{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:35:47Z","timestamp":1791333347199,"version":"4.3.1"},"reference-count":51,"publisher":"BMJ","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2012,5,28]]},"published-print":{"date-parts":[[2012,8]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Bardet-Biedl syndrome (BBS) is a pleiotropic recessive disorder that belongs to the rapidly growing family of ciliopathies. It shares phenotypic traits with other ciliopathies, such as Alstr\u00f6m syndrome (ALMS), nephronophthisis (NPHP) or Joubert syndrome. BBS mutations have been detected in 16 different genes (<jats:italic>BBS1<\/jats:italic>-<jats:italic>BBS16<\/jats:italic>) without clear genotype-to-phenotype correlation. This extensive genetic heterogeneity is a major concern for molecular diagnosis and genetic counselling. While various strategies have been recently proposed to optimise mutation detection, they either fail to detect mutations in a majority of patients or are time consuming and costly.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Method<\/jats:title>\n                  <jats:p>We tested a targeted exon-capture strategy coupled with multiplexing and high-throughput sequencing on 52 patients: 14 with known mutations as <jats:italic>proof-of-principle<\/jats:italic> and 38 with no previously detected mutation. Thirty genes were targeted in total including the 16 BBS genes, the 12 known NPHP genes, the single ALMS gene <jats:italic>ALMS1<\/jats:italic> and the proposed modifier <jats:italic>CCDC28B<\/jats:italic>.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>This strategy allowed the reliable detection of causative mutations (including homozygous\/heterozygous exon deletions) in 68% of BBS patients without previous molecular diagnosis and in all <jats:italic>proof-of-principle<\/jats:italic> samples. Three probands carried homozygous truncating mutations in <jats:italic>ALMS1<\/jats:italic> confirming the major phenotypic overlap between both disorders. The efficiency of detecting mutations in patients was positively correlated with their compliance with the classical BBS phenotype (mutations were identified in 81% of \u2018classical\u2019 BBS patients) suggesting that only a few true BBS genes remain to be identified. We illustrate some interpretation problems encountered due to the multiplicity of identified variants.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>This strategy is highly efficient and cost effective for diseases with high genetic heterogeneity, and guarantees a quality of coverage in coding sequences of target genes suited for diagnosis purposes.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmedgenet-2012-100875","type":"journal-article","created":{"date-parts":[[2012,7,7]],"date-time":"2012-07-07T21:32:27Z","timestamp":1341696747000},"page":"502-512","source":"Crossref","is-referenced-by-count":113,"title":["Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases: efficient mutation detection in Bardet-Biedl and Alstr\u00f6m Syndromes"],"prefix":"10.1136","volume":"49","author":[{"given":"Claire","family":"Redin","sequence":"first","affiliation":[{"name":"1Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire (IGBMC), CNRS UMR7104, INSERM U964, Universit\u00e9 de Strasbourg, Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phanie","family":"Le Gras","sequence":"additional","affiliation":[{"name":"2Microarrays and Sequencing Platform, IGBMC, Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oussema","family":"Mhamdi","sequence":"additional","affiliation":[{"name":"3Laboratory of Human genetics, University of Medicine of Tunis, Tunis, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"Geoffroy","sequence":"additional","affiliation":[{"name":"4Bioinformatics Platform, IGBMC, Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne","family":"Stoetzel","sequence":"additional","affiliation":[{"name":"5Laboratoire de G\u00e9n\u00e9tique M\u00e9dicale EA3949 Inserm Avenir, Universit\u00e9 de Strasbourg, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Claire","family":"Vincent","sequence":"additional","affiliation":[{"name":"6Laboratoire de Diagnostic G\u00e9n\u00e9tique, H\u00f4pitaux Universitaires de Strasbourg, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Chiurazzi","sequence":"additional","affiliation":[{"name":"7Istituto di Genetica Medica, Universita' Cattolica, Roma, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Lacombe","sequence":"additional","affiliation":[{"name":"8CHU Bordeaux, University of Bordeaux, Department of Medical Genetics, Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"Ouertani","sequence":"additional","affiliation":[{"name":"3Laboratory of Human genetics, University of Medicine of Tunis, Tunis, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Petit","sequence":"additional","affiliation":[{"name":"9Service de G\u00e9n\u00e9tique Clinique, H\u00f4pital Jeanne de Flandre, CHRU de Lille, Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Till","sequence":"additional","affiliation":[{"name":"10Service de Cytog\u00e9n\u00e9tique Constitutionnelle, Hospices Civils de Lyon, CBPE, Bron Cedex, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Verloes","sequence":"additional","affiliation":[{"name":"11Department of Genetics, INSERM U676, Assistance Publique H\u00f4pitaux de Paris (AP-HP), Robert Debr\u00e9 University Hospital, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Jost","sequence":"additional","affiliation":[{"name":"2Microarrays and Sequencing Platform, IGBMC, Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Habiba Bouhamed","family":"Chaabouni","sequence":"additional","affiliation":[{"name":"3Laboratory of Human genetics, University of Medicine of Tunis, Tunis, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helene","family":"Dollfus","sequence":"additional","affiliation":[{"name":"5Laboratoire de G\u00e9n\u00e9tique M\u00e9dicale EA3949 Inserm Avenir, Universit\u00e9 de Strasbourg, Strasbourg, France"},{"name":"12Service de G\u00e9n\u00e9tique M\u00e9dicale, Centre de R\u00e9f\u00e9rence pour les Affections Rares en G\u00e9n\u00e9tique Ophtalmologique (CARGO), H\u00f4pitaux Universitaires de Strasbourg, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Louis","family":"Mandel","sequence":"additional","affiliation":[{"name":"1Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire (IGBMC), CNRS UMR7104, INSERM U964, Universit\u00e9 de Strasbourg, Illkirch, France"},{"name":"6Laboratoire de Diagnostic G\u00e9n\u00e9tique, H\u00f4pitaux Universitaires de Strasbourg, Strasbourg, France"},{"name":"13Chaire de G\u00e9n\u00e9tique Humaine, Coll\u00e9ge de France, Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Muller","sequence":"additional","affiliation":[{"name":"1Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire (IGBMC), CNRS UMR7104, INSERM U964, Universit\u00e9 de Strasbourg, Illkirch, France"},{"name":"6Laboratoire de Diagnostic G\u00e9n\u00e9tique, H\u00f4pitaux Universitaires de Strasbourg, Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2012,7,7]]},"reference":[{"key":"2025101722374801000_49.8.502.1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI37041"},{"key":"2025101722374801000_49.8.502.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1010172"},{"key":"2025101722374801000_49.8.502.3","doi-asserted-by":"crossref","first-page":"18","DOI":"10.3109\/13816810.2011.620055","article-title":"Differentiating alstrom from Bardet-Biedl syndrome (BBS) using systematic ciliopathy genes sequencing","volume":"33","author":"Aliferis","year":"2011","journal-title":"Ophthalmic Genet"},{"key":"2025101722374801000_49.8.502.4","doi-asserted-by":"publisher","DOI":"10.1086\/428679"},{"key":"2025101722374801000_49.8.502.5","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2010.207"},{"key":"2025101722374801000_49.8.502.6","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1136\/jmg.36.6.437","article-title":"New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey","volume":"36","author":"Beales","year":"1999","journal-title":"J Med Genet"},{"key":"2025101722374801000_49.8.502.7","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21480"},{"key":"2025101722374801000_49.8.502.8","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1159\/000331268","article-title":"Mutations in SDCCAG8\/NPHP10 cause Bardet-Biedl syndrome and are associated with penetrant renal disease and absent polydactyly","volume":"1","author":"Schaefer","year":"2011","journal-title":"Mol Syndromology"},{"key":"2025101722374801000_49.8.502.9","doi-asserted-by":"crossref","unstructured":"Marshall JD Maffei P Beck S Barrett TG Paisey RB . Clinical utility gene card for: Alstrom syndrome. Eur J Hum Genet 2011;19.","DOI":"10.1038\/ejhg.2011.72"},{"key":"2025101722374801000_49.8.502.10","doi-asserted-by":"publisher","DOI":"10.3109\/13816810.2011.567319"},{"key":"2025101722374801000_49.8.502.11","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-010-0804-9"},{"key":"2025101722374801000_49.8.502.12","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-010-0902-8"},{"key":"2025101722374801000_49.8.502.13","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1374"},{"key":"2025101722374801000_49.8.502.14","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-12-184"},{"key":"2025101722374801000_49.8.502.15","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2010-11-10-r106"},{"key":"2025101722374801000_49.8.502.16","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J R Stat Soc Ser B (Methodological)"},{"key":"2025101722374801000_49.8.502.17","doi-asserted-by":"crossref","first-page":"527137","DOI":"10.4061\/2011\/527137","article-title":"Nephronophthisis: a genetically diverse ciliopathy","volume":"2011","author":"Simms","year":"2011","journal-title":"Int J Nephrol"},{"key":"2025101722374801000_49.8.502.18","doi-asserted-by":"publisher","DOI":"10.1038\/nature04370"},{"key":"2025101722374801000_49.8.502.19","doi-asserted-by":"publisher","DOI":"10.1038\/88925"},{"key":"2025101722374801000_49.8.502.20","doi-asserted-by":"publisher","DOI":"10.1126\/science.1063525"},{"key":"2025101722374801000_49.8.502.21","doi-asserted-by":"publisher","DOI":"10.1038\/ng.97"},{"key":"2025101722374801000_49.8.502.22","doi-asserted-by":"publisher","DOI":"10.1126\/science.1191184"},{"key":"2025101722374801000_49.8.502.23","doi-asserted-by":"publisher","DOI":"10.1038\/ng.662"},{"key":"2025101722374801000_49.8.502.24","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20441"},{"key":"2025101722374801000_49.8.502.25","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2004.026617"},{"key":"2025101722374801000_49.8.502.26","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20577"},{"key":"2025101722374801000_49.8.502.27","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-2633"},{"key":"2025101722374801000_49.8.502.28","doi-asserted-by":"crossref","first-page":"R65","DOI":"10.1093\/hmg\/ddh092","article-title":"The oligogenic properties of Bardet-Biedl syndrome","volume":"1","author":"Katsanis","year":"2004","journal-title":"Hum Mol Genet"},{"key":"2025101722374801000_49.8.502.29","doi-asserted-by":"publisher","DOI":"10.1086\/341031"},{"key":"2025101722374801000_49.8.502.30","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201372"},{"key":"2025101722374801000_49.8.502.31","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ejhg.5201688"},{"key":"2025101722374801000_49.8.502.32","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.05-1334"},{"key":"2025101722374801000_49.8.502.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.03.053"},{"key":"2025101722374801000_49.8.502.34","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0910268107"},{"key":"2025101722374801000_49.8.502.35","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg188"},{"key":"2025101722374801000_49.8.502.36","doi-asserted-by":"publisher","DOI":"10.1086\/375178"},{"key":"2025101722374801000_49.8.502.37","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-0465"},{"key":"2025101722374801000_49.8.502.38","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-002-0733-3"},{"key":"2025101722374801000_49.8.502.39","doi-asserted-by":"publisher","DOI":"10.1038\/75637"},{"key":"2025101722374801000_49.8.502.40","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1000219107"},{"key":"2025101722374801000_49.8.502.41","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0910672106"},{"key":"2025101722374801000_49.8.502.42","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0908094"},{"key":"2025101722374801000_49.8.502.43","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1002\/mds.24020","article-title":"Genetic diagnosis of neuroacanthocytosis disorders using exome sequencing","volume":"27","author":"Walker","year":"2011","journal-title":"Mov Disord"},{"key":"2025101722374801000_49.8.502.44","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr151"},{"key":"2025101722374801000_49.8.502.45","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e318226fbf2"},{"key":"2025101722374801000_49.8.502.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygeno.2011.04.004"},{"key":"2025101722374801000_49.8.502.47","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2011-12-9-r89"},{"key":"2025101722374801000_49.8.502.48","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGENETICS.110.958322"},{"key":"2025101722374801000_49.8.502.49","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1012989107"},{"key":"2025101722374801000_49.8.502.50","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1007983107"},{"key":"2025101722374801000_49.8.502.51","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2010.082552"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmedgenet-2012-100875","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T05:37:56Z","timestamp":1760765876000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmedgenet-2012-100875"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,7,7]]},"references-count":51,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2012,8,12]]},"published-print":{"date-parts":[[2012,8]]}},"alternative-id":["10.1136\/jmedgenet-2012-100875"],"URL":"https:\/\/doi.org\/10.1136\/jmedgenet-2012-100875","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,7,7]]}}}