{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T07:45:19Z","timestamp":1782287119786,"version":"3.54.5"},"reference-count":16,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2020,6,26]],"date-time":"2020-06-26T00:00:00Z","timestamp":1593129600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Grant-in-Aid for Early-Career Scientists by JSPS KAKENHI","award":["JP19K17342"],"award-info":[{"award-number":["JP19K17342"]}]},{"name":"Initiative on Rare and Undiagnosed Diseases from the Japan Agency for Medical Research and Development","award":["JP17ek0109151"],"award-info":[{"award-number":["JP17ek0109151"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>A weakness of exome analysis lies in inability to characterize aberrant splicing other than those involving consensus donor\u2010acceptor sequence. To overcome this limitation, we developed a novel analytic method SAVNet that combines transcriptome and exome analysis which enabled the successful detection of carriers of splicing variants in the disease\u2010causing genes of autosomal recessive disorders within a normal cohort. However, the clinical utility of the SAVNet analysis in delineating splicing defects in patients without a diagnosis has yet to be documented.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>We performed SAVNet analysis using the integrated analysis of exome and transcriptome analysis from the peripheral blood of the patient. The patient is an undiagnosed Japanese female patient with submucous cleft palate, scaphocephaly and intellectual disability with no words at 8\u00a0years of age. Dysmorphic features included a long face, a short palpebral fissure, thick lips with an open month, premaxillary hypoplasia, a depressed nasal bridge, and satyr ears.<\/jats:p><\/jats:sec><jats:sec><jats:title>Result<\/jats:title><jats:p>A SAVNet analysis showed that a heterozygous intronic variant located at the \u221210 position of exon 5 of the <jats:italic>HNRNPK<\/jats:italic> gene on chromosome 9 created a new splice acceptor sequence \u201cag\u201d and led to the incorporation of 9 intronic nucleotides into the coding sequence. The mutant protein would have three extra amino acid residues, Leu\u2010Leu\u2010Gln, inserted within the critical KH domain. The patient was diagnosed as having recently delineated Au\u2013Kline syndrome, which is characterized by cleft palate, craniosynostosis, and intellectual disability.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The successful molecular diagnosis of the presently reported patient illustrates the diagnostic utility of the SAVNet analysis as an innovative way of implementing an integrated exome\u2010transcriptome analysis in clinical settings.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.1364","type":"journal-article","created":{"date-parts":[[2020,6,27]],"date-time":"2020-06-27T08:26:21Z","timestamp":1593246381000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Diagnostic utility of integrated analysis of exome and transcriptome: Successful diagnosis of Au\u2010Kline syndrome in a patient with submucous cleft palate, scaphocephaly, and intellectual disabilities"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4039-8899","authenticated-orcid":false,"given":"Mamiko","family":"Yamada","sequence":"first","affiliation":[{"name":"Center for Medical Genetics Keio University School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Shiraishi","sequence":"additional","affiliation":[{"name":"Section of Genome Analysis Platform Center for Cancer Genomic and Advanced Therapeutics National Cancer Center Research Institute Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1497-7686","authenticated-orcid":false,"given":"Tomoko","family":"Uehara","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Keio University School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisato","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Keio University School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7311-4135","authenticated-orcid":false,"given":"Toshiki","family":"Takenouchi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Keio University School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chihiro","family":"Abe\u2010Hatano","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics Kanagawa Children's Medical Center Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Kurosawa","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics Kanagawa Children's Medical Center Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenjiro","family":"Kosaki","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Keio University School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,6,26]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431\u2010018\u20100187\u20102"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22837"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.10.025"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks504"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.4161\/fly.19695"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13029"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2016.150"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.12.015"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12773"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.107524.110"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13023"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr667"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.231951.117"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2014.10.015"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgmr.2019.100531"}],"container-title":["Molecular Genetics &amp; 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