Sudden unexplained nocturnal death syndrome (SUNDS), a subtype of sudden unexplained death, predominantly affects young, otherwise healthy individuals, with a higher prevalence in males and a geographic concentration in Southeast Asia, particularly Thailand. Despite extensive investigation, the genetic basis of SUNDS remains incompletely understood. Sarcomeric and non-sarcomeric gene variants were investigated in 98 SUNDS cases using whole-exome sequencing (WES). Postmortem cardiac examination and molecular modeling were performed to assess myocardial abnormalities and the structural impact of selected sarcomeric variants. Eleven missense variants in five sarcomeric genes (MYBPC3, MYH7, TNNI3, TNNT2, and TPM1) were identified in 12 cases (12.2%), whereas 37 variants across 18 non-sarcomeric genes were detected in 29 cases (29.6%). The MYH7 variant c.1562T>C (p.Ile521Thr) was identified as likely pathogenic. Cardiac histopathology revealed heterogeneous myocardial remodeling, including myocyte hypertrophy and interstitial fibrosis; some MYH7 variant carriers showed increased left ventricular wall thickness (>1.5 cm). Molecular modeling of the TPM1 variant c.641A>G (p.Tyr214Cys), located in the hinge region of the tropomyosin-troponin regulatory complex, suggested disruption of a native π-π stacking interaction, potentially affecting thin-filament stability. Sarcomeric variants were associated with heterogeneous myocardial remodeling in SUNDS. These findings highlight the genetic and pathological heterogeneity of SUNDS and suggest that sarcomeric gene variants represent a previously underrecognized contributor to myocardial remodeling and arrhythmogenic risk.
Gene-specific variant interpretation guidelines are constantly being published to refine variant classification. The development, implementation, and benefit of such guidelines require careful assessment. This study evaluates the utility of these guidelines on variant interpretation. All actionable genes listed in American College of Medical Genetics and Genomics-Secondary findings version 3.3 genes with available Clinical Genome Resource (ClinGen) Variant Curation Expert Panel criteria specifications were analyzed. A total of 1223 variants in these genes were classified using the American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria and revised according to the Variant Curation Expert Panel specifications. Reclassification outcomes were compared using high-confidence variants. Application of the revised guidelines resulted in score changes in 63.1% of variants, although most did not cross classification thresholds. Reclassification occurred in 20.3% of cases, predominantly as downgrades and improved concordance with ClinVar by 5.8%, particularly for benign classifications. Of 622 variants of uncertain significance (VUSs), 25.1% were resolved, with the highest resolution rates in BRCA1, BRCA2, and PALB2, whereas LDLR and TPM1 remained largely unchanged. No consistent correlation was found between the extent of criteria modification for each guideline and VUS resolution. The utility of the guidelines was shown to be variable and gene dependent. Although most reduced VUS rates and refined benign classifications, in some, only a minor impact was achieved, suggesting standardization and calibration of future guidelines are necessary.
Post-transplant engraftment monitoring is essential to assess the risk of complications after allogeneic hematopoietic transplantation, such as graft failure and disease relapse. It is based on the analysis of the percentage of chimerism detected in the recipient. Chimerism analysis has been routinely performed using short tandem repeats (STRs). Next-generation sequencing (NGS) has made possible the use of other genetic markers, such as single-nucleotide polymorphisms and insertions/deletions (indels). This study evaluated the performance characteristics of the NGStrack assay from GenDx to verify its accuracy, sensitivity, and reproducibility. It was determined that the assay can detect DNA contributed by donor and recipient within the range of 0.5% to 99.5%. The results of this assay were compared with an STR-based method, and examples of clinical utilization of the assay were provided using patient cases, including chimerism analysis on different cell subsets. It was confirmed that chimerism analysis using indel markers provides an increased sensitivity with respect to the reported sensitivity of assays using STR. The sensitivity for STR-based methods is in the range of 1% to 5%, whereas the sensitivity for the indel NGS-based method assessed here is 0.5%. The increased sensitivity and precise correlation between chimerism results with clinical events validates the usefulness of this assay for early diagnosis of disease relapse and graft failure and allows for more precise clinical management.
Lower respiratory tract (LRT) infections represent a major cause of mortality, particularly among critically ill patients. Molecular diagnostic tests have improved the detection of respiratory pathogens; however, most commercial assays are validated exclusively in upper RT (URT) specimens, limiting their applicability in LRT samples, which better reflect disease severity. This study evaluated the diagnostic performance of two commercially available assays, the BioFire Respiratory Panel 2.1 Plus and the Panther Fusion SARS-CoV-2/Flu A/B/RSV assay, on bronchoalveolar lavage (BAL) specimens, using the Allplex Respiratory Panel 1/2/3 and the Allplex SARS-CoV-2 assay as reference methods validated for both matrices. Overall, 132 BAL samples were analyzed. BioFire identified more positives than Allplex, particularly for human rhinovirus/enterovirus (HRV/EV), human parainfluenza virus (HPIV), and non-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The overall agreement was fair (κ = 0.237), and pathogen-specific concordance was almost perfect for SARS-CoV-2 (κ = 0.841), influenza A/B (κ = 0.808), and HPIV (κ = 0.884). The Panther assay showed substantial agreement with Allplex (κ = 0.719) and near-perfect concordance for SARS-CoV-2 and influenza viruses, while BioFire and Panther exhibited almost perfect interassay agreement (κ = 0.903). These findings demonstrate that assays validated for URT specimens can perform reliably on BAL samples, underlining the diagnostic potential of LRT matrices and the need for expanded validation of molecular respiratory panels across specimen types.
RT-PCR is the gold standard to determine the etiology of respiratory tract viral infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A, influenza B, and respiratory syncytial virus (RSV). Multiplex testing panels can test for infections or coinfections with these viruses at the point of care. Treatment using antiviral drugs and/or monoclonal antibodies and public health measures using vaccines and specific infection prevention practices depend on accurate diagnoses. The AMDI Fast PCR Mini Respiratory Panel is a 10-minute RT-PCR test for use at the point of care to detect these viruses from a single anterior nasal swab. It is run on the Fast PCR Instrument with integrated cloud connectivity for data management. The clinical performance of the Fast PCR Mini Respiratory Panel test was established in a multicenter clinical study of 1906 participants using the Cepheid Xpert Xpress CoV-2/Flu/RSV plus test as the comparator. The study population included 242 influenza A-, 77 influenza B-, 71 RSV-, and 87 SARS-CoV-2-positive samples and had an overall percentage agreement of 97.2%, 99.7%, 99.3%, and 99.3%, respectively. Of the total 85 (4.4%) discrepant results, 61 (72%) were associated with a low viral load. The AMDI Fast PCR Mini Respiratory Panel has excellent clinical performance, providing clinically useful information at the point of care in <10 minutes.
The first national human papillomavirus (HPV)-based cervical screening programs began in 2017. Since then, a growing list of countries have moved, or want to move, to HPV-based screening. One of the benefits of HPV-based screening is that a sample does not need to be collected from the cervix by a health care practitioner. Self-collection has been demonstrated to give equivalent accuracy as practitioner-collected specimens when a PCR-based clinically validated HPV assay is used. However, there are few clinically validated, PCR-based, HPV assays with on-label claims for self-collection. The current study, Self-Collection or Practitioner-Collection Evaluation 2 (SCoPE2), undertook a Validation of Human Papillomavirus Assays and Collection Devices for Self-Samples and Urine Samples (VALHUDES) protocol evaluation with individuals recruited in a colposcopy population in the context of an HPV-based screening program. SCoPE2 recruited 400 participants who each took a self-collected vaginal sample using a FLOQSwab. A practitioner-collected cervical sample was then collected at colposcopy. HPV testing was performed using both the cobas 4800 and the cobas HPV tests. The self-collected specimens demonstrated equivalent and noninferior relative sensitivity for histologically confirmed cervical intraepithelial neoplasia grade ≥2 (n = 58) when compared with the practitioner-collected specimen for both the cobas 4800 (0.982) and cobas (1.037), but relative specificity was inferior. Additional analyses were undertaken to resolve referral, self-collected, and practitioner-collected discordant results. SCoPE2 demonstrates that the assessed self-collection method is noninferior for the detection of cervical intraepithelial neoplasia grade ≥2 when compared with a practitioner-collected specimen.
Acute respiratory infections in children contribute to a significant volume of pediatric emergency department (PED) visits annually. Rapid molecular respiratory pathogen panels (RPPs) have increasingly been integrated into diagnostic workup. This study aims to investigate RPPs' impact on clinical management of children presenting to the PED and the effect of implementing restrictive criteria for RPP orders. Retrospective analysis of PED RPP orders from June 2023 through June 2024 was performed with a randomized subset of 400 patients in two cohorts (infants <1 year old and children 1 to 5 years old) selected for in-depth chart abstraction, including clinical presentation and management, with even distribution of RPP-positive and RPP-negative patients. Of 2052 RPPs performed from children age 5 years or younger, 1464 (71.3%) were positive for one or more targets. Regardless of RPP result or patient age, no significant differences in disease severity (mean Emergency Severity Index of 3.7 versus 3.7) or clinical management (infants, 6.0%; young children, 5.0%) were observed. Applying stewardship criteria retrospectively to both cohorts demonstrated a potential 48% reduction in unnecessary testing by RPP. RPP results, positive or negative for one or more targets, had limited impact on clinical management in the PED. The data support the potential value of stewardship intervention to reduce cost while maintaining critical pathogen identification.
Large-scale tumor molecular profiling has enabled the discovery of diagnostic, prognostic, and therapeutic biomarkers, and expanded the clinical utility of alterations such as gene amplifications (GAMPs), homozygous deletions (HMZ-Dels), and biallelic inactivation (BI) of tumor suppressor genes. Comprehensive clinical detection of these events is essential for optimal patient management. Illumina's TruSight Oncology 500 (TSO500) kit detects multiple biomarkers, including GAMPs for select genes, but does not assess HMZ-Del or BI events. To address this gap, OncCNV, a genome-wide copy number analysis and visualization pipeline that integrates both on-target and off-target probe data from TSO500 sequencing, was developed. Performance optimization evaluated copy number calling tools, on-target and off-target probe selection strategies, off-target bin sizes, and panel-of-normal configurations. Clinical validation was conducted using 132 unique solid tumors characterized by a clinically validated microarray assay. OncCNV showed >96% positive percentage agreement, >99% negative percentage agreement, and >99% accuracy at the assay's established limit of detection (40 ng DNA at 40% tumor content). Sensitivity for HMZ-Del and BI detection decreased to 62%-70% at tumor content of 20%-39% in in silico dilution experiments; however, intrarun, interrun, and interanalyst precision remained >99%. OncCNV extends the analytical capabilities of TSO500 by enabling robust and precise detection of GAMP, HMZ-Del, and BI events, enhancing solid tumor comprehensive molecular profiling.
Pediatric HIV-1 viral load monitoring is often limited by the small blood volumes that can be safely obtained from infants and young children. Standard assays typically require 0.5 to 0.7 mL of plasma, which can pose challenges in these settings. This study evaluated a modified low-volume protocol using 100 μL of plasma, diluted for use with the Hologic Aptima HIV-1 Quant Dx assay, to determine whether performance was equivalent to the standard 700 μL protocol. An analytical validation was conducted by using de-identified EDTA plasma samples spanning a wide range of HIV-1 RNA concentrations. Each specimen was tested by using both protocols on the Panther system. Agreement between methods was assessed by using log10 differences, correlation analysis, and Bland-Altman analysis; within-run and between-run precision was evaluated by using replicate testing of negative, low-positive, and high-positive samples. The 100 μL protocol displayed excellent concordance with the standard method, with a mean log10 difference of approximately 0.00 and a maximum difference of 0.12 log10 copies/mL. No false-positive or false-negative results were observed among 30 fully suppressed samples. Precision analyses showed minimal variability, with all results within predefined acceptability criteria. These findings indicate that the low-volume Aptima protocol provides accurate and reliable HIV-1 RNA quantification and can expand access to viral load testing in pediatric patients and other clinical settings in which plasma volume is limited.
Molecular profiling of solid tumors is increasingly essential in oncology practice, guiding diagnosis-prognosis and providing patients with access to molecularly matched therapies that can improve outcomes. In this study, 554 patients with advanced solid tumors were evaluated through the POWER (Precision Oncology at Western University) study, a first of its kind Canadian study, designed to prospectively assess the clinical impact of expanded pan-cancer next-generation sequencing (NGS) panel testing on patient management, in real-world oncology practice and evaluate the overall health system impact. The findings reveal that 79% of patients had clinically relevant variants, and nearly 28% experienced changes in treatment eligibility because of the identification of novel druggable mutations. Additionally, the analysis shows that a pan-cancer NGS panel significantly impacted patient management, with 18% of patients receiving access to clinical trials and off-label therapy with expected better outcomes and 19% (31/162) patients, previously tested by tumor-specific panels, experiencing management changes when tested through POWER. This study also highlights the broader health system impact: access to safer treatment options (14.5%), change in management (17.6%), treatment sequence changed (17.3%), and Ministry of Health formulary treatment saved (12.5%). These results underline the benefits of expanded NGS testing over tumor-specific panels in guiding personalized treatment decisions, optimizing patient care, and enhancing health care delivery in oncology.
Accurate and reproducible interpretation of somatic variants is fundamental for therapy decision-making in patients with cancer. To harmonize and automate oncogenicity classification, Oncogenicity Variant Interpreter (OncoVI), an open-source, Python-based implementation of the Clinical Genome Resource/Cancer Genomics Consortium/Variant Interpretation for Cancer Consortium oncogenicity guidelines, was developed. For each of the guideline criteria, the textual descriptions were interpreted, and publicly available resources were identified to be used as reference. Starting from the genomic coordinates of a variant, OncoVI automatically performs functional annotation, collects relevant evidence from the integrated resources, evaluates each criterion, and provides a final oncogenicity classification. OncoVI achieved an accuracy of 80% on a gold standard set of 93 somatic variants provided by the guidelines, with a sensitivity of 88% for oncogenic/likely oncogenic variants. When applied to a real-world set of 7802 variants from 557 participants previously evaluated by the Molecular Tumor Board (MTB) Erlangen, OncoVI showed 79% concordance with the prior MTB assessment of variant impact on protein function. In addition, expert reassessment of 135 MTB variants, conducted in accordance with the oncogenicity guidelines, further confirmed both the validity of OncoVI implementation and the appropriateness of the identified resources. Taken together, OncoVI provides significant support for the harmonized and reproducible oncogenicity classification of somatic variants across institutions.
This large-scale retrospective study investigated the allele, diplotype, and phenotype frequencies of CYP2B6, CYP2C19, and CYP2D6 in a Han Chinese population (N > 10,000), using real-world genetic data from The First Hospital of Hebei Medical University, assessed between March 2021 and April 2025. Single-nucleotide polymorphism genotyping was performed using the Agena MassARRAY assay. CYP2D6 copy number variation (CNV) was analyzed by TaqMan real-time quantitative PCR. The sample sizes were 9729 for CYP2B6, 11,479 for CYP2C19, and 11,315 for CYP2D6, all from the Han Chinese population. The high frequencies of alleles were CYP2B6∗6 (16.19%), CYP2C19∗2 (30.36%), and CYP2D6∗10 (41.67%), with the most common diplotypes being CYP2B6 ∗1/∗6 (23.65%), CYP2C19 ∗1/∗2 (37.62%), and CYP2D6 ∗1/∗10 (16.05%), respectively. At the phenotype level, normal metabolizer was most common for CYP2B6 (57.86%) and CYP2D6 (60.50%), whereas the intermediate metabolizer phenotype was noted for CYP2C19 (44.77%). CYP2D6 CNVs included zero copies (0.43%), one copy (13.64%), two copies (83.79%), three copies (2.11%), and more than three copies (0.03%). This large-scale, real-world study of a Northern Han Chinese cohort provides a valuable pharmacogenomic reference and demonstrates the necessity of integrating CNV analysis with single-nucleotide polymorphism genotyping to ensure accurate clinical phenotyping of CYP2D6.
Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder with extensive allelic heterogeneity. Although RNA-based assays can increase sensitivity, their cost and complexity limit their routine use. A DNA-only tiered diagnostic approach was evaluated in 1917 unrelated Korean individuals with clinically suspected NF1. The process began with targeted sequencing of blood-derived genomic DNA, followed by reflex multiplex ligation-dependent probe amplification for copy number variants and a lesional tissue test for suspected mosaicism. Initial targeted sequencing of the NF1 gene established a diagnostic yield of 74.0%. The addition of reflex multiplex ligation-dependent probe amplification and tissue testing increased the cumulative yield to 79.2%. Subsequent post-report variant reclassification and whole-genome sequencing further increased the overall diagnostic yield to 81.6%. Among 901 distinct pathogenic variants identified-81.4% of which were private-truncating variants were predominant (79.0%). Notably, several variants enriched in European cohorts and with established genotype-phenotype correlations (eg, p.Arg1809Cys, p.Met992del, and p.Arg1276Gln) were rare in this cohort, highlighting population-specific differences. Individuals with large deletions were referred at younger ages, suggesting potential genotype-phenotype associations. These data demonstrate that a stepwise, DNA-only strategy delivers high yield and scalability for routine NF1 diagnostics, while delineating a Korean-specific mutational landscape. This practical workflow offers a robust alternative to RNA-based approaches in real-world clinical settings.
Quantitative real-time PCR assays often lack harmonization, leading to variability in viral load reporting. Differences in calibration materials, assay design, extraction methods, and gene targets further complicate standardization. This study evaluated the Qiagen QIAcuityDx digital PCR (dPCR) platform for absolute quantification of adenoviruses and compared its performance with Bio-Rad droplet dPCR and the standard-of-care quantitative real-time PCR assays. Viral loads of commercially available quality control materials, calibrators, and clinical samples were assessed. Whether adenovirus genotype affects quantification precision across platforms was also examined. Replicates of the human adenovirus (HAdV) verification panel and control materials (Bio-Rad HAdV E4 and ZeptoMetrix HAdV B3) were tested using both dPCR systems. Both demonstrated excellent correlation and equivalent analytical sensitivity at 1000 copies/mL. Remnant clinical samples representing 16 HAdV genotypes were tested in serial dilutions with both digital PCR methods and the standard-of-care assay. Strong agreement was observed across assays for viral loads ≥1000 copies/mL, regardless of genotype. The Qiagen QIAcuityDx platform showed an average bias of -0.31 (SD, 0.44) log copies/mL relative to quantitative real-time PCR. These findings demonstrate that dPCR enables accurate and reproducible HAdV quantification and support its utility for calibration and standardization in clinical molecular testing. Despite minor platform differences, both dPCR systems were highly concordant with each other and with standard-of-care quantification.
Gastrointestinal stromal tumors (GISTs) are predominantly characterized by mutations in KIT or PDGFRA. Mutation detection is important for optimal therapy. Next-generation sequencing (NGS) panels are useful in GIST assessment as they allow for simultaneous evaluation of multiple genes. However, inherent to use of NGS with short-read sequences on formalin-fixed specimens is the potential to miss larger insertion or deletion variants. Over 9 years, GIST testing was performed on specimens from 55 patients by amplicon-based, semiconductor NGS using the Ion AmpliSeq Cancer Hotspot Panel version 2, a Cancer Hotspot Panel version 2-based GIST panel, or the Oncomine Precision Assay. Negative cases were evaluated by dideoxy sequencing for detection of mutations in KIT and PDGFRA, as per the clinical protocol. Before reflexive sequencing, of 55 completed analyses, 47 (85%) were positive for KIT or PDGFRA mutations by NGS. Three cases were attributed to positivity for pathogenic variants in other genes. Of the five cases evaluated by dideoxy sequencing, all five (9% of all specimens) were positive for pathogenic or likely pathogenic KIT mutations. A total of 12% of KIT mutations required dideoxy sequencing for identification. Mutations were 12 to 39 nucleotide deletion or duplication variants. The results suggest that short-read, amplicon-based NGS assays may miss a significant number of clinically actionable KIT mutations and that follow-up of KIT and PDGFRA NGS-negative cases by alternative testing modalities should be considered.
Tumor next-generation sequencing (NGS) is widely used to refine diagnosis and identify therapy targets. However, reporting criteria, schemas, and formats vary greatly, which can affect uniformity of clinical cancer care. With the aim of promoting harmonization, the current state of NGS reporting practices was profiled across Genomics Organization for Academic Laboratories members. The assessment included a group landscape analysis to refine topics followed by a survey of member laboratories and post-survey discussions. A total of 28 surveys covering hematology and/or solid tumor panels from 21 academic laboratories were analyzed. Most responses indicated use of one or more variant tiering systems and reporting of all presumed somatic variants of uncertain significance. Most indicated significant manual effort by directors in generating final reports related to variant annotation using multiple external and internal laboratory databases, evaluation for potential germline variants, and correlation with prior NGS studies and clinical context. Report differences by indication related to more frequent inclusion of longitudinal comparisons for hematologic neoplasms and potential therapies for solid tumor reports. On the basis of areas of strong consensus among survey participants, considerations for best practices are presented along with opportunities for future harmonization, which may require improvements in classification schemas or better software tools.
The Idylla GeneFusion Assay detects gene fusions with fusion-specific and expression imbalance methods. The purpose of this study was to evaluate the diagnostic utility of detecting fusions with expression imbalance alone in non-small-cell lung cancer. Results of ALK, ROS1, and RET fusion detection with expression imbalance were compared with results of orthogonal testing. Of 1982 cases reviewed from October 2022 through August 2024, 63 (3.2%) had fusions detected with the expression imbalance method alone, including 47 ALK, 10 ROS1, and 7 RET fusions. One case had ALK and RET fusions. Fluorescence in situ hybridization (FISH) confirmation for 51 cases revealed 8 positive (15.7%), 3 equivocal (5.9%), and 40 negative (78.4%) results. Anaplastic lymphoma kinase (ALK) immunohistochemistry performed for 22 ALK-detected cases revealed 3 positive (13.6%) and 19 negative (86.4%) results that were concordant with ALK FISH results. The positive predictive value of expression imbalance detection alone varied by gene (12.5% for ALK, 16.7% for ROS1, and 33.3% for RET). RNA next-generation sequencing results for seven select cases (three ALK, two ROS1, and two RET) showed six novel fusions (eg, STRN::ALK, SQSTM1::ROS1, and ERC1::RET) and had 100% concordance with FISH results. One case showed an NOL10::ALK out-of-frame fusion with negative ALK immunohistochemistry and equivocal ALK FISH results. Because the expression imbalance method can detect novel fusions, its implementation with confirmation testing is recommended.
Cytologic specimens, often the only available sample, are increasingly relied upon for comprehensive genomic profiling in patients with advanced malignancies, necessitating detailed characterization of next-generation sequencing (NGS) assay performance. Whether quality thresholds based predominantly on formalin-fixed, paraffin-embedded (FFPE) tissue can be directly applied to cytologic preparations remains uncertain. This study retrospectively analyzed 10,900 unique specimens sequenced on a custom NGS panel, including a focused subset of 455 consecutive cytologic specimens and 2759 FFPE surgical pathology controls. Specimen types included Diff-Quik-stained smears, Papanicolaou-stained smears, cell-block sections, and FFPE tissue. Sequencing quality was assessed by the percentage of targeted bases achieving ≥100× coverage. Cell blocks performed comparably to FFPE tissue across all quality metrics (median percentage target coverage ≥98%). Cytologic smears yielded DNA of adequate quantity and quality for sequencing but demonstrated reduced target coverage uniformity (median percentage target coverage 74.7% for Papanicolaou-stained smears and 89.2% for combined preparations), increased GC bias, and elevated mean absolute pairwise difference values relative to FFPE controls (P < 2.2 × 10-16). These differences were driven by intrinsic physicochemical properties of smear preparation and staining rather than by DNA input concentration or tumor purity. Although cytologic smears yield DNA suitable for hybrid-capture NGS, specimen-type-specific validation criteria and cytology-aware normalization strategies are essential for maximizing clinical yield and reliability.
Large genomic rearrangements (LGRs) account for at least 10% of the mutations in BRCA1 and 5% of BRCA2 mutations in outbred families with hereditary breast and ovarian cancer. A total of 21 probands with breast cancer who carried BRCA1 or BRCA2 LGRs were identified from a cohort of 4678 Chinese patients. There was a total of 13 BRCA1 LGR carriers and 8 BRCA2 LGR carriers, including 12 large genomic deletions and 1 duplication. Ten and three specific breakpoints from BRCA1 and BRCA2, respectively, were identified by either whole-genome sequencing by nanopore sequencing or long-range PCR. Five of these LGRs were recurrent LGRs. Three LGRs were novel founder LGRs in the southeast Chinese population. Chinese LGR carriers exhibited clinical phenotypes that were generally similar to those of non-LGR mutation carriers. However, there was a notable tendency for triple-negative breast cancer to be more prevalent among Chinese LGR carriers (P = 0.007), largely because of the predominance of BRCA1 mutations. This suggests a potential association that warrants further investigation.
Inherited retinal dystrophies (IRDs) represent a diverse group of rare pathologies affecting vision, with significant genetic and clinical variability. Clinical exome sequencing was performed on 143 families clinically diagnosed with IRDs. The obtained variants were filtered and classified according to the American College of Medical Genetics and Genomics guidelines. Overall, a genetic diagnosis was achieved for 68.53% of the families in the cohort; 35 causative genes were identified, predominantly ABCA4 and USH2A. A total of 170 clinically relevant variants were identified, 45 (26.47%) of which were novel, with missense variants being the most common type (40.59%). This study reported aberrant splicing generated by the ABCA4 (NM_000350.2): c.1299A>G mutation through the functional assay of a minigene. Furthermore, the genes FAM161A and GUCY2D were associated with IRDs that are not typically linked to these genes. Consequently, this study expands the current understanding of IRDs and supports the use of clinical exome sequencing as an effective strategy for the genetic diagnosis of these pathologies.