{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:00:59Z","timestamp":1790834459176,"version":"4.1.0"},"reference-count":16,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabet Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>\n                      <jats:italic>HNF1B<\/jats:italic>\n                      variants cause autosomal dominant tubulointerstitial kidney disease (ADTKD\u2010\n                      <jats:italic>HNF1B<\/jats:italic>\n                      ), but the phenotypic spectrum of variants of uncertain significance (VUS) remains incompletely defined. We aimed to characterise the multisystem phenotype associated with the\n                      <jats:italic>HNF1B<\/jats:italic>\n                      p.E105K variant and to examine the mechanism underlying insulin resistance in this setting.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A 15\u2010year\u2010old male proband with chronic kidney disease and multisystem developmental abnormalities underwent clinical, biochemical and genetic evaluation, including trio\u2010based whole\u2010exome sequencing. The identified variant was classified according to American College of Medical Genetics and Genomics\/Association for Molecular Pathology criteria.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The proband presented with chronic kidney disease G3b, bilateral renal cysts, growth delay, delayed puberty and borderline intellectual disability. A heterozygous\n                      <jats:italic>HNF1B<\/jats:italic>\n                      c.313G\u27e9A (p.E105K) variant was identified, currently classified as a VUS (PM2_supporting\u2009+\u2009PS3_moderate\u2009+\u2009PP3). Oral glucose tolerance testing showed impaired glucose tolerance with postprandial hyperinsulinaemia (2\u2010h insulin 3556\u2009pmol\/L) and preserved \u03b2\u2010cell function. His mother, who has diabetes with normal renal morphology, carried the same variant.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This case suggests a possible expansion of the p.E105K phenotypic spectrum and indicates that insulin resistance in ADTKD\u2010\n                      <jats:italic>HNF1B<\/jats:italic>\n                      is best interpreted as multifactorial and predominantly chronic kidney disease\u2010driven rather than variant\u2010specific. Classification of p.E105K and its metabolic associations await confirmation in further cases and functional studies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dme.70457","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:40:46Z","timestamp":1790833246000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multisystem developmental abnormalities and insulin resistance in\n                    <scp>ADTKD<\/scp>\n                    \u2010\n                    <scp>HNF1B<\/scp>\n                    with the p.\n                    <scp>E105K<\/scp>\n                    variant: A clinical conundrum"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9924-2212","authenticated-orcid":false,"given":"YunZe","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Nephrology Shuyang Hospital of Traditional Chinese Medicine  Suqian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"KangChun","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Nephrology Shuyang Hospital of Traditional Chinese Medicine  Suqian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"PengFei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Nephrology Shuyang Hospital of Traditional Chinese Medicine  Suqian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1606-5004","authenticated-orcid":false,"given":"Bin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhongda Hospital Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Zhongda Hospital Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3995-5524","authenticated-orcid":false,"given":"ShanZhai","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Nephrology Shuyang Hospital of Traditional Chinese Medicine  Suqian China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"issue":"4","key":"e_1_2_12_2_1","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/ki.2015.28","article-title":"Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management\u2014a KDIGO consensus report","volume":"88","author":"Eckardt KU","year":"2015","journal-title":"Kidney Int"},{"issue":"8","key":"e_1_2_12_3_1","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1111\/pedi.13426","article-title":"ISPAD Clinical Practice Consensus Guidelines 2022: the diagnosis and management of monogenic diabetes in children and adolescents","volume":"23","author":"Greeley SAW","year":"2022","journal-title":"Pediatr Diabetes"},{"issue":"5","key":"e_1_2_12_4_1","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards S","year":"2015","journal-title":"Genet Med"},{"issue":"2","key":"e_1_2_12_5_1","doi-asserted-by":"crossref","first-page":"321","DOI":"10.4093\/dmj.2024.0159","article-title":"Exon sequencing of HNF1B in Chinese patients with early\u2010onset diabetes","volume":"49","author":"Gong S","year":"2025","journal-title":"Diabetes Metab J"},{"issue":"1","key":"e_1_2_12_6_1","article-title":"HNF1B mutation in a patient with maturity\u2010onset diabetes of the young 5 and renal cysts: a case report and literature review","volume":"21","author":"Din YM","year":"2020","journal-title":"BMC Med Genet"},{"issue":"2","key":"e_1_2_12_7_1","doi-asserted-by":"crossref","DOI":"10.1002\/ccr3.70173","article-title":"Maturity\u2010onset diabetes of the young (MODY) with HNF1B p.Glu105Lys mutation achieving significant insulin reduction on tirzepatide: a case report","volume":"13","author":"Sue M","year":"2025","journal-title":"Clin Case Reports"},{"issue":"7","key":"e_1_2_12_8_1","doi-asserted-by":"crossref","first-page":"2320","DOI":"10.3390\/jcm9072320","article-title":"Genotype and phenotype analyses in pediatric patients with HNF1B mutations","volume":"9","author":"Lim SH","year":"2020","journal-title":"J Clin Med"},{"issue":"6","key":"e_1_2_12_9_1","doi-asserted-by":"crossref","DOI":"10.1002\/mgg3.720","article-title":"Identifying gene mutations of Chinese patients with polycystic kidney disease through targeted next\u2010generation sequencing technology","volume":"7","author":"Wang T","year":"2019","journal-title":"Mol Genet Genomic Med"},{"issue":"2","key":"e_1_2_12_10_1","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/nrneph.2014.232","article-title":"HNF1B\u2010associated renal and extra\u2010renal disease\u2014an expanding clinical spectrum","volume":"11","author":"Clissold RL","year":"2015","journal-title":"Nat Rev Nephrol"},{"issue":"6","key":"e_1_2_12_11_1","doi-asserted-by":"crossref","first-page":"2905","DOI":"10.1210\/jc.2003-031828","article-title":"Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys: phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor\u20101\u03b2 gene due to germline mosaicism","volume":"89","author":"Yorifuji T","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"issue":"12","key":"e_1_2_12_12_1","doi-asserted-by":"crossref","first-page":"2341","DOI":"10.1016\/j.ekir.2020.09.042","article-title":"Variable expressivity of HNF1B nephropathy, from ADTKD\u2010HNF1B to medullary sponge kidney through tubulo\u2010interstitial kidney disease","volume":"5","author":"Izzi C","year":"2020","journal-title":"Kidney Int Rep"},{"issue":"8","key":"e_1_2_12_13_1","first-page":"1459","article-title":"HNF1B\u2010associated renal disease: more than renal cysts and diabetes","volume":"37","author":"Tholen S","year":"2022","journal-title":"Nephrol Dial Transplant"},{"issue":"2","key":"e_1_2_12_14_1","doi-asserted-by":"crossref","first-page":"405","DOI":"10.2337\/diabetes.55.02.06.db05-1019","article-title":"Contrasting insulin sensitivity of endogenous glucose production rate in subjects with hepatocyte nuclear factor\u20101beta and \u20101alpha mutations","volume":"55","author":"Brackenridge A","year":"2006","journal-title":"Diabetes"},{"issue":"1","key":"e_1_2_12_15_1","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1007\/s125-002-8259-5","article-title":"Identification of a gain\u2010of\u2010function mutation in the HNF\u20101\u03b2 gene in a Japanese family with MODY","volume":"45","author":"Yorifuji T","year":"2002","journal-title":"Diabetologia"},{"issue":"7","key":"e_1_2_12_16_1","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1111\/j.1464-5491.2008.02460.x","article-title":"Lack of pancreatic body and tail in HNF1B mutation carriers","volume":"25","author":"Haldorsen IS","year":"2008","journal-title":"Diabet Med"},{"issue":"4","key":"e_1_2_12_17_1","doi-asserted-by":"crossref","DOI":"10.1590\/2175-8239-jbn-2023-0203en","article-title":"Growth in children with chronic kidney disease and associated risk factors for short stature","volume":"46","author":"Melo VB","year":"2024","journal-title":"J Bras Nefrol"}],"container-title":["Diabetic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/dme.70457","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/dme.70457","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/dme.70457","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:40:49Z","timestamp":1790833249000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/dme.70457"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,30]]},"references-count":16,"alternative-id":["10.1111\/dme.70457"],"URL":"https:\/\/doi.org\/10.1111\/dme.70457","archive":["Portico"],"relation":{},"ISSN":["0742-3071","1464-5491"],"issn-type":[{"value":"0742-3071","type":"print"},{"value":"1464-5491","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,30]]},"assertion":[{"value":"2026-06-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70457"}}