{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:59:00Z","timestamp":1791896340460,"version":"4.3.4"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007776","name":"Deanship of Academic Research, University of Jordan","doi-asserted-by":"publisher","award":["2013\/39"],"award-info":[{"award-number":["2013\/39"]}],"id":[{"id":"10.13039\/100007776","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007776","name":"Deanship of Academic Research, University of Jordan","doi-asserted-by":"publisher","award":["2238"],"award-info":[{"award-number":["2238"]}],"id":[{"id":"10.13039\/100007776","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Inherited retinal diseases (IRDs) may present as an isolated ocular condition or as part of multisystem disorders, such as Bardet\u2013Biedl syndrome (BBS). Several BBS-related manifestations are age-dependent and variably expressed. Therefore, patients with early or subtle extra-ocular features may be incorrectly diagnosed as having non-syndromic IRD. There are two diagnostic frameworks for BBS: a phenotype-based, Beales-derived approach and a genotype-first approach, as recommended by the InterEuropean Reference Networks (ERNs) criteria. Here, we aimed to conduct comprehensive evaluations of patients with IRD carrying BBS-related variants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Nineteen patients from nine Jordanian families initially diagnosed with non-syndromic IRD underwent detailed ophthalmic evaluation and molecular testing. Post-genetic testing, participants underwent targeted reverse phenotyping to reveal potentially overlooked syndromic features.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Ophthalmic assessment revealed a spectrum ranging from advanced IRDs to phenotypes inclining toward rod\u2013cone, cone\u2013rod, and macular dystrophies. Molecular testing identified potential causative variants in BBS-related genes known to cause both isolated IRD and BBS, namely,\n                      <jats:italic>CFAP418<\/jats:italic>\n                      ,\n                      <jats:italic>BBS2<\/jats:italic>\n                      ,\n                      <jats:italic>BBS1<\/jats:italic>\n                      ,\n                      <jats:italic>BBS5<\/jats:italic>\n                      , and\n                      <jats:italic>CEP290<\/jats:italic>\n                      . A splice donor variant in\n                      <jats:italic>CFAP418<\/jats:italic>\n                      was the most frequent in our cohort (numbers [n] = 3\/9 families), followed by a missense variant in\n                      <jats:italic>BBS2<\/jats:italic>\n                      (n = 2\/9 families). These findings prompted genotype-guided reverse phenotyping, which uncovered previously unrecognized multisystemic involvement. BBS-related major and minor features were discovered across the cohort. The extraretinal major features included obesity (n = 16 patients), polydactyly (n = 7 patients), renal anomalies (n = 7 patients), genitourinary abnormalities (n = 4 patients), and intellectual disability (n = 4 patients). Using Beales-derived criteria, 11 patients met the threshold for BBS. Under ERNs genotype-first recommendations, 18 patients reached the BBS diagnostic limit.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Wide intra- and inter-familial clinical variability was observed, even among patients with the same variants in\n                      <jats:italic>CFAP418<\/jats:italic>\n                      and\n                      <jats:italic>BBS2<\/jats:italic>\n                      . Furthermore, applying genotype-guided diagnostic criteria reclassified multiple patients who did not meet the traditional Beales-based clinical criteria as having BBS. These findings demonstrate that a genotype-first approach can detect patients with unrecognized BBS and facilitate appropriate clinical surveillance, genetic counseling, and management. To our knowledge, this is the first study from Jordan to integrate molecular testing with reverse phenotyping in patients carrying BBS-related genotypes. Importantly, we present the most comprehensive extra-retinal characterization of patients with\n                      <jats:italic>CFAP418<\/jats:italic>\n                      , so far.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1802945","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T05:41:37Z","timestamp":1780378897000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinical heterogeneity associated with Bardet\u2013Biedl syndrome-related genes in presumed non-syndromic inherited retinal disease"],"prefix":"10.3389","volume":"14","author":[{"given":"Bilal","family":"Azab","sequence":"first","affiliation":[{"name":"Department of Pathology and Microbiology and Forensic Medicine, School of Medicine, The University of Jordan","place":["Amman, Jordan"]},{"name":"Division of Pathology and Laboratory Medicine, Phoenix 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