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The typical central yellowish yolk-like lesion usually appears in childhood and gradually worsens. Most cases are caused by variants in the <jats:italic>BEST1<\/jats:italic> gene which encodes bestrophin-1, an integral membrane protein found primarily in the retinal pigment epithelium.<\/jats:p>\n              <\/jats:sec>\n              <jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Here we describe the spectrum of <jats:italic>BEST1<\/jats:italic> variants identified in a cohort of 57 Italian patients analyzed by Sanger sequencing. In 13 cases, the study also included segregation analysis in affected and unaffected relatives. We used molecular mechanics to calculate two quantitative parameters related to calcium-activated chloride channel (CaCC composed of 5 BEST1 subunits) stability and calcium-dependent activation and related them to the potential pathogenicity of individual missense variants detected in the probands.<\/jats:p>\n              <\/jats:sec>\n              <jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Thirty-six out of 57 probands (63% positivity) and 16 out of 18 relatives proved positive to genetic testing. Family study confirmed the variable penetrance and expressivity of the disease. Six of the 27 genetic variants discovered were novel: p.(Val9Gly), p.(Ser108Arg), p.(Asn179Asp), p.(Trp182Arg), p.(Glu292Gln) and p.(Asn296Lys). All <jats:italic>BEST1<\/jats:italic> variants were assessed in silico for potential pathogenicity. Our computational structural biology approach based on 3D model structure of the CaCC showed that individual amino acid replacements may affect channel shape, stability, activation, gating, selectivity and throughput, and possibly also other features, depending on where the individual mutated amino acid residues are located in the tertiary structure of BEST1. Statistically significant correlations between mean logMAR best-corrected visual acuity (BCVA), age and modulus of computed BEST1 dimerization energies, which reflect variations in the in CaCC stability due to amino acid changes, permitted us to assess the pathogenicity of individual <jats:italic>BEST1<\/jats:italic> variants.<\/jats:p>\n              <\/jats:sec>\n              <jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Using this computational approach, we designed a method for estimating BCVA progression in patients with <jats:italic>BEST1<\/jats:italic> variants.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12967-019-2080-3","type":"journal-article","created":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T03:01:15Z","timestamp":1569898875000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Pathogenicity of new BEST1 variants identified in Italian patients with best vitelliform macular dystrophy assessed by computational structural biology"],"prefix":"10.1186","volume":"17","author":[{"given":"Vladimir","family":"Frecer","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giancarlo","family":"Iarossi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna Paola","family":"Salvetti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1974-4937","authenticated-orcid":false,"given":"Paolo Enrico","family":"Maltese","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia","family":"Delledonne","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Oldani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Staurenghi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benedetto","family":"Falsini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelo Maria","family":"Minnella","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia","family":"Ziccardi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriano","family":"Magli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonardo","family":"Colombo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabiana","family":"D\u2019Esposito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Miertus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Viola","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcella","family":"Attanasio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emilia","family":"Maggio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matteo","family":"Bertelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,10,1]]},"reference":[{"issue":"3","key":"2080_CR1","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.preteyeres.2009.04.002","volume":"28","author":"CJF Boon","year":"2009","unstructured":"Boon CJF, Klevering BJ, Leroy BP, Hoyng CB, Keunen JEE, den Hollander AI. 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All the data reported here was collected as part of routine diagnosis and did not require specific ethical committee approval.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Informed consent to the use of anonymized genetic and clinical results was obtained from all patients or from parents in the case of minors.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The author declares that they have no competing interests. The authors declare that they have no proprietary interest in the development or marketing of the instruments described.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"330"}}