{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T19:44:56Z","timestamp":1775591096879,"version":"3.50.1"},"reference-count":29,"publisher":"Proceedings of the National Academy of Sciences","issue":"45","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,11,10]]},"abstract":"<jats:p>\n                    Protein coding genes constitute only approximately 1% of the human genome but harbor 85% of the mutations with large effects on disease-related traits. Therefore, efficient strategies for selectively sequencing complete coding regions (i.e., \u201cwhole exome\u201d) have the potential to contribute to the understanding of rare and common human diseases. Here we report a method for whole-exome sequencing coupling Roche\/NimbleGen whole exome arrays to the Illumina DNA sequencing platform. We demonstrate the ability to capture approximately 95% of the targeted coding sequences with high sensitivity and specificity for detection of homozygous and heterozygous variants. We illustrate the utility of this approach by making an unanticipated genetic diagnosis of congenital chloride diarrhea in a patient referred with a suspected diagnosis of Bartter syndrome, a renal salt-wasting disease. The molecular diagnosis was based on the finding of a homozygous missense D652N mutation at a position in\n                    <jats:italic>SLC26A3<\/jats:italic>\n                    (the known congenital chloride diarrhea locus) that is virtually completely conserved in orthologues and paralogues from invertebrates to humans, and clinical follow-up confirmed the diagnosis. To our knowledge, whole-exome (or genome) sequencing has not previously been used to make a genetic diagnosis. Five additional patients suspected to have Bartter syndrome but who did not have mutations in known genes for this disease had homozygous deleterious mutations in\n                    <jats:italic>SLC26A3<\/jats:italic>\n                    . These results demonstrate the clinical utility of whole-exome sequencing and have implications for disease gene discovery and clinical diagnosis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0910672106","type":"journal-article","created":{"date-parts":[[2009,10,27]],"date-time":"2009-10-27T21:56:01Z","timestamp":1256680561000},"page":"19096-19101","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1104,"title":["Genetic diagnosis by whole exome capture and massively parallel DNA sequencing"],"prefix":"10.1073","volume":"106","author":[{"given":"Murim","family":"Choi","sequence":"first","affiliation":[{"name":"Department of Genetics, Howard Hughes Medical Institute,"}]},{"given":"Ute I.","family":"Scholl","sequence":"additional","affiliation":[{"name":"Department of Genetics, Howard Hughes Medical Institute,"}]},{"given":"Weizhen","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Genetics, Howard Hughes Medical Institute,"}]},{"given":"Tiewen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Genetics, Howard Hughes Medical Institute,"}]},{"given":"Irina R.","family":"Tikhonova","sequence":"additional","affiliation":[{"name":"Keck Foundation for Biotechnology Resources, Yale University School of Medicine, New Haven, CT 06510;"}]},{"given":"Paul","family":"Zumbo","sequence":"additional","affiliation":[{"name":"Keck Foundation for Biotechnology Resources, Yale University School of Medicine, New Haven, CT 06510;"}]},{"given":"Ahmet","family":"Nayir","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology, Istanbul Medical Faculty, Istanbul 34390, Turkey;"}]},{"given":"Ays\u0326in","family":"Bakkalo\u011flu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology and Rheumatology, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey; and"}]},{"given":"Seza","family":"\u00d6zen","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology and Rheumatology, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey; and"}]},{"given":"Sami","family":"Sanjad","sequence":"additional","affiliation":[{"name":"American University of Beirut, Beirut 11072020, Lebanon"}]},{"given":"Carol","family":"Nelson-Williams","sequence":"additional","affiliation":[{"name":"Department of Genetics, Howard Hughes Medical Institute,"}]},{"given":"Anita","family":"Farhi","sequence":"additional","affiliation":[{"name":"Department of Genetics, Howard Hughes Medical Institute,"}]},{"given":"Shrikant","family":"Mane","sequence":"additional","affiliation":[{"name":"Keck Foundation for Biotechnology Resources, Yale University School of Medicine, New Haven, CT 06510;"}]},{"given":"Richard P.","family":"Lifton","sequence":"additional","affiliation":[{"name":"Department of Genetics, Howard Hughes Medical Institute,"}]}],"member":"341","published-online":{"date-parts":[[2009,11,10]]},"reference":[{"key":"e_1_3_3_1_2","first-page":"259","volume-title":"The Metabolic and Molecular Bases of Inherited Disease","author":"Cooper DN","year":"1995","unstructured":"DN Cooper, M Krawczak, SE Antonorakis, The nature and mechanisms of human gene mutation. 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