Biomedical subjects

Siddharth Narendran

Publications and source records attributed to Siddharth Narendran.

2 recordsLinked to original sources

PubMed2026

Whole-Exome Sequencing in a Consanguinity-Enriched South Indian Retinitis Pigmentosa Cohort: Diagnostic Yield and Molecular Spectrum.

PURPOSE: To determine the molecular diagnostic yield, variant spectrum, inheritance architecture, and influence of consanguinity on whole-exome sequencing outcomes in a South Indian retinitis pigmentosa (RP) cohort. DESIGN: Prospective, registry-based cohort study. SUBJECTS: A total of 113 affected participants were enrolled through the Aravind Registry for Inherited Diseases of the Eye, including 109 unrelated probands and 4 affected relatives from already represented families. Primary analyses were restricted to the 109 unrelated probands. METHODS: Whole-exome sequencing was performed using a clinical exome workflow. Variants were interpreted using American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria and cases were categorized as solved, possibly solved, inconclusive, or unsolved using prespecified inheritance-aware rules. MAIN OUTCOME MEASURES: Molecular diagnostic yield, distribution of implicated genes and variant classes, inheritance architecture, and diagnostic yield stratified by consanguinity status. RESULTS: Among the 109 unrelated probands, mean age at testing was 39.3 ± 14.1 years and 58.7% were male. Whole-exome sequencing identified 186 distinct rare variants across 92 inherited retinal disease genes, including 26 pathogenic and 33 likely pathogenic variants. A molecular diagnosis was established in 50 of 109 probands (45.9%), including 42 solved and 8 possibly solved cases; 45 (41.3%) were inconclusive and 14 (12.8%) remained unsolved, including 4 (3.7%) in whom no candidate variant was identified. EYS, USH2A, and ADGRV1 were the most frequently implicated genes. Autosomal recessive (AR) disease predominated (44/50, 88.0%). Consanguineous AR cases were exclusively homozygous (17/17); notably, 68.0% of nonconsanguineous AR cases were also homozygous (P = 0.013). Diagnostic yield was higher in consanguineous probands (51.4% vs. 41.7%), without reaching significance. Recurrent alleles included an established South Asian founder variant (MFSD8 c.1361T>C) and candidate founder alleles in EYS (c.4321C>T) and ADGRV1 (c.14329C>T). CONCLUSIONS: Whole-exome sequencing established a molecular diagnosis in nearly half of this South Indian RP cohort and revealed a predominantly recessive, homozygosity-enriched architecture shaped by consanguinity. These findings define a region-specific variant landscape to support clinical interpretation, genetic counseling, and future trial enrollment in this underrepresented population. FINANCIAL DISCLOSURES: The authors have no proprietary or commercial interest in any materials discussed in this article.

Consanguinity↗

PubMed2026

Diagnostic Accuracy of a CRISPR-Based Assay in Smear- and Culture-Negative Fungal Keratitis.

IMPORTANCE: Diagnosing fungal keratitis (FK) in patients with negative smear and culture results remains clinically challenging, highlighting the need for alternative diagnostic approaches. OBJECTIVE: To determine the diagnostic accuracy of the clustered regularly interspaced short palindromic repeats (CRISPR)-based Rapid Identification of Mycoses using CRISPR (RID-MyC) assay for detecting FK in patients with negative smear and culture results using in vivo confocal microscopy (IVCM) as the reference standard. DESIGN, SETTING, AND PARTICIPANTS: This prospective diagnostic accuracy study was conducted from December 2024 to March 2025 at Aravind Eye Hospital, a tertiary ophthalmology referral hospital in Coimbatore, India. Consecutive patients clinically suspected to have microbial keratitis with negative smear and culture results were eligible for inclusion. Data were analyzed from March 2025 to June 2025. INTERVENTIONS: All included participants underwent corneal scraping for RID-MyC assay and imaging by IVCM. MAIN OUTCOMES AND MEASURES: The primary outcomes were sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic concordance of the RID-MyC assay compared with IVCM results. RESULTS: Of 245 consecutive patients clinically suspected to have microbial keratitis, 82 were smear negative. After exclusions due to contraindications or positive subsequent cultures, 41 patients with smear- and culture-negative results were ultimately included in the final analysis. Of these 41 patients (mean [SD] age, 51.0 [14.6] years; 21 [51.2%] women), RID-MyC demonstrated sensitivity of 82.1% (95% CI, 63%-94%) and specificity of 76.9% (95% CI, 46%-95%). Positive predictive value was 88.5% (95% CI, 74%-95%) and negative predictive value was 66.7% (95% CI, 46%-82%). Concordance between RID-MyC and IVCM was observed in 33 cases (80.5%). Notably, prior antifungal treatment was most frequent (4 of 5 [80%]) among patients with positive IVCM but negative RID-MyC results. Conversely, all patients (3 of 3 [100%]) with negative IVCM but positive RID-MyC findings had smaller, peripheral, or paracentral lesions. CONCLUSIONS AND RELEVANCE: In this diagnostic study, in patients with smear- and culture-negative FK, the RID-MyC assay showed good diagnostic accuracy comparable with IVCM and was feasible in all cases, including those in whom imaging was not possible. With its rapid turnaround and minimal equipment needs, RID-MyC may serve as a practical adjunct to conventional diagnostics, particularly in high-burden, resource-limited settings where IVCM is unavailable or contraindicated.

Humans↗