{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T23:15:41Z","timestamp":1782947741307,"version":"3.54.5"},"reference-count":17,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>\n                      Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder caused by mutations in\n                      <jats:italic>NTRK1<\/jats:italic>\n                      that is characterized by pain insensitivity, anhidrosis, and recurrent fever. While genetic testing is the gold standard for CIPA diagnosis, the complexity of\n                      <jats:italic>NTRK1<\/jats:italic>\n                      variants poses major challenges. Conventional sequencing that is limited to the coding regions of\n                      <jats:italic>NTRK1<\/jats:italic>\n                      results in misdiagnoses or missed diagnoses in approximately 57% of patients. Accordingly, to improve the diagnostic efficiency of CIPA, we integrated whole-genome sequencing (WGS) with functional assays to identify deep intronic variants in\n                      <jats:italic>NTRK1<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      All 18 probands were initially screened using polymerase chain reaction (PCR) and Sanger sequencing covering all exons and canonical splice sites of\n                      <jats:italic>NTRK1<\/jats:italic>\n                      . For patients with only one identified pathogenic allele, WGS was performed to detect potential deep intronic variants. Candidate variants were functionally validated using reverse transcription PCR (RT-PCR) and T cloning sequencing to evaluate their effects on pre-mRNA splicing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Total 23 pathogenic variants including 11 novel variants in\n                      <jats:italic>NTRK1<\/jats:italic>\n                      were identified in 18 unrelated families with CIPA. Functional assays confirmed that five of these variants disrupted the normal splicing of\n                      <jats:italic>NTRK1<\/jats:italic>\n                      , resulting in multiple aberrant splicing patterns, including two exon-skipping events (c.428 + 273A&amp;gt;T, c.850 + 5G&amp;gt;A), three intron retentions (c.2187 + 389C&amp;gt;T, c.2188\u2013459G&amp;gt;T, c.287 + 4A&amp;gt;C), and one pseudoexon insertion (c.2188\u2013459G&amp;gt;T).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study expands the spectrum of pathogenic variants in\n                      <jats:italic>NTRK1<\/jats:italic>\n                      and improves the genetic diagnosis of CIPA. The functional characterization of five novel non-canonical splicing variants provides deeper insight into the molecular pathogenesis of this disorder and establishes a foundation for future precision medicine approaches in CIPA.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1852317","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T22:10:30Z","timestamp":1782943830000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel deep intronic variants in NTRK1 underlying congenital insensitivity to pain with anhidrosis"],"prefix":"10.3389","volume":"17","author":[{"given":"Xin","family":"Chen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Complex, Severe, and Rare Diseases, Center for Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Beijing, China"]},{"name":"State Key Laboratory for Complex, Severe, and Rare Diseases, Department of Medical Genetics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Complex, Severe, and Rare Diseases, Department of Medical Genetics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College","place":["Beijing, China"]},{"name":"Stem Cell Facility, National Infrastructures for Translational Medicine, Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Complex, Severe, and Rare Diseases, Center for Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Cheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Complex, Severe, and Rare Diseases, Center for Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Beijing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuzhi","family":"Ren","sequence":"additional","affiliation":[{"name":"Children\u2019s Hospital of Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuli","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Complex, Severe, and Rare Diseases, Center for Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","place":["Beijing, China"]},{"name":"State Key Laboratory for Complex, Severe, and Rare Diseases, Department of Medical Genetics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College","place":["Beijing, China"]},{"name":"Children\u2019s Hospital of Soochow University","place":["Suzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/1750-1172-2-39","article-title":"Hereditary sensory and autonomic neuropathies: types II, III, and IV","volume":"2","author":"Axelrod","year":"2007","journal-title":"Orphanet J. 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