{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T23:43:05Z","timestamp":1790206985998,"version":"4.1.0"},"reference-count":30,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2021,3,14]],"date-time":"2021-03-14T00:00:00Z","timestamp":1615680000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Endocrinology"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The most severe forms of congenital hyperinsulinism (CHI) are caused by inactivating mutations of two KATP channel genes, <jats:italic>KCNJ11<\/jats:italic> and <jats:italic>ABCC8<\/jats:italic>. Unresponsiveness to diazoxide and need for subtotal pancreatectomy can usually be predicted by genetic form, particularly biallelic mutations in KATP channel genes. A few reports indicated marked clinical heterogeneity in siblings with identical biallelic mutations in <jats:italic>ABCC8<\/jats:italic>. The clinical heterogeneity in biallelic KATP CHI was speculated to be caused by epigenetic and environmental factors or related to differences in splicing factor machinery.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To elucidate the clinical pathophysiology, especially heterogeneity, among three cases with CHI caused by a homogenous novel mutation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients and Methods<\/jats:title><jats:p>We report a case series that includes two siblings and one unrelated individual with CHI caused by a homogenous 1\u2010bp deletion around the splice acceptor site at the exon 35 mutation of <jats:italic>ABCC8<\/jats:italic>, which exhibited markedly distinct phenotypes. To assess the effect of the mutation on splicing, we performed digital droplet polymerase chain reaction (ddPCR) on normal pancreas tissue and a patient\u2019s lymphocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>ddPCR of <jats:italic>ABCC8<\/jats:italic> cDNA revealed that expression of exon 35 and its upstream and downstream regions did not differ. These data suggested that clinical heterogeneity may not be caused by differences in splicing factor machinery.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The phenotypic variation in homozygotes could not be explained by splicing abnormalities. Though early genetic diagnosis of KATP CHI could contribute to selecting appropriate therapeutic options, more deliberate selection of therapeutic options in diffuse CHI due to biallelic <jats:italic>ABCC8<\/jats:italic> mutations may be required.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cen.14443","type":"journal-article","created":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T03:59:26Z","timestamp":1613620766000},"page":"940-948","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Marked clinical heterogeneity in congenital hyperinsulinism due to a novel homozygous <i>ABCC8<\/i> mutation"],"prefix":"10.1111","volume":"94","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6947-4034","authenticated-orcid":false,"given":"Kei","family":"Takasawa","sequence":"first","affiliation":[{"name":"Department of Pediatrics and Developmental Biology Tokyo Medical and Dental University Tokyo 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