{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T14:01:55Z","timestamp":1773756115504,"version":"3.50.1"},"reference-count":40,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T00:00:00Z","timestamp":1772928000000},"content-version":"vor","delay-in-days":66,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100001032","name":"Chicago Community Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001032","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R03TR003869"],"award-info":[{"award-number":["R03TR003869"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Human Mutation"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>\n                    Pathogenic heterozygous variants in\n                    <jats:italic>PHOX2B<\/jats:italic>\n                    are associated with congenital central hypoventilation syndrome (CCHS), which is characterized by autonomic nervous system dysregulation severely affecting respiratory control. The interpretation of\n                    <jats:italic>PHOX2B<\/jats:italic>\n                    missense variation is challenging due to their rarity and the lack of available functional evidence. Consequently, most\n                    <jats:italic>PHOX2B<\/jats:italic>\n                    missense variants are classified as variants of uncertain significance (VUSs), complicating the timely diagnosis and clinical management of the condition. To generate an improved model for assessments of\n                    <jats:italic>PHOX2B<\/jats:italic>\n                    missense variants, a methodology was derived to evaluate all\n                    <jats:italic>PHOX2B<\/jats:italic>\n                    missense variants in the literature and public\/private databases according to a consensus classification framework and assigned pathogenicity classifications. Pathogenicity prediction scores from the in silico prediction tools CADD, REVEL, BayesDel, and AlphaMissense were obtained for all variants. A weighted logistic regression in a multiple imputation framework was performed to assess the strength of evidence supporting application of ACMG\/AMP guidelines\u2032 PP3\/BP4 criteria. CADD, REVEL, and BayesDel meet the predictive strengths for PP3\/BP4 recommended by the Clinical Genome Resource (ClinGen). Based on their areas under the curve and low proportions of variants with indeterminate pathogenicity predictions, BayesDel and REVEL were the strongest predictive tools and should be utilized for routine\n                    <jats:italic>PHOX2B<\/jats:italic>\n                    missense variant assessment with this study\u2032s calculated score thresholds for PP3\/BP4 strength levels. Furthermore, the positional distribution of pathogenic and benign variants was analyzed to assess potential hotspots or critical functional domains in\n                    <jats:italic>PHOX2B<\/jats:italic>\n                    , and pathogenic variants were found to cluster in the homeodomain. The enrichment of pathogenic variation was substantiated by the prediction tools, supporting the use of the PM1 criterion for variants in the homeodomain. This calibration of existing computational prediction tools for\n                    <jats:italic>PHOX2B<\/jats:italic>\n                    missense variant classification and recognition of the homeodomain variants will enable fewer VUS classifications in favor of conclusive results, aiding in these individuals\u2032 care.\n                  <\/jats:p>","DOI":"10.1155\/humu\/8001520","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T05:18:35Z","timestamp":1773033515000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Recognition of a Critical Functional Domain and Improved\n                    <i>PHOX2B<\/i>\n                    Missense Variant Interpretation by Utilization of In Silico Prediction Tools"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1822-1728","authenticated-orcid":false,"given":"Andy","family":"Drackley","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7530-8127","authenticated-orcid":false,"given":"Andrew D.","family":"Skol","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1077-8978","authenticated-orcid":false,"given":"Casey M.","family":"Rand","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6061-220X","authenticated-orcid":false,"given":"Debra E.","family":"Weese-Mayer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4496-5464","authenticated-orcid":false,"given":"Kai Lee","family":"Yap","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,3,8]]},"reference":[{"key":"e_1_2_12_1_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200807-1069ST"},{"key":"e_1_2_12_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1130"},{"key":"e_1_2_12_3_2","volume-title":"Gene Reviews","author":"Weese-Mayer D. 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