{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T04:23:26Z","timestamp":1769228606872,"version":"3.49.0"},"reference-count":19,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T00:00:00Z","timestamp":1730073600000},"content-version":"vor","delay-in-days":27,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Congenital insensitivity to pain with anhidrosis (CIPA) (OMIM 256800) is a rare autosomal\u2010recessive condition, also known as hereditary sensory and autonomic neuropathy type IV (HSAN\u2010IV). The most commonly reported features include anhidrosis, intellectual disability, self\u2010mutilation, febrile episodes, impaired temperature perception, recurrent infections and\/or autonomic nervous system impairment. Major joint destruction and joint deformity known as Charcot (neuropathic) joints are also seen in CIPA patients attributed to insensitivity to joint pain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We present a case of a 46\u2010year\u2010old female affected with CIPA with a known <jats:italic>NTRK1<\/jats:italic> variant and previously unidentified variant. Minigene reporter constructs were generated encompassing the exon 8 to exon 13 of the <jats:italic>NTRK1<\/jats:italic> gene using the reference sequence and one harboring c.1483\u2009+\u20095G\u2009&gt;\u2009A variant identified in our proband. Minigene constructs were transfected into HEK293T cells, and the transcript was analysed for splicing to evaluate the effect of this variant in splicing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The patient (46\u2010year\u2010old female) exhibited right ankle joint deformity around 5\u2009years of age. Patient also experienced lumbar compression and knee damage in adulthood. She had undergone a significant number of evaluations without clear diagnosis. Her presentation lacked many of the common clinical presentations of CIPA, and therefore, the focus of her evaluation was directed towards her unexplained joint deformities. Exome sequencing revealed a known pathogenic variant in <jats:italic>NTRK1<\/jats:italic> (c.851\u00a0\u2010\u00a033T\u2009&gt;\u2009A:p.? [Intron 7]) and a novel <jats:italic>NTRK1<\/jats:italic> variant (c.1483\u2009+\u20095G\u2009&gt;\u2009A:p.? [Intron 11]), which was later re\u2010classified as likely pathogenic. The patient was started on a biologic disease\u2010modifying anti\u2010rheumatic medication (bDMARD) due to a possible inflammatory etiology of her joint deformity. Molecular diagnosis allowed for modification of her treatment and surveillance strategies. Our minigene splicing assay demonstrated that the presence of the c.1483\u2009+\u20095G\u2009&gt;\u2009A variant has a negative effect on splicing, supporting the pathogenicity of this novel variant.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.70027","type":"journal-article","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T09:39:14Z","timestamp":1730108354000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Atypical Presentation of Congenital Insensitivity to Pain With Anhidrosis Leading to Diagnostic Odyssey"],"prefix":"10.1002","volume":"12","author":[{"given":"Tomoyasu","family":"Higashimoto","sequence":"first","affiliation":[{"name":"Division of Genetic Medicine, Department of Internal Medicine University of Michigan  Ann Arbor Michigan USA"},{"name":"Division of Genetics, Genomics, and Metabolism, Department of Pediatrics University of Michigan  Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin\u00a0E.","family":"Garber","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine University of Michigan  Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren","family":"Hipp","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine, Department of Internal Medicine University of Michigan  Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenna","family":"Damon","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine, Department of Internal Medicine University of Michigan  Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Department of Internal Medicine University of Michigan  Ann Arbor Michigan USA"},{"name":"Department of Cell and Developmental Biology University of Michigan  Ann Arbor Michigan USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,10,28]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2021.11.006"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.59959"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s10038-023-01185-7"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcna.2022.12.008"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2023.100896"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-021-00668-z"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12939-022-01809-y"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1515\/jpem-2012-0151"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1620\/tjem.2022.J060"},{"key":"e_1_2_8_11_1","volume-title":"GeneReviews((R))","author":"Indo Y.","year":"1993"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2018.01.013"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2016.08.009"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.1839"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12920-020-00764-3"},{"key":"e_1_2_8_16_1","article-title":"The Role of Biologics in Rheumatoid Arthritis: A Narrative Review","volume":"15","author":"Patel J. 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