{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:13:12Z","timestamp":1783487592398,"version":"3.55.0"},"reference-count":41,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: False-positive variant calls generated within low-complexity regions (LCRs) remain a persistent bottleneck in clinical genomics, complicating downstream analysis. This study evaluates a targeted spatial masking strategy designed to suppress deterministic artifacts in short-read sequencing data, while preserving clinically actionable variants residing outside LCRs. We implemented a selective masking protocol prior to variant calling across analytical reference standards (EQA, NA12878) and two independent breast cancer whole-exome sequencing cohorts (n = 25). Methods: Callsets were evaluated for diagnostic sensitivity, precision gains, mutational signatures, VAF behavior, pseudo-multiallelic noise and ClinVar\/dbSNP annotation. Results: The protocol removed thousands of sequencing and alignment artifacts while maintaining the retained biological callset, with negligible disease-associated diagnostic variants detected in the excluded artifact fraction. LCR masking preserved physiological Ti\/Tv and Ins\/Del profiles in retained calls, resolved pseudo-multiallelic noise, and distinguished excluded artifact calls by distorted mutational and VAF signatures. dbSNP profiling showed cohort-dependent behavior: TCGA-BRCA reproduced an intriguing phenomenon, with excluded calls showing higher dbSNP annotation than retained calls, whereas AURORA showed the opposite direction. Conclusions: These findings demonstrate the potential vulnerability of one-dimensional database annotation for variant authentication and highlight targeted spatial filtration as a critical, early pipeline intervention for high-fidelity clinical genomics of non-LCR-associated germline variants using short reads.<\/jats:p>","DOI":"10.3390\/genes17070772","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T03:06:34Z","timestamp":1782875194000},"page":"772","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeted Genomic Region Masking Supports Accurate Variant Calling While Suppressing Low-Complexity Sequencing Artifacts"],"prefix":"10.3390","volume":"17","author":[{"given":"Chrysoula","family":"Kaligerou","sequence":"first","affiliation":[{"name":"Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Athina","family":"Tsagkalidou","sequence":"additional","affiliation":[{"name":"Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1543-2418","authenticated-orcid":false,"given":"Vasiliki","family":"Pogka","sequence":"additional","affiliation":[{"name":"Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8800-1701","authenticated-orcid":false,"given":"Dimitrios Christos","family":"Tremoulis","sequence":"additional","affiliation":[{"name":"Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0841-9159","authenticated-orcid":false,"given":"Timokratis","family":"Karamitros","sequence":"additional","affiliation":[{"name":"Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2235","DOI":"10.1056\/NEJMsr1406261","article-title":"ClinGen\u2014The Clinical Genome Resource","volume":"372","author":"Rehm","year":"2015","journal-title":"N. 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