{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T05:00:09Z","timestamp":1781067609848,"version":"3.54.1"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"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. Cardiovasc. Med."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Long QT syndrome (LQTS) is a life-threatening inherited channelopathy that is prone to triggering torsades de pointes (TdP), ventricular tachycardia (VT), ventricular fibrillation (VF), and sudden cardiac death.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>Whole-exome sequencing (WES) was performed on a proband with LQTS, and candidate variants were validated by Sanger sequencing. Bioinformatics methods were used to analyze the pathogenicity of the variants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A proband who was a 16-year-old girl presented with a prolonged QT interval, TdP, VT, and VF. She carried the\n                      <jats:italic>de novo KCNH2<\/jats:italic>\n                      p.D501N mutation, which is localized to the S3 helix of the voltage-sensing domain of Kv11.1 and predicted to be \u201cdeleterious\u201d by the SIFT, PolyPhen-2, and MetaSVM algorithms. Secondary structure prediction showed that this mutation increases the proportion of alpha helices and extended strands, while decreasing the proportion of the random coil. In addition, this substitution induces buried charge replacement, breakage of the buried salt bridge formed by p.D501 and p.R534, and cavity expansion (with p.R537 moving markedly outward). It also leads to abnormal changes in the interactions among p.R537, p.R534, p.Y493, p.V533, and p.W497, resulting in spatial structure displacement and deflection. Compared with wild-type\n                      <jats:italic>KCNH2<\/jats:italic>\n                      ,\n                      <jats:italic>KCNH2<\/jats:italic>\n                      p.D501N exhibits decreased molecular weight, total number of negatively charged residues (Arg\u2009+\u2009Lys), oxygen content, charged residues (B: Asx, D: Asp, E: Glu, H: His, K: Lys, R: Arg, Z: Glx), and acidic residues (B\u2009+\u2009D\u2009+\u2009E\u2009+\u2009Z), while it shows increased theoretical isoelectric point (PI), hydrogen and nitrogen content, isoelectric point, net charge, and reduced probability of the formation of inclusion bodies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>KCNH2<\/jats:italic>\n                      p.D501N mutation significantly alters the secondary\/tertiary structure and physicochemical properties of the K\n                      <jats:sub>v<\/jats:sub>\n                      11.1 protein, which may impair the cardiac I\n                      <jats:sub>Kr<\/jats:sub>\n                      current and ultimately induce early-onset malignant LQT2 in a Chinese family. This condition requires ICD therapy combined with long-term \u03b2-blocker administration and potassium\u2013magnesium supplementation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcvm.2026.1592799","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T04:29:56Z","timestamp":1781065796000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Rare pathogenic mutation of KCNH2 p.D501N associated with early-onset malignant long QT syndrome"],"prefix":"10.3389","volume":"13","author":[{"given":"Yubi","family":"Lin","sequence":"first","affiliation":[{"name":"The Dongguan TaiXin Hospital, Affiliated to Guangdong Medical University","place":["Dongguan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingchen","family":"Li","sequence":"additional","affiliation":[{"name":"The Dongguan TaiXin Hospital, Affiliated to Guangdong Medical 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