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Coban Akdemir, Z.

Publications and source records attributed to Coban Akdemir, Z..

3 recordsLinked to original sources
bioRxiv2026

Unveiling the Hidden Rules: Enhancing NMD Prediction for Protein-Truncating Variants

Nonsense-mediated decay (NMD) is a conserved RNA quality-control pathway that degrades transcripts containing premature termination codons. Because roughly a third of pathogenic variants in ClinVar can lead to truncated protein synthesis, predicting whether such transcripts undergo NMD is central to interpreting variant effects, yet the canonical 50-55 nucleotide rule explains only about half of observed outcome variability. Using paired whole-genome and RNA-sequencing from 10,306 individual samples in the Trans-Omics for Precision Medicine (TOPMed) program, we quantified NMD efficiency for 5,749 germline truncating variants via allele-specific expression and trained a gradient-boosting classifier, TrunCat, that distinguished NMD-sensitive from NMD-escape transcripts with [~]78% ROC-AUC (Receiver Operating Characteristic - Area Under the Curve). A reduced model using the ten features with the highest mean SHAP (SHapley Additive exPlanations) value as a measure of each features average contribution to predictions nearly matched this performance. Applied across large variant databases and a rare-disease cohort, the model produced NMD outcome predictions, with variants of uncertain significance showing higher predicted escape than pathogenic ones. This framework confirms the canonical rule, identifies non-canonical determinants, and offers a scalable resource for interpreting protein-truncating variants.

genomics↗
bioRxiv2020

De novo mutation in ancestral generations evolves haplotypes contributing to disease

PurposeThe variome of the Turkish (TK) population, a population with a considerable history of admixture and consanguinity, has not been deeply investigated deeply for its potential impact on the genomic architecture of disease traits. MethodsWe generated and analyzed a database of variants derived from exome sequencing (ES) data of 773 TK unrelated, clinically affected individuals with various suspected Mendelian disease traits, and 643 unaffected relatives. ResultsUsing uniform manifold approximation and projection (UMAP), we showed that the TK genomes are more similar to those of Europeans and consist of two main subpopulations: clusters 1 and 2 (N=235 and 1,181) that differ in admixture proportion and variome (https://turkishvariomedb.shinyapps.io/tvdb/). Furthermore, the higher inbreeding coefficient (F) values observed in the TK affected compared to unaffected individuals correlated with a larger median span of long-sized (>2.64 Mb) runs of homozygosity (ROH) regions (p-value=2.09e-18). We show that long-sized ROHs are more likely to be formed on recently configured haplotypes enriched for rare homozygous deleterious variants in the TK-affected compared to TK-unaffected individuals (p-value= 3.35e-11). Analysis of genotype-phenotype correlations reveals that genes with rare homozygous deleterious variants in long-sized ROHs provide the most comprehensive set of molecular diagnoses for the observed disease traits with a systematic quantitative analysis of HPO (Human Phenotype Ontology) terms. ConclusionOur findings support the notion that novel rare variants on newly configured haplotypes arising within the recent past generations of a family or clan contribute significantly to recessive disease traits in the TK population.

genomics↗
bioRxiv2019

Integrated Sequencing & Array Comparative Genomic Hybridization in Familial Parkinson’s Disease

BackgroundParkinsons disease (PD) is a genetically heterogeneous condition; both single nucleotide variants (SNVs) and copy number variants (CNVs) are important genetic risk factors. We examined the utility of combining exome sequencing and genome-wide array-based comparative genomic hybridization (aCGH) for identification of PD genetic risk factors. MethodsWe performed exome sequencing on 110 subjects with PD and a positive family history; 99 subjects were also evaluated using genome-wide aCGH. We interrogated exome sequencing and array comparative genomic hybridization data for pathogenic SNVs and CNVs at Mendelian PD gene loci. SNVs were confirmed via Sanger sequencing. CNVs were confirmed with custom-designed high-density aCGH, droplet digital PCR, and breakpoint sequencing. ResultsUsing exome sequencing, we discovered individuals with known pathogenic single nucleotide variants in GBA (p.E365K, p.T408M, p.N409S, p.L483P) and LRRK2 (p.R1441G and p.G2019S). Two subjects were each double heterozygotes for variants in GBA and LRRK2. Based on aCGH, we additionally discovered cases with an SNCA duplication and heterozygous intragenic GBA deletion. Five additional subjects harbored both SNVs (p.N52fs, p.T240M, p.P437L, p.W453*) and likely disrupting CNVs at the PARK2 locus, consistent with compound heterozygosity. In nearly all cases, breakpoint sequencing revealed microhomology, a mutational signature consistent with CNV formation due to DNA replication errors. ConclusionsIntegrated exome sequencing and aCGH yielded a genetic diagnosis in 19.3% of our familial PD cohort. Our analyses highlight potential mechanisms for SNCA and PARK2 CNV formation, uncover multilocus pathogenic variation, and identify novel SNVs and CNVs for further investigation as potential PD risk alleles.

genetics↗