Background/Objectives: Congenital anomalies and neurodevelopmental disorders frequently co-occur and exhibit substantial genetic and phenotypic heterogeneity, posing a persistent diagnostic challenge. Exome sequencing has become an important first- or second-tier diagnostic tool for these conditions, yet diagnostic yields vary considerably depending on phenotype, ancestry, sequencing strategy, and interpretation, with over half of referrals remaining without a definitive genetic diagnosis. Methods: We analyzed data from 692 patients referred to the Department of Cytogenetics and Genomics at the Cyprus Institute of Neurology and Genetics between January 2021 and December 2025 for clinical exome sequencing or whole-exome sequencing as part of the diagnostic work-up for congenital disorders and/or syndromic or non-syndromic neurodevelopmental disorders. Results: A total of 134 distinct variants were identified, corresponding to an overall diagnostic yield of 17.9% out of which 52 (38.8%) were novel, and 50 variants (37.3%) were de novo, as expected from the high proportion of severe neurodevelopmental presentations. Missense variants were the most prevalent within our cohort, while chromatin and transcriptional regulator genes constituted the largest functional gene category, followed by variants in collagen-encoding genes. Conclusions: This study provides the first systematic, mutational-level characterization of a Cypriot Mendelian disease cohort, establishing a local baseline diagnostic yield and revealing a high proportion of novel variants that reflect the underrepresentation of Eastern Mediterranean populations in global databases. These findings underscore the value of submitting population-specific variants to public repositories and of phenotype-driven reanalysis targeting recurrent gene families, supporting more efficient diagnostics and future precision medicine initiatives in Cyprus.
BACKGROUND:People with cystic fibrosis (pwCF) and primary ciliary dyskinesia (pwPCD) are particularly vulnerable to the harmful effects of air pollution due to the impairment of mucociliary clearance (MCC). Despite growing evidence supporting the use of indoor air purification in common lung conditions, its role in CF and PCD remains unexplored. METHODS:The Clean Air for Rare MCC dIsorders (CARMUCI) study is a randomized, double-blind, cross-over, sham-controlled trial aiming to evaluate the impact of indoor air purification on the respiratory health of pwCF and pwPCD (children and adults) in Cyprus. Sixty-two participants will receive two 3-month intervention periods using identical-looking air purifiers: one 3-month period with active filtration via high-efficiency filters and one 3-month period with a sham unit. Primary outcome will be a mean difference of at least 10% change in lung clearance index, and secondary outcomes will include spirometry, pulmonary exacerbations, inflammatory biomarkers, and health-related quality of life. Exposure to indoor particulate matter (PM) will be continuously monitored using device operation logs and wearable activity trackers. RESULTS:By August 2025, 24 pwCF and 26 pwPCD (20 females, age: 31 [16.1] years) have been enrolled. CARMUCI continues enrollment and will start data collection in September 2025. Results are expected to provide novel evidence on the efficacy of air purification in reducing indoor PM exposure and improving respiratory outcomes in people with chronic MCC disorders. CONCLUSION:CARMUCI trial first results are expected in late-2027 and may inform future clinical guidelines and environmental health strategies for managing rare MCC disorders.
Purpose We aimed to broaden the understanding of autosomal recessive neurodevelopmental disorders caused by VARS1 by describing new clinical and molecular findings and assessing the predicted structural impact of identified variants. Methods We clinically evaluated 13 affected individuals from 10 unrelated families presenting with a neurodevelopmental disorder. We used exome sequencing and cosegregation analyses to identify disease-causing variants, followed by three-dimensional in silico analyses and molecular dynamics simulations to assess the likely functional consequences of both previously reported and novel variants. Results In all affected individuals who presented with a neurodevelopmental syndrome with progressive microcephaly, seizures, and intellectual disability, we identified biallelic disease-causing variants in VARS1. Two variants were predicted to induce premature protein truncation leading to loss of VARS1 function. The remaining 13 detected missense variants were located in the catalytic and aminoacylation domains, and in silico analysis of the affected residues showed that such substitutions can disrupt local protein dynamics, RNA-interaction surfaces, or catalytic geometry, thereby affecting ligand recognition, substrate specificity, and tRNA interaction. Conclusion Together with prior reports, our results provide strong additional evidence supporting VARS1 as a recurrent cause of autosomal recessive neurodevelopmental disorders and expand the known clinical and allelic spectrum. While in silico analyses provide mechanistic plausibility for novel variants, functional studies will be important to confirm variant-specific effects and disease mechanisms.
