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<p>Type 2 Long QT Syndrome (type 2 LQTS) is a cardiac channelopathy caused by pathogenic variants in the <i>KCNH2</i> gene, often associated with delayed cardiac repolarization and increased risk of arrhythmias. While its impact is traditionally considered cardiac, emerging studies suggest a potential role of <i>KCNH2</i> dysfunction in neurogical disorders. We describe monozygotic twin sisters carrying the pathogenic frameshift variant <i>KCNH2</i> c.2959_2960delCT (p.Leu987Valfs*131; rs748706373), inherited from their asymptomatic father. Clinically, both twins presented with severe language delay, absence of pointing, impaired social interaction, and stereotyped behaviors features consistent with neurogical disorders. Diagnostic diagnostic testing included whole exome sequencing (WES), chromosomal microarray (aCGH), and Fragile X screening. The <i>KCNH2</i> variant emerged as the sole clinically significant finding. Cardiac evaluation through ECG and 24-hour Holter monitoring revealed no significant QT prolongation or arrhythmic episodes in either the twins or their father. No history of syncope, seizures, or cardiac events was reported. This report supports the variable expressivity and incomplete penetrance of <i>KCNH2</i> variants in type 2 LQTS and raises the possibility that <i>KCNH2</i> dysfunction may contribute to neurogical phenotypes manifestations. Causality remains to be established between <i>KCNH2</i> and neurologic disorders. Though whole-genome sequencing remains to be completed in this pedigree, the potential association between <i>KCNH2</i> and neurologic disorders is strengthened by the unique monozygotic presentation and the absence of known perinatal complications. Further studies are needed to clarify the association between <i>KCNH2</i> variants and their contribution to neurological disorders, either through direct neural effects or indirectly via unrecognized perinatal arrhythmic events.</p>

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Pathogenic KCNH2 variant in monozygotic twins with speech delay and lower risk type 2 long QT syndrome

  • 期刊论文

  • 发表日期：

    2025年8月15日

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  • Katia Margiotti,
  • Marco Fabiani,
  • Costanza Zangheri,
  • Antonella Cima,
  • Francesca Monaco,
  • Francesco Libotte,
  • Chiara Ali’,
  • Maria Antonietta Barone,
  • Antonella Viola,
  • Alvaro Mesoraca,
  • Claudio Giorlandino

摘要

Type 2 Long QT Syndrome (type 2 LQTS) is a cardiac channelopathy caused by pathogenic variants in the KCNH2 gene, often associated with delayed cardiac repolarization and increased risk of arrhythmias. While its impact is traditionally considered cardiac, emerging studies suggest a potential role of KCNH2 dysfunction in neurogical disorders. We describe monozygotic twin sisters carrying the pathogenic frameshift variant KCNH2 c.2959_2960delCT (p.Leu987Valfs*131; rs748706373), inherited from their asymptomatic father. Clinically, both twins presented with severe language delay, absence of pointing, impaired social interaction, and stereotyped behaviors features consistent with neurogical disorders. Diagnostic diagnostic testing included whole exome sequencing (WES), chromosomal microarray (aCGH), and Fragile X screening. The KCNH2 variant emerged as the sole clinically significant finding. Cardiac evaluation through ECG and 24-hour Holter monitoring revealed no significant QT prolongation or arrhythmic episodes in either the twins or their father. No history of syncope, seizures, or cardiac events was reported. This report supports the variable expressivity and incomplete penetrance of KCNH2 variants in type 2 LQTS and raises the possibility that KCNH2 dysfunction may contribute to neurogical phenotypes manifestations. Causality remains to be established between KCNH2 and neurologic disorders. Though whole-genome sequencing remains to be completed in this pedigree, the potential association between KCNH2 and neurologic disorders is strengthened by the unique monozygotic presentation and the absence of known perinatal complications. Further studies are needed to clarify the association between KCNH2 variants and their contribution to neurological disorders, either through direct neural effects or indirectly via unrecognized perinatal arrhythmic events.