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Depicting the whole clinical spectrum of\n                    <jats:italic>COL4A1\/2<\/jats:italic>\n                    \u2010related manifestations is challenging, and there is no consensus on management and preventative strategies. Based on a systematic review of current evidence on\n                    <jats:italic>COL4A1\/2<\/jats:italic>\n                    \u2010related disease, we developed a clinical questionnaire that we administered to 43 individuals from 23 distinct families carrying pathogenic variants. In this cohort, we extended ophthalmological and cardiological examinations to asymptomatic individuals and those with only limited or mild, often nonspecific, clinical signs commonly occurring in the general population (i.e., oligosymptomatic). The most frequent clinical findings emerging from both the literature review and the questionnaire included stroke (203\/685, 29.6%), seizures or epilepsy (199\/685, 29.0%), intellectual disability or developmental delay (168\/685, 24.5%), porencephaly\/schizencephaly (168\/685, 24.5%), motor impairment (162\/685, 23.6%), cataract (124\/685, 18.1%), hematuria (63\/685, 9.2%), and retinal arterial tortuosity (58\/685, 8.5%). In oligosymptomatic and asymptomatic carriers, ophthalmological investigations detected retinal vascular tortuosity (5\/13, 38.5%), dysgenesis of the anterior segment (4\/13, 30.8%), and cataract (2\/13, 15.4%), while cardiological investigations were unremarkable except for mild ascending aortic ectasia in 1\/8 (12.5%). Our multimodal approach confirms highly variable penetrance and expressivity in\n                    <jats:italic>COL4A1\/2<\/jats:italic>\n                    \u2010related conditions, even at the intrafamilial level with neurological involvement being the most frequent and severe finding in both children and adults. We propose a protocol for prevention and management based on individualized risk estimation and periodic multiorgan evaluations.\n                  <\/jats:p>","DOI":"10.1002\/ajmg.c.32099","type":"journal-article","created":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T06:19:23Z","timestamp":1721197163000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Multiorgan manifestations of\n                    <scp>\n                      <i>COL4A1<\/i>\n                    <\/scp>\n                    and\n                    <scp>\n                      <i>COL4A2<\/i>\n                    <\/scp>\n                    variants and proposal for a clinical management protocol"],"prefix":"10.1002","volume":"196","author":[{"given":"Simone","family":"Gasparini","sequence":"first","affiliation":[{"name":"Neuroscience and Human Genetics Department Meyer Children's Hospital IRCCS (full member of the European Reference 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