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<p>Timothy syndrome is a multisystemic genetic disorder, classically characterised by prolonged QT interval and subsequent cardiac arrhythmias, neurodevelopmental disorders including developmental delay and autism and syndactyly or hip dysplasia. It is caused by variants in the <i>CACNA1C</i> gene, which encodes the widely expressed Ca<sub>v</sub>1.2 voltage-gated calcium channel. Since its characterisation in 2004, the number of variants in <i>CACNA1C</i> associated with Timothy syndrome has expanded. With advances in sequencing and the inclusion of <i>CACNA1C</i> in genomic screening, further variants have been identified presenting with incomplete features of Timothy syndrome or further aligned phenotypes, which are inconsistent with the original description. In the absence of a formal nomenclature, these presentations have been reported in a proliferation of ill-defined terms, e.g. Atypical Timothy Syndrome. At the same time, advances in knowledge and therapeutics have improved morbidity and life expectancy for these individuals when appropriately identified and managed. Here, we present guidelines for the diagnosis of individuals presenting with variants in <i>CACNA1C</i>, developed by an international panel of experts through Delphi consensus with the involvement of the <i>CACNA1C</i> community. We formalise the language around syndromic presentations linked to <i>CACNA1C</i> variants, reassert and demarcate the classical Timothy syndrome phenotype and provide a structured co-produced definition for CACNA1C-Related Disorder. Finally, we present minimum expected standards of clinical care for individuals with CACNA1C-Related Disorder or Timothy syndrome, with implications for long-term management and improved outcomes for affected individuals.</p>

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Timothy syndrome and CACNA1C-Related Disorder: first international language and management guidelines consensus statement

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月9日

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  • Jack F. G. Underwood,
  • Katherine W. Timothy,
  • Holly Tyroll,
  • Rebecca J. Levy,
  • Ivy E. Dick,
  • Geoffrey S. Pitt,
  • Elizabeth M. Tunbridge,
  • Anwar Baban,
  • Gemma Wilkinson,
  • Nicola A. L. Hall,
  • Georgia Sarquella Brugada,
  • Rosemary Bauer,
  • Dominic Abrams,
  • Jeremy Hall,
  • Sophie Muir,
  • Nick Muir,
  • Meg McLaughlin,
  • Galina Gardiner,
  • Gemma Duncan,
  • Susan Bresnahan,
  • Achsah James,
  • Glenn Miller,
  • Christine Ziegler

摘要

Timothy syndrome is a multisystemic genetic disorder, classically characterised by prolonged QT interval and subsequent cardiac arrhythmias, neurodevelopmental disorders including developmental delay and autism and syndactyly or hip dysplasia. It is caused by variants in the CACNA1C gene, which encodes the widely expressed Cav1.2 voltage-gated calcium channel. Since its characterisation in 2004, the number of variants in CACNA1C associated with Timothy syndrome has expanded. With advances in sequencing and the inclusion of CACNA1C in genomic screening, further variants have been identified presenting with incomplete features of Timothy syndrome or further aligned phenotypes, which are inconsistent with the original description. In the absence of a formal nomenclature, these presentations have been reported in a proliferation of ill-defined terms, e.g. Atypical Timothy Syndrome. At the same time, advances in knowledge and therapeutics have improved morbidity and life expectancy for these individuals when appropriately identified and managed. Here, we present guidelines for the diagnosis of individuals presenting with variants in CACNA1C, developed by an international panel of experts through Delphi consensus with the involvement of the CACNA1C community. We formalise the language around syndromic presentations linked to CACNA1C variants, reassert and demarcate the classical Timothy syndrome phenotype and provide a structured co-produced definition for CACNA1C-Related Disorder. Finally, we present minimum expected standards of clinical care for individuals with CACNA1C-Related Disorder or Timothy syndrome, with implications for long-term management and improved outcomes for affected individuals.