random-effects model of single proportions to determine yield across included studies. The pooled diagnostic yield for bilateral hearing loss was ~47%, while unilateral cases demonstrated a yield of only ~5% across both testing methods. These findings demonstrate that the diagnostic yield for bilateral hearing loss exceeds that of other conditions frequently requiring clinical genetic testing, such as epilepsy and intellectual disability, though this advantage does not extend to unilateral hearing loss. These results have important implications for healthcare policy decisions regarding genetic testing guidelines and funding. Full article

We devised a quantitative scoring function to assess the cumulative effects of somatic nonsynonymous single-nucleotide variants (SNVs) on protein-coding genes in patients with ovarian cancer (OvCa) and thyroid cancer (ThCa). The goal is to find novel candidate cancer-related genes for downstream bioinformatics analyses and wet-lab studies. With the Genomic Data Commons as primary data resource, SNV information was extracted from whole-exome sequencing data from patients with these cancers. A cumulative variant scoring function, Q(G), was developed to sum up the deleterious effects of the individual SNVs on gene G. While Q(G) can be computed using any popular functional effect analyzers such as FATHMM-XF, SIFT, PolyPhen, and CADD, we have also established an integrative scoring function iQ(G) that combines the deleterious assessments from different analyzers and demonstrated that iQ(G) is a more effective method for identifying likely cancer-related genes. Based on the iQ(G) rankings, the top three novel genes for OvCa are AHNAK2, UNC13A, and PCDHB4; and those for ThCa are PLEC, HECTD4, and CES1. Furthermore, the top 1% genes with highest iQ(G) scores for each cancer were submitted for KEGG pathway analysis. The results revealed that several genes of the CACNA1 family within the type II diabetes mellitus pathway are likely related to both OvCa and ThCa and suggested other molecular interactions that should be further studied in connection with OvCa prognosis and ThCa treatment. Full article

Background/Objectives: Paediatric cataract is among the most common treatable causes of childhood blindness, caused by a genetically diverse disorder with variable clinical features. Although genetic factors significantly contribute to the development of paediatric cataracts, recent data on their genetic makeup and genotype–phenotype relationships in Saudi Arabia is limited. This study aims to investigate the genetic spectrum, inheritance patterns, and genotype–phenotype correlations of paediatric cataract in a Saudi population over twenty years. Methods: We conducted a retrospective cohort study of children diagnosed with congenital or juvenile cataracts between 2000 and 2019 at two major referral centres in Riyadh. Clinical, ocular, and systemic data were collected through multidisciplinary evaluations. Genetic analysis involved whole-exome and whole-genome sequencing performed at College of American Pathologists (CAP)-accredited laboratories. Variant interpretation was supported by bioinformatic and Artificial Intelligence (AI) prediction tools. Genotype–phenotype relationships were systematically analysed. Results: The study included 28 cases of genetically confirmed paediatric cataracts. Variants classified as pathogenic or likely pathogenic were identified in 13 genes. Autosomal recessive inheritance was predominant, with many patients exhibiting homozygous variants, often due to consanguinity. Two novel variants were identified in the Collagen Type XVIII Alpha 1 Chain (COL18A1) and the RAB3 GTPase-activating protein catalytic subunit 2 (RAB3GAP2) genes. Considerable phenotypic variability was observed, even among patients with the same mutation, particularly those with the recurrent CRYBB1 c.171del (p.Asn58fs) mutation. Syndromic cataracts were more frequently associated with loss-of-function variants and multisystem features. Conclusions: This study offers updated insights into the genetics and clinical presentation of paediatric cataract in Saudi Arabia. It highlights high genetic diversity, unique inheritance patterns, and notable genotype–phenotype variability, emphasising the importance of early genetic testing and multidisciplinary assessment for improved diagnosis, management, and counselling. Full article

Background/Objectives: Multiple Sclerosis (MS) is a chronic immune-mediated disorder characterized by neuroinflammation and neurodegeneration. Increasing evidence implies the kynurenine pathway (KP) in the MS pathophysiology; however, data from Mexican populations are lacking. This exploratory study aimed to characterize central and circulating KP metabolites in Mexican patients with MS and to investigate potential genetic variants in KP-related genes. Methods: Serum concentrations of kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK), as well as cerebrospinal fluid (CSF) levels of KYNA, quinolinic acid (QUIN), interleukin-4 (IL-4), and interleukin-6 (IL-6), were determined in treatment-naïve relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and treated PMS patients. Serum levels were compared with those of healthy controls, and CSF findings contrasted with those of non-MS neurological patients and individuals with neurocysticercosis (NCC). Public whole-exome datasets were analyzed for variants in KP-related genes, and target exome sequencing was performed in three Mexican patients with MS. Results: Serum concentrations of KYNA and 3-HK were decreased in MS patients compared with healthy controls. CSF KYNA and QUIN levels did not differ significantly among MS subtypes or the non-MS neurological group, but they were lower than those observed in NCC. IL-4 and IL-6 were detectable in MS CSF samples, supporting the presence of intrathecal inflammation. Genetic and bioinformatic analyses identified variants in genes encoding KP enzymes in both public MS datasets and in Mexican patients with MS. Conclusions: These findings indicate an altered KP metabolism in Mexican MS patients, particularly during the relapse phase, and suggest a possible contribution of genetic variability. Further large-scale studies are needed to confirm these observations and to determine the functional implications of KP-related genetic variants in MS. Full article

Objectives: The patient presented various neurological symptoms in her 50s, such as memory issues, insomnia, depression, and motor impairment. Diverse investigations were performed to identify the underlying causes on her neurological symptoms and understand her neuro- deteriorations. Methods: Clinical neurological and brain imaging analyses: CT, MRI and PET were performed on the patient. Blood was drawn for the whole-exome sequencing and functional studies with biomarker for amyloid-beta oligomers and SLC20A2 protein in plasma. Results: Brain imaging revealed calcifications in multiple regions, including the subcortical white matter, basal ganglia, thalami, and dentate nuclei. Genetic analysis revealed a c.1152_1153delCA, p.Asn384Lysfs*30 variant in SLC20A2 gene. The decreased SLC20A2 protein levels in plasma in comparison to healthy controls suggested a loss-of-function mechanism from the mutation. The patient had a positive AlzOn result, indicating an increased tendency for amyloid oligomerization and suggesting a potential indirect link between SLC20A2 and amyloid-beta pathways. Conclusions: A novel frameshift mutation, Asn384Lysfs*30, in the SLC20A2 gene was identified in a patient with Primary Brain Calcification (PBC). This mutation was located in a critical large loop region of the protein, where other similar mutations (e.g., Gly366fs89, Ser385Ilefs*70) were previously reported. These findings indicated that mutations in SLC20A2 caused the reduced protein expressions, potentially resulting PBC through haploinsufficiency. Full article

Next-generation sequencing (NGS) and antisense oligonucleotide (ASO) technologies are converging to transform the diagnosis and treatment of rare monogenic disorders. NGS enables comprehensive, single-test molecular diagnoses through targeted panels, whole-exome sequencing, and whole-genome sequencing, which together reveal pathogenic variants across coding, intronic, and structural domains. Integration with transcriptomic analyses, including RNA sequencing, further refines genotype–phenotype correlations and identifies splicing aberrations amenable to correction by ASOs. Therapeutic advances now span RNase H1-dependent gapmers for transcript knockdown, splice-modulating phosphorodiamidate morpholino oligomers (PMOs), and peptide/antibody-conjugated PMOs that enhance muscle and cardiac delivery. These platforms underpin the rise in N-of-1 ASO therapies—customized drugs developed for individual patients with unique pathogenic variants. Landmark cases such as Milasen and Atipeksen illustrate the clinical feasibility and ethical complexities of personalized RNA therapeutics, while updated FDA guidance supports expedited, patient-specific investigational pathways. Despite progress, challenges persist in delivery efficiency, long-term efficacy, and equitable access. Emerging approaches—including long-read sequencing, AI-driven oligo design, and improved delivery—promise to extend ASO precision and reach. This review synthesizes current advances linking genomic diagnosis to individualized RNA-targeted interventions, outlining how integrated NGS-ASO pipelines are reshaping the therapeutic landscape for rare genetic diseases. Full article

Cervical small-cell neuroendocrine carcinoma (SCNEC) is a rare cervical cancer with high metastatic potential and is frequently associated with high-risk human papillomavirus (HPV) infection. Because of its low incidence, SCNEC remains understudied and treatment options are limited, posing major therapeutic challenges. This study aimed to characterize SCNEC at the molecular and functional levels to support more informed therapeutic strategies. Organoids and spheroids were generated from a cervical SCNEC biopsy, and a matched organoid-derived xenograft was established in immunodeficient mice. Model fidelity was evaluated by histopathology and immunohistochemistry. HPV status was assessed by p16 immunostaining and HPV18 PCR, and viral–host integration sites were inferred using whole-exome sequencing (WES) junction reads. WES was also used to compare shared somatic variants and copy-number alterations across the patient tumor, organoid, and xenograft. Drug responses were assessed in organoids and spheroids following exposure to a panel of chemotherapeutic agents and a targeted inhibitor. Organoids exhibited robust growth, morphologic maturation, and efficient recovery after cryopreservation. The organoids and matched xenografts faithfully recapitulated SCNEC, with preserved neuroendocrine differentiation (CD56, synaptophysin, and NSE positivity), a high Ki-67 proliferative index (>80%), and strong p16 expression. HPV18 status was conserved across the primary tumor, organoids, and xenografts, with an integration site at chr8 (8q24.21) associated with increased MYC expression. WES revealed strong cross-model concordance, including 26 shared somatic variants with a canonical PIK3CA hotspot mutation (p.E542K) and conserved oncogenic copy-number gains of PIK3CA, TERT, and MYC, as well as copy number loss of TP53. Functional assays showed dose-dependent loss of viability following exposure to conventional cytotoxic agents or an mTOR pathway inhibitor. This study presents the first integrated molecular and functional analyses of patient tumors and matched organoid and xenograft models in cervical SCNEC. These models offer robust resources for mechanistic studies and may enable precision therapeutic strategies for this rare malignancy. Full article

Background: Goldenhar syndrome (oculo–auriculo–vertebral spectrum, OAVS) is a rare congenital disorder characterized by craniofacial malformations, systemic anomalies, and significant phenotypic variability. Although it is the second most common craniofacial malformation after a cleft palate, the genetic etiology of Goldenhar syndrome remains largely unexplored. This study aimed to identify genetic variants contributing to Goldenhar syndrome in a Lebanese family with three affected individuals, using whole-exome sequencing and complementary genomic approaches. Methods: Whole-exome sequencing was performed on the nuclear family to identify variants associated with the syndrome. Complementary DNA methylation and gene ontology analyses were conducted to explore epigenetic modifications. Results: A missense shared variant in the MID1 between the affected individuals [NP_000372.1): p. Ile593Phe] gene was observed in the family, while current ACMG evidence was insufficient to establish causality. Additional variants were identified, including a de novo mutation in FBXW11 and a rare frameshift alteration in NDUFAF8, with limited segregation, implicating these genes in associated phenotypes such as craniofacial anomalies and cardiac defects. DNA methylation analysis revealed hypomethylation at CpG sites within the ZC3H3 gene, suggesting an epigenetic contribution to disease variability. Conclusions: Our findings underscore the genetic and epigenetic complexity of Goldenhar syndrome, providing new insights into its molecular etiology and highlighting the challenges of variant interpretation in familial cases of rare congenital disorders. Full article

Colibactin, a genotoxin produced by pks⁺ E. coli, imprints highly specific mutational signatures SBS88 and ID18 in colorectal cancer (CRC) and even in normal colonic crypts. Population-scale analyses show these signatures are enriched in early-onset CRC, vary geographically, and are imprinted early during tumor evolution, where probabilistic attribution indicates that colibactin contributes to a measurable fraction of APC driver mutations in colibactin-positive cancers. Beyond colibactin, Fusobacterium nucleatum exerts clade-specific effects on tumor ecology and therapy response, with data supporting both chemoresistance and sensitization to anti-PD-1 in microsatellite stable (MSS) CRC. This article covers mechanistic, genomic, and molecular epidemiology evidence, outlines analytic standards for signature detection (whole-genome sequencing (WGS)/whole-exome sequencing (WES), single-sample fitting, and limits at low mutation counts), and charts translational paths spanning noninvasive screening (stool metagenomics + mutational signatures in tissue/circulating tumor DNA (ctDNA)), risk stratification, and microbial-targeted interventions (antibiotics, phages, ClbP inhibitors). Framing microbiome–genome crosstalk as a tractable axis enables testable clinical hypotheses for precision oncology. Full article

Background: Gastric-type adenocarcinoma (GAS) of the uterine cervix is a rare malignancy with poor clinical outcomes. However, the carcinogenic processes involved remain unclear. Methods: Normal cervical glands, lobular endocervical glandular hyperplasia (LEGH), and GAS from the same patients were collected using laser microdissection for whole-exome sequencing. Single nucleotide variants (SNVs) and copy number alterations (CNAs) were analyzed. Phylogenetic trees were constructed based on the SNV and CNA profiles. Results: Analysis of seven matched samples demonstrated higher frequency of somatic mutations in the exonic regions in GAS than in LEGH. CNAs were prevalent in GAS but rare in LEGH. The phylogenetic analyses revealed various branching patterns. However, in three cases, the data suggested a sequential transition from LEGH to GAS, potentially associated with mutations in receptor-type protein tyrosine phosphatases such as PTPRF and PTPRT. STK11 and ARID1A mutations were present in LEGH, with an increased variant allele frequency observed in GAS. In contrast, SMAD4 and SMAD2 showed frequent loss-of-function–type alterations in GAS, including copy-number loss, but were not detected in LEGH. Conclusions: These findings provide insights into the genomic landscapes of LEGH and GAS and suggest potential molecular markers for this transition, which may inform future diagnostic and therapeutic research. Full article

Congenital vertebral malformations (CVMs), affecting approximately 0.5–1 per 1000 live births, occur either in an isolated form or as part of syndromic disorders. Despite the identification of numerous causative genes for CVMs, the molecular etiology of most cases remains unknown. In this study, we applied a three-tiered diagnostic approach (chromosomal microarray analysis, followed by custom gene panel analysis, and exome/genome sequencing) in a cohort of 34 patients with CVMs. We achieved a 12% diagnostic success rate, identifying a deletion upstream of SOX9 and pathogenic or likely pathogenic variants in FLNB and KMT2D. Most pathogenic variants were detected by exome or genome sequencing, while earlier-tier analyses yielded limited results. We also identified two candidate genes, NSD2 and TBXT, that may contribute to the phenotype observed in our patients, but warrant future functional validation. Our work expands the molecular spectrum of CVMs and highlights the utility of comprehensive genomic testing for improving diagnosis and understanding of vertebral development disorders. Full article

Early-onset breast cancer (EOBC) is disproportionately common in Saudi Arabia, where women present nearly a decade earlier than in Western countries, suggesting unique inherited susceptibility. While BRCA1/2 explain part of the hereditary risk, the contribution of rare coding variants in Arab EOBC remains unclear. Whole-exome sequencing was performed on germline DNA from 102 unrelated Saudi EOBC patients and 1395 cancer-free controls recruited from the same national Saudi cohort. Rare variants were defined by stringent frequency and quality thresholds and classified as rare loss-of-function (RLOF) or rare predicted damaging variants (RPDVs). Gene-level case–control analyses were conducted using burden tests, with exome-wide significance set at p < 2.5 × 10⁻⁶. RLOF variants in BRCA1 (6.9% of EOBC vs. 0.14% of controls; OR = 51.3; p < 1.0 × 10⁻¹⁰) and RPDVs in TP53 (4.9% vs. 0.36%; OR = 14.3; p = 5.39 × 10⁻⁸) demonstrated strong associations. Sequence Kernel Association Test (SKAT) analysis identified NOTCH4 and OR12D3 and reinforced burden-based significance in GUCY2F, FRMPD3, and SHROOM2. No enriched signaling pathway emerged, indicating heterogeneous rare-variant mechanisms. This first germline exome-wide rare-variant association study in Saudi EOBC identifies substantial enrichment driven by BRCA1, TP53, and additional candidate genes, supporting population-specific genetic risk evaluation and the need for replication in larger Arab cohorts. Full article

Background/Objectives: Human-driven environmental change can promote cancer development in wild species, yet the pathophysiology of wildlife cancers remain largely unexplored. Urogenital carcinoma (UGC) in the California sea lion (CSL) (Zalophus californianus) is one of the most common cancer types documented in any wild mammal. The pathogenesis of UGC in CSLs is known to be multifactorial, with links to environmental contaminant exposure and infection by Otarine Herpesvirus-1 (OtHV-1); however, the genomic features of these cancers have not been thoroughly explored. Understanding UGC pathogenesis in the CSL has important implications for the health of humans and other species that share environment and diet. Methods: We leveraged the evolutionary conservation between the domestic dog and CSL genomes to perform cross-species whole-exome sequencing (WES) of CSL UGC tumors and matched normal tissue pairs. We also used PCR and Sanger sequencing to investigate the prevalence of DNA from OtHV-1. Results: Bioinformatic analyses identified shared somatic variants and DNA copy number aberrations in UGC tumor samples, including recurrent exonic single-nucleotide variants in CD274/PD-L1, and recurrent copy number gains in CD274/PD-L1, TNFRSF14, CD200, CDK4, and PLCG2. In an extended cohort of 70 CSLs (tumor, matched normals, and controls), a recurrent C > T single-nucleotide variant in exon 4 of CD274/PD-L1 was identified in 54 of 68 (79.4%) CSLs with diagnosed UGC. OtHV-1 DNA was detected in 67 of 70 individuals (95.8%). Conclusions: These results demonstrate that cross-species exome capture provides a means to identify genomic alterations that may play a role in the molecular pathogenesis of UGC in the CSL and adds to the body of evidence for an association between OtHV-1 and UGC in this species. Full article

Background/Objectives: Hypermobile Ehlers–Danlos syndrome (hEDS) remains genetically unexplained despite decades of clinical investigation, with the molecular basis undefined for the vast majority of cases. This study employs integrated machine learning approaches with rigorous subject-level statistical methods to decode the genetic architecture underlying hEDS. Methods: We analyzed 35,923 rare genetic variants (gnomAD MAF < 0.2) across 116 subjects from 43 families (86 hEDS patients diagnosed per 2017 international criteria; 30 unaffected intrafamilial controls) using whole-exome sequencing. Machine learning analysis employed Random Forest feature selection, deep neural networks, and ensemble methods with subject-stratified cross-validation to prevent data leakage. Statistical association testing used subject-level Fisher’s exact tests with Bonferroni correction (α = 3.77 × 10⁻⁶ for 13,281 genes). Sensitivity analyses assessed robustness to family structure. Results: Subject-level analysis identified statistically significant enrichment in variants associated with three major biological systems: (1) collagen biosynthesis pathway variants (present in 63% of hEDS subjects vs. 17% of controls, Fisher’s p = 1.06 × 10⁻⁵, OR = 8.4), predominantly affecting COL5A1, COL18A1, COL17A1, and post-translational modification enzymes; (2) HLA/adaptive immune axis variants (74% of hEDS vs. 30% of controls, p = 2.23 × 10⁻⁵, OR = 6.8), involving HLA-B, HLA-A, HLA-C, and TAP transporters; (3) mitochondrial respiratory chain variants (34% of hEDS vs. 7% of controls, p = 2.29 × 10⁻³, OR = 7.1), with striking 4.2-fold enrichment in pediatric fracture cases (52% vs. 21%, p = 0.021, 95% CI: 1.2–14.6). These associations require independent validation and functional studies to determine their mechanistic relevance. Genome-wide analysis identified seven genes achieving Bonferroni significance (p < 3.77 × 10⁻⁶), all encoding structural/cytoskeletal proteins. Machine learning models with proper subject-stratified cross-validation achieved 80% accuracy (95% CI: 73–86%, sensitivity = 82%, specificity = 77%). Conclusions: Our findings suggest that hEDS may involve genetic variation across multiple biological systems beyond classical collagen pathways. These hypothesis-generating associations require validation in independent cohorts and functional studies before mechanistic or clinical conclusions can be drawn. Full article

Background: Cholesterol imbalances and elevated blood pressure (BP) are closely interrelated risk factors for cardiovascular disease (CVD) and are subject to genetic influences. We sought to identify novel associations between candidate genetic coding variants and CVD traits in our isolated study cohort and validate them in a general population cohort. Methods: We leveraged the population genetic features of the Norfolk Island Health Study (NIHS, n = 601), to identify candidate functional variants which were analysed for association with CVD and metabolic syndrome traits. We followed up suggestive variant-trait associations in the 2022 release of UK Biobank whole exome data (n = 200,625). Results: We identified a novel ten-base-pair in-frame missense multi-nucleotide variant (MNV), tagged by rs35724886, in the lipid metabolism gene ACOT4, which was associated with cholesterol levels and blood pressure. The MNV was associated with a lower incidence of ‘elevated BP’—systolic BP ≥ 130 mmHg or diastolic BP ≥ 80 mmHg—(OR: 0.70; 95% CI: 0.51, 0.97; p = 0.03), and higher total cholesterol levels (β = 0.08; p = 0.04) in the NIHS. Validation in the UK Biobank revealed consistent associations between the MNV (proxied by rs35725886) and lower incidence of ‘elevated BP’ (p = 0.0001), higher total cholesterol (p = 0.01), and reduced use of medication for managing blood pressure (p = 1.8 × 10⁻⁶) and cholesterol (p = 0.002). Structural modelling and in-silico predictions suggested that the MNV introduced destabilising changes in the ACOT4 protein, likely influencing peroxisomal lipid metabolism pathways critical to CVD risk. Conclusions: This study identified a coding MNV with potential implications for understanding the genetic regulation of lipid metabolism and its impact on cardiovascular health. Full article