Search Results (1,663)

Background/Objectives: Infantile cardiomyopathy is a rare but often life-threatening condition in which monogenic causes are particularly relevant, especially when cardiac disease is preceded by hypotonia or multisystem involvement. Among sarcomeric genes, MYL2, encoding the ventricular regulatory myosin light chain, plays a critical role in myocardial contractility. However, biallelic MYL2-associated disease remains exceptionally rare, and its clinical spectrum is not fully defined. This study aims to describe a novel case and further delineate the phenotype of recessive MYL2-related cardiomyopathy. Methods: We report a male infant with congenital hypotonia and delayed motor development who underwent extensive metabolic, neuromuscular, and neuroimaging evaluation. Trio-based whole-exome sequencing was performed to identify a potential genetic etiology, followed by variant interpretation using standard bioinformatic and ACMG/AMP criteria. Results: The patient developed acute decompensated heart failure at approximately 10 months of age, with severe left ventricular systolic dysfunction and multiorgan failure, and died at 12 months despite maximal intensive care support. Whole-exome sequencing identified a homozygous MYL2 c.413T>A (p.Met138Lys) missense variant. The variant is absent or extremely rare in population databases, affects a highly conserved residue, is predicted to be deleterious by multiple in silico tools, and is compatible with autosomal recessive inheritance, with both parents confirmed as heterozygous carriers. In the context of a phenotype consistent with recessive MYL2-associated disease, these findings support a likely pathogenic interpretation. Conclusions: This case expands the allelic and phenotypic spectrum of recessive MYL2-associated cardiomyopathy and highlights the value of early genomic testing in infants with unexplained hypotonia and rapidly progressive cardiac dysfunction. Molecular diagnosis may aid in prognosis, clinical decision-making, and genetic counseling. Full article

Background: In clinical practice, LDL-dominant familial hypercholesterolemia (FH) may overlap phenotypically with triglyceride-dominant or mixed familial dyslipidemia. Rule-based diagnostic approaches like the Dutch Lipid Clinic Network (DLCN) and Simon Broome (SB) criteria are frequently used in countries with limited genetic testing, but their concordance with molecular confirmation is inconsistent. In a large Turkish tertiary-care cohort, we studied phenotype-related discordance between clinical criteria and molecular data and tested whether machine learning (ML) models could improve the prediction of reportable pathogenic/likely pathogenic variant positivity among patients with a clinical FH phenotype. Methods: Patients referred for suspected familial hyperlipidemia underwent targeted next-generation sequencing with a 9-gene panel. For the ML analysis, we focused on FH cases with a definitive molecular status (pathogenic/likely pathogenic vs. no reportable variant; variants of uncertain significance were excluded) and applied an 80/20 stratified split (n = 200; 82 molecular-positive cases). Elastic-net logistic regression, random forest, and XGBoost models trained on routinely available clinical variables were compared with dichotomized SB and DLCN classifications. Results: SB positivity was significantly more frequent in triglyceride-dominant phenotypes than in FH (68.4% vs. 52.3%, p = 0.041), despite the substantially lower molecular positivity (14.0% vs. 36.9%, p = 0.002), indicating FH-like false-positive clinical classification in mixed dyslipidemia. In the FH test set, the ML models showed higher discrimination for reportable pathogenic/likely pathogenic variant positivity than dichotomized rule-based criteria (AUC: XGBoost 0.808; random forest 0.769; elastic-net 0.747 vs. SB 0.639; and DLCN 0.598). Thirteen novel variants absent from gnomAD were identified, predominantly in LDLR. Conclusions: In this real-world Turkish cohort, within clinically defined FH cases, ML models performed better at predicting LP/P variant positivity than dichotomized DLCN and Simon Broome criteria. ML-based risk stratification may support prioritization for genetic testing; however, external validation is warranted. Full article

This study investigates the impact of inoculating seeds with bacterial endophytes isolated from Vitis amurensis Rupr. on endophytic community composition in Arabidopsis thaliana (L.) Heynh. Ten bacterial isolates of the genera Agrobacterium, Bacillus, Curtobacterium, Erwinia, Frondihabitans, Gordonia, Pantoea, Pseudomonas, Sphingomonas, and Xanthomonas were applied to seeds and some visible phenotypic effects were observed on plant growth after two weeks. High-throughput sequencing of 16S rRNA revealed that the native endophytic microbiome of A. thaliana was dominated by Gammaproteobacteria, Actinomycetes, Bacteroidia, and Alphaproteobacteria. The key families were Microscillaceae, Chitinophagaceae, Rhizobiaceae, Rhodanobacteraceae, Nocardioi-daceae, Nocardiaceae, Xanthomonadaceae, Devosiaceae, Microbacteriaceae, Crocinitomi-caceae, Pseudomonadaceae, Solimonadaceae, Comamonadaceae, Caulobacteraceae, and Micrococcaceae. Arabidopsis seed inoculation with Agrobacterium sp. R8SCh-B12, Curtobacterium sp. P7SA-B3, and Gordonia aichiensis P6PL2 significantly reduced alpha diversity (Shannon index) and altered beta diversity relative to controls, indicating strong community restructuring. These three isolates, along with Pseudomonas sp. R8SCh-B2, Sphingomonas sp. RA62c-B5, Xanthomonas sp. R7SCh-B6, and Bacillus velezensis AMR25, successfully colonized the plant tissues, as evidenced by significant increases in genus-specific amplicon sequence variants, ASVs (up to 17,820-fold for Curtobacterium sp. ASV33). In contrast, Pantoea sp. P7SCH-B5, Erwinia sp. R8SCh-B3, and Frondihabitans sp. RA62c-B2 failed to colonize A. thaliana, despite being applied to the seeds, suggesting the existence of mechanisms restraining colonization. These findings demonstrate that only a subset of grapevine-derived endophytes can effectively colonize A. thaliana, and that successful colonization correlates with significant shifts in the native microbiome, even in the absence of overt phenotypic changes. This emphasizes the importance of strain-specific compatibility in plant–endophyte interactions. Thus, we report the first descriptions of several novel endophytes that colonized Arabidopsis plants and establish a convenient model to investigate plant–bacterial interactions. Full article

Bovine leukemia virus (BLV) is an oncogenic retrovirus and the etiological agent of enzootic bovine leukosis (EBL), which is spread worldwide. This study presents data on the genetic diversity of BLV in the Novosibirsk region of Russia. ELISA-positive samples were selected from six districts of the Novosibirsk region (Dovolnoye, Barabinsk, Tatarsk, Toguchin, Bolotnoye, and Kochenyovo districts). To assess the diversity of circulating BLV genotypes, samples were collected from settlements and districts that were geographically distant from each other and had no shared pasture lands. In total, 1410 bp fragments encoding the env gene region were obtained from 417 BLV-positive samples. Phylogenetic analysis classified 325 BLV strains (77.9%) as genotype 4 (G4) and 92 strains (22.1%) as genotype 7 (G7). A pairwise identity matrix was constructed for 268 amino acid residues. Pairwise identity of BLV amino acid sequences in the gp51 region ranged from 96.6% to 100% for G4 and from 97.4% to 100% for G7. Multiple alignment of the amino acid sequences identified 74 mutations found in the Russian BLV variants. Through the addition of 417 novel env BLV sequences to GenBank, this study significantly expands the foundational data and knowledge of BLV molecular epidemiology in Russia. Full article

Background: CD8A-related CD8α deficiency (Immunodeficiency 116) is a rare autosomal recessive primary immunodeficiency disease characterized by absent CD8⁺ T cells and variable sinopulmonary disease. Case Presentation: A seven-year-old boy from a consanguineous family was referred for chronic wet cough and “uncontrolled asthma” despite being prescribed high-dose inhaled corticosteroids and montelukast. He was hospitalized seven times over a two-year period for presumed asthma exacerbations complicated by pneumonia. An examination revealed bilateral crackles without wheezing. Throat culture tested positive for Haemophilus influenzae. CT imaging showed signs of chronic rhinosinusitis (maxillary mucosal thickening) and chronic airway disease with bronchiectatic changes. The patient’s immunoglobulin levels were within normal ranges for his age group. Flow cytometry revealed profound CD8⁺ T-cell lymphopenia (CD8⁺ 0.21%; 11 cells/µL; near-absent after excluding dual-positive cells) with expansion of CD3⁺CD4⁻CD8⁻ T cells (29.5%). CD8A gene sequencing identified a novel homozygous nonsense variant NM_001768.7:c.319C>T (p.Arg107Ter; GRCh38: chr2:86790412G>A), consistent with loss of CD8α and secondary loss of CD8β surface expression. A literature review identified three previously reported symptomatic patients (and two asymptomatic sisters in the first family), all with recurrent respiratory infections and variable structural lung disease. Conclusions: This case highlights CD8A deficiency as a rare mimic of pediatric asthma and expands the genotype spectrum with a truncating CD8A variant. Early lymphocyte immunophenotyping in children with recurrent sinopulmonary infections may prevent delayed diagnosis and progressive airway damage. Full article

Background: Parental imprinting plays a crucial role in epigenetic regulation and is increasingly recognized for its involvement in neurodevelopmental disorders. Although ATP8A2 is considered a non-imprinted gene; However, the marked phenotypic variability observed across related disorders suggests that additional regulatory layers may influence its expression. Methods: We investigated the imprinting-like status of ATP8A2 through functional analyses of a splicing variant (c.1580-3C>G) identified in a patient diagnosed with Cerebellar Ataxia, Mental Retardation, and Disequilibrium syndrome type 4 (CAMRQ4). Sanger sequencing was used to assess allelic expression and identify aberrant transcripts. Results: Our analyses revealed an allelic expression imbalance suggestive of parental imprinting of ATP8A2. Moreover, Sanger sequencing led to the identification of a novel ATP8A2–RAB3GAP2 chimeric transcript, pointing to a previously unreported transcriptional event, the functional relevance of which remains to be determined. Conclusions: These findings indicate that ATP8A2 may be subject to imprinting-like regulation and involved in atypical splicing events with unknown significance. This highlights the need for further investigation into the epigenetic and transcriptional complexity of ATP8A2-related neurodevelopmental disorders. Full article

Introduction: Spondyloenchondrodysplasia with immune dysregulation (SPENCDI) is a rare autosomal recessive disorder caused by biallelic variants in the tartrate-resistant acid phosphatase 5 (ACP5) and characterized by variable skeletal, immunological, and neurological manifestations. Because early skeletal abnormalities may be subtle, diagnosis can be challenging in infancy. Materials and methods: We conducted a detailed clinical, immunological, radiological, and molecular evaluation of an infant with early-onset cytopenia, recurrent infections, seizures, and developmental delay. Genomic analysis was performed using whole exome sequencing (WES) and copy number variation sequencing (CNV-seq). In addition, we performed a structured narrative review of published ACP5-related SPENCDI cases to summarize the clinical spectrum and the currently reported use of Janus kinase (JAK) inhibitors. Results: Genomic analysis identified an ACP5 stop-gain variant (c.311G>A; p.Trp104*) with an apparently homozygous signal on WES. Re-evaluation of the copy-number data demonstrated an overlapping heterozygous 19p13.2–p13.13 deletion encompassing ACP5, indicating biallelic ACP5 defects consisting of a sequence variant on one allele and deletion of the other allele. Clinically, the patient showed prominent extra-osseous manifestations, including impaired T- and NK-cell cytotoxicity, before the emergence of definite radiographic skeletal abnormalities. Our literature review showed that skeletal abnormalities were repeatedly documented across published ACP5-related SPENCDI reports, although radiographic changes were often subtle and could be preceded by immune manifestations. Reported use of JAK inhibitors suggests potential benefit for immune dysregulation in selected patients, whereas the neurological response remains uncertain. Conclusions: This study reports a novel ACP5 variant and expands the known phenotypic spectrum of SPENCDI. SPENCDI should be considered in children with unexplained immune dysfunction and developmental delay, and suggestive neuroimaging findings, even when overt skeletal deformities are absent. Early genetic testing and targeted skeletal imaging may facilitate diagnosis. Full article

Chinese rice-field eels (Monopterus albus) are a commercially farmed freshwater fish species in China. In recent years, the rapid expansion of aquaculture has been accompanied by frequent outbreaks of viral diseases, posing a serious threat to the sustainability of the Chinese rice-field eel farming industry. In this study, a rhabdovirus strain was isolated from diseased Chinese rice-field eels at a farm located in Xiantao, Hubei Province, China. Although the complete genomic sequence of CrERV-XT showed higher identity to the infectious hemorrhagic syndrome virus (IHSV) (96.16%) than to CrERV (94.39%), phylogenetic analysis based on the L protein placed CrERV-XT within the same clade as CrERV, supporting its tentative classification as a novel variant of CrERV. Furthermore, the amino acid sequence of the L protein showed greater similarity to that of CrERV (97.89%) than to IHSV, while the N, P, M and G proteins exhibited higher homology with their counterparts in IHSV. CrERV-XT displayed considerable genetic divergence from known CrERV isolates, which is presumably attributed to its geographic isolation in different locations. Alignment of the G protein sequences from five strains (CrERV-XT, CrERV, CrERV-TYY25, CrERV-XY0907 and IHSV) revealed a total of 39 amino acid mutation sites. These findings provide valuable insights for investigating conserved functional domains within the CrERV G protein for the rational design of vaccine antigens against this emerging virus. Full article

Canine parvovirus (CPV) is a major pathogen causing severe gastroenteritis in dogs. Since its emergence, CPV has undergone continuous evolution, leading to the predominance of variants such as CPV-2a, CPV-2b, and CPV-2c. To characterize the genetic features and evolutionary trends of CPV-2 at a regional level, 775 fecal samples were collected from domestic and stray dogs with suspected CPV-2 infection in Shanghai between 2016 and 2025. The overall positivity rate was 23.2% (180/775); incidence was substantially higher in stray dogs (30.2%) than in domestic dogs (15.9%). Thirty-one CPV-2 strains were successfully isolated. Temporal analysis revealed a pronounced genotype shift: isolates from 2016 to 2020 were predominantly New CPV-2a, whereas CPV-2c became the dominant genotype from 2021 through 2025. Sequence analysis identified the polymorphism of VP2 gene and characteristic mutations F267Y, Y324I, N426E, Q370R and A440T in CPV-2c strains. A novel I447M mutation was detected in several isolates. Phylogenetic analysis showed that Shanghai isolates formed distinct clusters; CPV-2c strains were closely related to the Asian lineage. Structural modeling indicated that mutations at residues L87M, T101I, Y267F, A297S, G300A, Y305D, I324Y, Q370R, N426E, A440T, and I447M may alter the tertiary structure of the VP2 protein, potentially affecting antigenicity and receptor recognition. Collectively, these results demonstrate the complete genotype replacement of CPV-2 in Shanghai; CPV-2c is now predominant. Identification of the novel I447M mutation and structural analysis of key amino acid substitutions provide insight into CPV molecular evolution. These findings suggest that vaccines primarily based on older CPV-2 or CPV-2b genotypes offer suboptimal protection, highlighting the need for updated vaccine strategies targeting prevalent CPV-2c variants. Full article

Background: Genetic causes of growth failure should be suspected in patients born small for gestational age (SGA) who fail to show postnatal catch-up growth, present with severe short stature (SS), and exhibit a poor or absent response to growth hormone (rhGH) therapy. Mutations in the insulin-like growth factor 1 receptor (IGF1R) gene are associated with impaired growth, intrauterine growth restriction (IUGR), low birth weight and/or length, and postnatal SS. Case Description: A 9-year-old boy, born SGA for birth length, was evaluated for severe SS. Common causes of SS were excluded. At 9 years and 7 months of age, his height was 112.6 cm (−3.99 SDS), weight 18 kg (−3.79 SDS), and BMI 14.2 kg/m² (−1.8 SDS); pubertal development was Tanner stage 1. The target height was 158 cm (−2.62 SDS). Bone age was delayed by approximately one year compared with chronological age. Serum IGF-1 levels were within the upper-normal range for age. GH therapy (0.035 mg/kg/day) was initiated due to the lack of catch-up growth in an SGA subject. After three years of treatment, the height gain was only 0.5 SDS. IGF-1 levels showed a transient treatment-related increase, followed by persistent normalization during ongoing therapy. Next-generation sequencing (NGS) analysis identified novel heterozygous paternal nonsense variant in the IGF1R gene: c.3498C>G (p.Tyr1166Ter). At 12 years of age, impaired fasting glucose and reduced glucose tolerance were detected; consequently, it was decided to discontinue rhGH therapy, also in light of the IGF1R mutation and the lack of height recovery. Conclusions: This case underlines the critical role of genetic testing in the evaluation of patients born SGA. The coexistence of SGA status and an IGF1R gene mutation may provide a clear explanation for both the poor response to rhGH therapy and the increased risk of alterations in glucose metabolism. An extensive narrative review of the literature on growth outcomes and glucose metabolism abnormalities during GH treatment in SGA patients carrying IGF1R variants was also performed. 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

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare lung malignancy characterized by an aggressive clinical course and an unfavorable prognosis. Next-generation sequencing (NGS) has revealed that LCNECs exhibit molecular features resembling either small-cell lung carcinoma (SCLC-like LCNEC) or non-small cell lung carcinoma (NSCLC-like LCNEC). This study aimed to characterize the incidence of actionable gene variants in a retrospective cohort of LCNEC patients using a targeted NGS approach. Microscopic diagnosis was established according to the 2021 World Health Organization (WHO) classification using a standard immunohistochemical (IHC) panel. In total, 216 LCNEC tumor samples were analyzed for molecular variants in 17 genes using the RNA-based Archer FusionPlex Lung NGS assay (Integrated DNA Technologies, USA) and the MiSeq platform (Illumina, USA)—an algorithm utilized for routine NSCLC diagnosis. Overall, 46 variants were identified in 46/216 (21.3%) tumor samples, with 28/216 (13%) LCNECs harboring at least one actionable molecular variant potentially targetable by registered or investigational agents. KRAS variants (5%; including G12C at 2%) and PIK3CA variants (5%) were the most prevalent, followed by RET single-nucleotide variants (3%), uncommon EGFR variants (1%), and BRAF class II and III variants (<1%). Notably, no classical EGFR exon 18–21 mutations nor ALK, FGFR1/2/3, or ROS1 alterations (mutations or fusions) were detected, despite the technical capability of the assay to identify such variants. A novel in-frame gene fusion (TMEM79::NTRK1) was identified in a single tumor sample (0.5%). Our results confirm that LCNECs harbor potentially targetable alterations in KRAS, PIK3CA, RET, BRAF, and NTRK1, albeit at lower frequencies than those typically observed in NSCLC. Full article

Background: Heimler syndrome (HS) is a rare autosomal recessive disorder representing the mildest end of the peroxisome biogenesis disorder spectrum. It is caused by hypomorphic mutations in peroxisomal assembly genes, most commonly PEX1 and PEX6, and is characterized by sensorineural hearing loss, amelogenesis imperfecta, and retinal dystrophy. Due to phenotypic overlap with other inherited sensory disorders, particularly Usher syndrome, diagnosis of this condition is frequently delayed. Methods: We investigated two unrelated Saudi families presenting with congenital hearing loss and retinal dystrophy who were initially diagnosed with Usher syndrome. Detailed clinical evaluation, including comprehensive ophthalmologic and audiologic assessments, was performed. Whole-exome sequencing (WES) was conducted to identify the underlying genetic cause, followed by variant filtering and in silico pathogenicity prediction. Results: We identified a novel homozygous missense variant, p.Val97Gly (V97G), in the PEX6 gene that co-segregated with the disease phenotype in both families. This variant was absent from major population databases, including dbSNP, the 1000 Genomes Project, ExAC, and gnomAD, and was predicted to be deleterious by multiple in silico prediction tools. Clinically, affected individuals presented with congenital sensorineural hearing loss, pigmentary retinal dystrophy with electrophysiological evidence of cone–rod dysfunction, enamel abnormalities consistent with amelogenesis imperfecta, and mild dysmorphic facial features, supporting a diagnosis within the Heimler syndrome spectrum. Conclusions: Our findings expand the mutational spectrum of PEX6 and highlight Heimler syndrome as an important differential diagnosis in patients presenting with Usher-like phenotypes. To the best of our knowledge, this study represents the first report of the PEX6 p.Val97Gly variant associated with Heimler syndrome in a Saudi population, underscoring the value of whole-exome sequencing for accurate diagnosis and genetic counseling in individuals with inherited sensory disorders. Full article

Background: Chronic enteropathy associated with SLCO2A1 (CEAS) is a rare genetic disorder that is prone to misdiagnosis and characterized by significant challenges in achieving an early diagnosis. Current diagnosis relies on clinical manifestation combined with genetic sequencing. This study aimed to evaluate immunohistochemical (IHC) staining for SLCO2A1 protein deficiency as a diagnostic alternative, in addition to clinical pathological features. Method: Ten patients diagnosed with CEAS between January 2018 and August 2024 were enrolled. Clinicodemographic data, endoscopic findings, and treatment history were collected. Whole-exome sequencing identified SLCO2A1 variants. IHC staining for SLCO2A1 protein was performed from small intestine lesions and accessible GI sites. Results: Complete absence of SLCO2A1 protein expression was demonstrated by IHC in 9/10 patients, with significantly reduced expression in 1/10. This protein deficiency was consistently observed not only in the small intestine but also in the gastric antrum, duodenum, and terminal ileum. Genetic analysis revealed 7 novel SLCO2A1 variants among a total of 11 variants. A median diagnostic delay of 15 years (IQR 6–24) was observed. Ileal involvement and hypoalbuminemia (median albumin 28.02 g/L, IQR 22.1–33.0) were present in all patients. Common symptoms included abdominal pain (70%), melena (60%), and ileus (50%). Conclusions: The diagnosis of CEAS has been time-consuming and challenging. Detection of SLCO2A1 protein deficiency via IHC in either the disease-predominant small bowel or accessible non-lesional upper/lower GI mucosa demonstrates high diagnostic sensitivity for CEAS. This method could provide a practical, cost-effective alternative to genetic sequencing, particularly in resource-limited settings, and has the potential to significantly reduce diagnostic delays for this condition. 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