{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T10:02:34Z","timestamp":1789466554376,"version":"build-2803163510"},"reference-count":37,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Education and Science of the Republic of North Macedonia","award":["15-6171\/46"],"award-info":[{"award-number":["15-6171\/46"]}]},{"award":["15-6171\/46"],"award-info":[{"award-number":["15-6171\/46"]}],"id":[{"id":"https:\/\/ror.org\/0221ghv91","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Expanded carrier screening (ECS) panels often rely on pan-ethnic databases, such as the ACMG Tier 3 panel, but their ability to capture population-specific reproductive risk is uncertain. We characterized pathogenic\/likely pathogenic (P\/LP) variants and at-risk-couple (ARC) probabilities in an underrepresented population from North Macedonia to inform ECS gene prioritization. Methods: NGS data from 1438 subjects of Macedonian, Albanian, and other local ancestry, referred for rare-disease diagnostics, were analyzed across 1795 candidate autosomal recessive\/X-linked genes. P\/LP variants were compared with gnomAD exomes v2.1.1 non-Finnish European frequencies (Fisher\u2019s exact test). Gene-specific ARC probabilities ranked genes and generated cumulative ARC curves per subgroup. Results: We identified 2007 P\/LP variants across 1096 genes. One hundred variants in 89 genes reached an allele frequency \u2265 1\/200 in the Macedonian or Albanian subgroups; over one-third were absent from candidate ECS panels, mostly linked to severe or variable phenotypes. ARC saturated rapidly: genes with carrier counts \u2265 1\/100 (ACMG Tier 2) accounted for over 85% of total ARC, and with \u22651\/200 (ACMG Tier 3) for more than 93%. Total ARC among autosomal recessive panel genes (X-linked genes analyzed separately) was 3.42%, rising to 5.02% in the Albanian subgroup. Excluding top hypomorphic variants reduced ARC by 34\u201337%, highlighting variant-specific penetrance. The highest-ARC genes diverged between subgroups, with limited overlap with pan-ethnic panels. Conclusions: Population-specific carrier frequencies influence gene prioritization and estimated reproductive-risk probabilities for ECS. Population-tailored ECS panels that incorporate local carrier-frequency data, including embryonic\/fetal-lethal genes, and account for hypomorphic alleles to avoid overestimating reproductive risk probabilities could improve the identification of couples at increased reproductive risk, particularly in underrepresented populations.<\/jats:p>","DOI":"10.3390\/genes17091118","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T08:16:48Z","timestamp":1789460208000},"page":"1118","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Population-Specific Carrier Frequencies in an Underrepresented Genetically Heterogeneous Population: Implications for Expanded Carrier Screening"],"prefix":"10.3390","volume":"17","author":[{"given":"Predrag","family":"Noveski","sequence":"first","affiliation":[{"name":"Research Center for Genetic Engineering and Biotechnology \u201cGeorgi D. Efremov\u2019\u2019, Macedonian Academy of Sciences and Arts, 1000 Skopje, North Macedonia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"given":"Natalija","family":"Jovanovska","sequence":"additional","affiliation":[{"name":"Research Center for Genetic Engineering and Biotechnology \u201cGeorgi D. Efremov\u2019\u2019, Macedonian Academy of Sciences and Arts, 1000 Skopje, North Macedonia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6796-4793","authenticated-orcid":false,"given":"Ivana","family":"Maleva Kostovska","sequence":"additional","affiliation":[{"name":"Research Center for Genetic Engineering and Biotechnology \u201cGeorgi D. Efremov\u2019\u2019, Macedonian Academy of Sciences and Arts, 1000 Skopje, North Macedonia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Gjorgji","family":"Bozhinovski","sequence":"additional","affiliation":[{"name":"Research Center for Genetic Engineering and Biotechnology \u201cGeorgi D. Efremov\u2019\u2019, Macedonian Academy of Sciences and Arts, 1000 Skopje, North Macedonia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Sanja","family":"Kiprijanovska","sequence":"additional","affiliation":[{"name":"Research Center for Genetic Engineering and Biotechnology \u201cGeorgi D. Efremov\u2019\u2019, Macedonian Academy of Sciences and Arts, 1000 Skopje, North Macedonia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"given":"Marija","family":"Terzikj","sequence":"additional","affiliation":[{"name":"Research Center for Genetic Engineering and Biotechnology \u201cGeorgi D. Efremov\u2019\u2019, Macedonian Academy of Sciences and Arts, 1000 Skopje, North Macedonia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Marija","family":"Vujovikj","sequence":"additional","affiliation":[{"name":"Research Center for Genetic Engineering and Biotechnology \u201cGeorgi D. Efremov\u2019\u2019, Macedonian Academy of Sciences and Arts, 1000 Skopje, North Macedonia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5378-5070","authenticated-orcid":false,"given":"Emilija","family":"Shukarova Stefanovska","sequence":"additional","affiliation":[{"name":"Research Center for Genetic Engineering and Biotechnology \u201cGeorgi D. Efremov\u2019\u2019, Macedonian Academy of Sciences and Arts, 1000 Skopje, North Macedonia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Aleksandar","family":"Dimovski","sequence":"additional","affiliation":[{"name":"Research Center for Genetic Engineering and Biotechnology \u201cGeorgi D. Efremov\u2019\u2019, Macedonian Academy of Sciences and Arts, 1000 Skopje, North Macedonia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8877-2416","authenticated-orcid":false,"given":"Dijana","family":"Plaseska-Karanfilska","sequence":"additional","affiliation":[{"name":"Research Center for Genetic Engineering and Biotechnology \u201cGeorgi D. Efremov\u2019\u2019, Macedonian Academy of Sciences and Arts, 1000 Skopje, North Macedonia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"American College of Obstetricians and Gynecologists, and Committee on Genetics (2017). Committee Opinion No. 691: Carrier Screening for Genetic Conditions. Obstet. 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