Timothy Syndrome and CACNA1C-Related Disorder: First International Language and Management Guidelines Consensus Statement

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G. Underwood, Katherine W. Timothy, Holly Tyroll, Rebecca J. Levy, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8058536/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract 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 Ca v 1.2 voltage-gated calcium channel. Since it’s characterisation in 2004, the spread 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 define a new syndrome, 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. Timothy Syndrome CACNA1C-Related Disorders Long QT cardiac arrhythmia syndactyly developmental delay. Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Timothy Syndrome (TS) (Online Mendelian Inheritance in Man (OMIM) entry #601005) is a multisystemic disorder incorporating physical, neurodevelopmental and psychiatric features. It was first described in 1992, through cases of a novel prolonged QT arrhythmia syndrome associated with syndactyly (finger and toe webbing) ( 1 , 2 ). It was formally characterised in 2004 through the work of the Keating and Splawski labs ( 3 ), and named after Katherine Wilson Timothy (KWT), Clinical Coordinator and key force behind the search and triangulation of the genetic locus of TS. The causative locus for TS was isolated to a missense p.G406R variant in the CACNA1C gene at 12p13.33, encoding the Ca V 1.2 L-type voltage gated calcium channel ( 3 ). Its ultra-rare presentation was coupled with significant early-life mortality, which has been reduced with the uptake of screening for prolonged QT in infants born with syndactyly. Population prevalence estimates remain unknown, though some affected individuals are now living well into adulthood with proactive healthcare management and monitoring. KWT’s 2024 Natural History Study of TS included 87 cases ( 4 ), whilst the Timothy Syndrome Alliance’s (TSA’s) global CACNA1C Community Registry includes 104 individuals as of October 2025. Through efforts by KWT, the Timothy Syndrome Foundation (TSF) and the Timothy Syndrome Alliance (TSA) to raise awareness, the number of identified living individuals with CACNA1C -Related Disorders has risen in the past five years alone from ~ 40 to > 200, with rapid growth coinciding with the inclusion of CACNA1C in a range of gene-screening panels and clinical implementation of comprehensive non-targeted next-generation (exome or genome) sequencing. Since the first description of Timothy Syndrome, the phenotype has expanded, as further loci and affected organ systems have been identified. An early advance was the recognition that the thirteen children in whom TS was first identified all had the identical p.G406R variant in exon 8A ( 3 ). Exons 8 and 8A can be alternatively spliced in a mutually exclusive manner, and in 2005 a further individual with TS features, most notably an arrhythmia syndrome associated with marked QT prolongation but no syndactyly, was identified ( 4 , 5 ). This individual, with a p.G406R variant present in exon 8 and congenital hip dysplasia, was the first of a small number that led to the definition of TS Type II (TS2) linked to p.G406R in exon 8, differentiated from TS Type I (TS1) in exon 8A. An additional case in the same study, of an individual with a p.G402S variant in exon 8 and with a similar phenotype, was also included in TS2, extending the molecular diagnostic criteria to other loci within CACNA1C for the first time ( 5 ). It should be noted that the exon 8/8A nomenclature is not consistent in the literature, with many early papers referring imprecisely to Timothy Syndrome across exons 8 and 8A. Here, we utilise the nomenclature originally described in Splawski et al , with TS1 comprising a phenotype including syndactyly, and TS2 featuring hip dysplasia ( 5 ). The initial descriptions of TS invariably included prolongation of the QT interval, a feature which was soon classified as Long QT syndrome type 8 (LQT8). However, non-cardiac phenotypes are more variable. Thus, subsequent work focused on individuals with isolated prolonged QT intervals without the broader range of TS features ( 6 ). Initial studies indicated that these individuals did not exhibit cognitive impairment, facial dysmorphology or other non-cardiac features ( 6 , 7 ). LQT8 was observed with pathogenic variants at loci on the gene distinct from TS, for example, p.P857R in Boczek et al ’s study of 15 members of a multi-generational family ( 6 ), and p.R858H in Gardner et al ’s study of 26 individuals from a family across five generations ( 7 ). Systematic screening of individuals in long QT databases yielded further case series and novel loci amongst cohorts internationally ( 8 , 9 ). Such studies predominantly focused on cardiac manifestations, and reporting of extra-cardiac features was further complicated by cardiac arrest or hypoxic brain injuries causing neurological injury secondary to the primary arrhythmias. Moreover, most of these early studies did not include long-term follow-up evaluation, complicating the assessment of a cardiac-specific phenotype. Some reported cases of novel pathogenic CACNA1C rare variants have included symptoms that mirror or physiologically-oppose TS or LQT8, such as short QT duration or Brugada ECG patterns. Short QT syndrome (SQTS) and Brugada Syndrome (BrS) were first reported in individuals with CACNA1C p.A39V and p.G490R variants in 2007, not long after the definition of TS, however the evidence for such variants as a genetic aetiology of SQTS and BrS is disputed ( 10 – 12 ). As with LQT8, subsequent case series and reports drawn from clinical cohorts of individuals with established BrS or early repolarisation syndromes have proposed a spread of loci across the CACNA1C gene linked to a multisystemic phenotype ( 13 – 15 ). These studies, however, are predominantly single cases, lack familial genetic testing pedigrees, and often variants presented occur at relatively common population frequencies. In 2018 the Clinical Genome Resource (ClinGen) re-examined the gene-disease relationship for CACNA1C and Brugada Syndrome, and classified the evidence supporting a causal role for CACNA1C in Brugada Syndrome as limited ( 12 ). Subsequent international meetings held on topics of ultra-rare cardiac diseases have supported this opinion, based on insufficient case-level data and lack of functional validation evidencing an association between CACNA1C and Brugada Syndrome. Beyond cardiac presentations, rare variants in the CACNA1C gene have also been implicated as the cause of syndromic presentations in sporadic case series and reports (Fig. 1 )( 16 – 20 ). These symptomatically overlap with the original phenotype ascribed to TS, but include some, but not all, features. Neurodevelopmental disorders are frequently observed: developmental delay, intellectual disability, epilepsy, autism, attention-deficit hyperactivity disorder (ADHD), and hypotonia ( 16 , 17 , 19 , 20 ). Efforts establishing this phenotype over the past five years has led it to be added to multiple reference sources, including OMIM (#620029), Orphanet, Wikipedia and Gene Reviews ( 21 ). The largest and most rigorous case series and literature reviews now confirm that rare variants in the CACNA1C gene cause a highly penetrant multisystemic disorder, but no single review examines all potentially implicated phenotypic features (Table 1 ). As the literature on rare pathogenic variants in CACNA1C has expanded, the language and nomenclature used to describe those presentations has become chaotic and confusing. Beyond TS and LQT8, a range of other terms can be found across published literature and public-facing media, including Atypical Timothy Syndrome, Timothy Syndrome Type 3, Timothy Syndrome Variant, Timothy Syndrome-like CACNA1C Disorder, Cardiac-only Timothy Syndrome, CACNA1C -Related Disorders, and CACNA1C -Associated Neurological Disorders. These terms have no clear, established or defined clinical meaning. The number of identified individuals with rare pathogenic CACNA1C variants is increasing, support groups and communities are growing, and therapeutic treatments are in development ( 22 ). There is therefore a need for clarity to guide families, researchers and clinicians. In this work, we set out to achieve cohesion through convening an international network of experts and engaging with the leading TS charities. This resulting consensus document outlines a standard language definition for individuals presenting with variants suspected to be pathogenic in CACNA1C , along with the first guidelines for their diagnosis and management. Table 1 Overview of case series and literature reviews examining Timothy Syndrome, CACNA1C-related disorder and long QT syndrome 8 Timothy et al , A Natural History of Timothy Syndrome, 2024 ( 4 ) Walsh et al , A multicentre study of patients with Timothy syndrome, 2017 ( 23 ) Rodan et al , Phenotypic expansion of CACNA1C -associated disorders to include isolated neurological manifestations, 2021 ( 16 ) Borbás et al , Geno- and phenotypic characteristics and clinical outcomes of CACNA1C gene mutation associated Timothy syndrome, “cardiac only” Timothy syndrome and isolated long QT syndrome 8: A systematic review, 2022 ( 24 ) Levy et al , A cross-sectional study of the neuropsychiatric phenotype of CACNA1C -related disorder, 2022 ( 20 ) Matthews et al , International Cohort of Neonatal Timothy Syndrome, 2024 ( 25 ) Cipriano et al , Expanding the Phenotype of the CACNA1C -Associated Neurological Disorders in Children: Systematic Literature Review and Description of a Novel Mutation, 2024 ( 19 ) Sample size 87 6 25 59 24 44 35 Prolonged QT interval/ arrhythmia Identified Identified Identified Identified Identified Identified Excluded ^ Shortened QT interval Not discussed Not discussed Not observed Excluded $ Not discussed Not discussed Excluded ^ Intellectual disability Not discussed Not discussed Identified Not discussed Identified Not discussed Identified Developmental delay Identified Identified Identified Identified Identified Not discussed Identified Syndactyly Identified Identified Identified Identified Not discussed Identified Not discussed Hip dysplasia Identified Identified Identified Not discussed Not discussed Not discussed Not discussed Structural cardiac malformations Identified Identified Identified Not discussed Not discussed Identified Identified Arrhythmia Identified Identified Identified Identified Not discussed Identified Excluded ^ Autism Identified Not discussed Identified Identified Identified Not discussed Identified ADHD Identified Not discussed Identified Not discussed Identified Not discussed Not discussed Hypoglycaemia Identified Identified Not discussed Identified Not discussed Identified Not discussed Hypotonia Identified Not discussed Identified Not discussed Identified Not discussed Identified Epilepsy/ seizures Identified Identified Identified Identified Identified Not discussed Identified Immune dysfunction Identified Not discussed Not discussed Identified Not discussed Not discussed Not discussed Identified = assessed and observed in cases in study; Not discussed = not assessed in cases in study; $ = Borbás et al excluded case reports on short QT syndrome and Brugada syndrome associated with CACNA1C from their review; ^ = Cipriano et al excluded case reports with “ documented cardiac conduction defects ” Methods Development of the CACNA1C consensus guideline was modelled on the Delphi Process ( 26 ), incorporating multiple rounds of expert discussion, followed by engagement and co-production with the TS and CACNA1C community. The CACNA1C language consensus group consisted of twelve participants from ten institutions across the USA, UK and Europe, comprising clinicians, clinical scientists and researchers. Discussions occurred via video conference calls, e-mail communications and draft file outcomes exchanges. Key issues for discussion were initially identified following the Connect CACNA1C Global Network Conference held by the Timothy Syndrome Alliance (TSA) in June 2023. The language consensus group was convened, and after three rounds of discussions from January to August 2024 (Fig. 2 ), language options were presented to the TS and CACNA1C community for input, along with identification of any further relevant issues. Individuals with CACNA1C variants and their caregivers were contacted through social media, support groups and the Timothy Syndrome Alliance (TSA) community mailing lists, reaching > 200 families. The community voted on language options, which were then discussed along with further outcomes to generate consensus recommendations at a further two working group meeting rounds. Clinical Diagnostic Criteria Clinical features of Timothy Syndrome As noted, TS Type 1 was defined through cardinal features of prolonged QT interval, cardiac arrhythmia and syndactyly in individuals with a p.G406R gene variant in exon 8A of CACNA1C ( 3 ). Further features included autism, developmental delay, seizures, baldness at birth, characteristic facies (flattened nasal bridge, low-set ears, small upper jaw, thin upper lip), small teeth, hypoglycaemia, hypothermia, and hypotonia ( 3 , 23 ). Inclusion of individuals with p.G406R variants in exon 8 associated with a similar phenotype but featuring hip dysplasia led to the development of TS Type 2 ( 5 ). These remain the classical signs of TS Type 1 (hereafter TS1) and Type 2 (TS2), and our consensus reaffirmed the importance of these diagnostic entities. The p.G406R gene variant is highly penetrant, and we therefore expect individuals with p.G406R variants to present with symptoms of TS1 or TS2, dependent on whether the p.G406R variant is present in exon 8 or 8A ( 21 ). In Splawski et al ’s work defining TS2, they extended the loci to include p.G402S variants, although this appears to have more variable penetrance ( 5 ). Further case reports and series have presented individuals with the classical phenotypic features of TS, but novel de novo gene variants, notably p.R324W ( 16 ), p.V403M ( 16 ), p.E407G ( 27 ), p.E407A ( 28 ), p.C1021R ( 29 , 30 ), p.I1166T ( 6 , 9 , 28 ), and p.A1473G ( 31 ). On this basis, TS1 and TS2 diagnoses should be assigned based on phenotypic syndromic features and not be dependent upon the specific p.G406R loci. Any individual with a rare single nucleotide variant within the CACNA1C gene presenting with the classic dyad of prolonged QT interval and a neurodevelopmental disorder (e.g. developmental delay, intellectual disability, autism) should be diagnosed as TS following appropriate clinical genetic medical evaluation. In Fig. 3 below, we outline a flow chart for diagnostic interpretation of CACNA1C pathogenic rare variants based upon assessment and examination of all potential syndromic features. These individuals should be further assessed across all potentially affected organ systems, with ongoing follow-up on an annual basis to monitor for further symptoms driven by developmental changes. Of note, individuals with pathogenic variants in CACNA1C may present solely with bradycardia whilst in utero , and in the first year of life with bradycardia or hypotonia, prior to the development of other features. Neonates or infants may show prolonged QT intervals on electrocardiography, with or without 2:1 functional atrioventricular block (secondary to the prolonged QT). All individuals identified in utero or in the first year of life displaying these features should be treated as suspected TS and followed up closely with proactive intervention and management. CACNA1C-Related Disorders Individuals with other, non-G406R variants in the CACNA1C gene may also present with some, but not all, features of TS ( 16 , 17 , 19 , 20 , 32 ). Potential diagnostic and nomenclature structures were distilled to two options through the language consensus working group meetings, which were presented to the CACNA1C community. 31 individuals with CACNA1C variants or their families responded to requests for input, voting by 26 to 3 for the adoption of a new CACNA1C-Related Disorders diagnostic term (with two individuals suggesting further options). This new definition provides an umbrella term for all individuals with pathogenic rare variants in CACNA1C beyond those with TS1 or TS2 phenotypes, as laid out in Figs. 3 and 4 . This serves to bring those with LQT8 into the wider community, and to include those individuals who previously did not have a formal diagnosis, allowing them improved access to medical care and therapies. Within the CACNA1C-Related Disorders (CRDs) umbrella, syndromic presentations of pathogenic CACNA1C rare variant with multiple organ system involvement fitting published literature but inconsistent with TS can be diagnosed with CACNA1C-Related Disorder (Fig. 3 ). CACNA1C-Related Disorder (CRD) aligns the CACNA1C gene with the movement towards gene-based nomenclature, which has been observed across the field and particularly in channelopathies, e.g., CACNA1A-related disease ( 33 ), SCN2A-related disorders ( 34 ), and SCN8A-related disorders ( 35 ). Cardiac presentations of CACNA1C-Related Disorders Individuals may initially present with isolated cardiac features, encompassing a range of phenotypes featuring isolated prolonged QT interval, arrhythmias, hypertrophic cardiomyopathy, congenital heart disease, sinus node disease and congenital structural cardiac abnormalities (Fig. 3 ). The symptomatic presentation of LQT8 in individuals with rare CACNA1C variants has been robustly demonstrated ( 4 , 18 , 36 , 37 ). Further cardiac phenotypes have previously been linked with CACNA1C rare variants, including Brugada Syndrome (BrS) ( 14 , 38 , 39 ), short QT syndrome (SQTS) ( 10 , 14 , 15 ), and hypertrophic cardiomyopathy, congenital heart disease and sinus node disease ( 6 , 40 , 41 ), overlapping and characterised as cardiac-only TS ( 36 , 37 , 42 ). For BrS and SQTS studies provide only limited support for a link between CACNA1C and those phenotypes, and the causal relationship is disputed ( 11 ), as further evidenced by ClinGen’s re-evaluation of the literature ( 12 ). We recognise that there is no consensus on this evidence, with a need for further in-depth assessments and functional analyses of posited loci. Many existing case reports on individuals with LQT8 are limited to only cardiovascular symptom profiling; therefore, concern was raised throughout the consensus group meetings that this may represent under-reporting or under-assessment of non-cardiac phenotypic features. These single organ-system presentations may be due to splice variation, mosaicism, or decreased penetrance, but all individuals presenting in such a manner require a full, holistic, multisystemic medical work-up. Individuals presenting with single organ system presentations of a pathogenic CACNA1C rare variant (Fig. 3 ), for example LQT8, fall within the CACNA1C-Related Disorders umbrella term. Individuals identified via single organ-system presentations early in childhood often present later in development with further symptoms as CACNA1C expression regulation changes ( 4 ), and therefore, ongoing observation and follow-up is advised. In those with CACNA1C variants, each individual’s QT intervals can be highly variable with wide ranges, and cardiac risk does not clearly correlate with observed QT duration ( 43 ). Furthermore, some patients may initially present with borderline QT prolongation, which may evolve to LQT8 or place them at risk for acquired long QT syndromes. This evolution of symptoms further supports the umbrella term of CACNA1C-Related Disorders for all patients presenting with a pathogenic CACNA1C variant, and the need for regular cardiac monitoring as a baseline standard of care. Molecular Diagnostic Criteria Functional interpretation The initial novel missense p.G406R variant first identified in exon 8A results in a gain-of-function, manifesting as significant changes in channel activation, voltage-dependent inactivation (VDI) and calcium-dependent inactivation (CDI)( 3 , 5 , 44 , 45 ). Electrophysiological studies have demonstrated that this combination of effects is not isolated to the p.G406R variant, but the TS phenotype appears associated pathophysiologically with specific changes in the electrophysiological properties and functions of the Ca v 1.2 channel. These include hyperpolarised left-shifts of activation curves coupled to altered CDI and VDI, with notable differences observable within this grouping between individual variants such as p.G406R and p.G402S ( 23 , 44 , 45 ). Subsequent work has shown that these variants have further effects, including decreased synaptic inhibition, defects in cortical differentiation, altered long-term potentiation, and altered cortical interneuron migration ( 46 – 48 ). Variant function can therefore be understood to be more complex than simple ‘gain- or loss-of-function’, and many variants result in changes with mixed effects, as recently reviewed by Bauer et al ( 6 , 9 , 18 , 32 , 45 ). Further complicating this picture is evidence of both non-linear relationships between CACNA1C variants and Ca V 1.2 expression profiles ( 44 ). Variants may show increased cell surface expression due to decreased degradation ( 6 , 8 ), while some variants (notably p.G406R) increase basal transcription through excitation-transcription coupling ( 49 ), or alter neuronal gene expression ( 50 ), with enhanced activation of the Ca v 1.2 channel driving multiple pathological mechanisms at both the cellular and network level ( 44 , 51 , 52 ). Expression of Ca v 1.2 and development of symptoms at a system or organ level are subsequently dependent on transcription of the pathological variant. Ca v 1.2 is widely expressed in almost all tissues and is critical for development ( 3 , 4 , 53 ). Evidence from long-read sequencing suggests that CACNA1C incorporates at least 47 constituent exons, with > 240 novel transcripts, and those transcripts demonstrate developmental stage and tissue-specific splicing, which are predicted to alter channel function ( 54 ). These mechanisms, in combination with germline mosaicism, are hypothesised to drive the irregular penetrance and phenotypic variability seen across CRDs ( 4 , 18 , 19 , 23 , 29 ). Due to this complexity, clinical pathogenicity should not be extrapolated based upon inferred gain- or loss-of-function. We recommend supporting clinical variant interpretation with functional testing of the variant in established model systems. Tools and literature supporting variant interpretation are predicted to evolve, and therefore we advise periodic re-testing and re-evaluation utilising updated evidence. This guidance supports the recommendation that diagnoses should be made on a syndromic basis, and pathogenicity cannot yet be inferred from gain- or loss-of-function descriptors alone. Guidelines for Clinical Care Due to the widespread but variable expression and mixed effects of CACNA1C gene variants, presentations are individual specific but frequently multisystemic. All individuals with a CACNA1C pathogenic or likely pathogenic variant require a full multidisciplinary team clinical work-up, to include, at a minimum cardiac, neurodevelopmental, musculoskeletal and endocrine reviews. We expect individuals to show an evolution of risk and development of new syndromic features over time, secondary to changes in expression of CACNA1C and the Ca v 1.2 channel over the lifespan, necessitating consistent follow-up. For individuals with variants of unknown or uncertain significance (VUS) in the CACNA1C gene, it is reasonable to clinically screen for other organ involvement to determine if there is additional clinical evidence of a CRD. Cardiac features of CRDs including TS, as the most reported and historically most lethal phenotypic presentation, have received significant therapeutic study ( 4 , 18 ). Recent reviews and case series have demonstrated that beta-blocker medication and implantable cardioverter-defibrillators (ICDs) are the most effective current treatments ( 23 , 36 , 55 ). Surgical interventions, through left cardiac sympathetic denervation to attenuate heterogeneous sympathetic myocardial innervation, have also demonstrated efficacy ( 4 , 56 ). Calcium-channel blockers, perhaps counterintuitively, are not effective in the management of any CRDs (including TS) due to the complex gating changes in Ca v 1.2 ( 4 , 45 , 57 ). Implantation of an ICD early in life decreases mortality risk, and this change in practice has led to a dramatic increase in life expectancy of TS children since the syndrome was first described ( 4 , 23 , 57 ). No other comprehensive organ-level systematic reviews have been undertaken in TS or more broadly across CRDs. Timothy et al ’s 2024 Natural History Study of TS covers a broad range of phenotypic features in depth, including discussion of key areas for clinical concern ( 4 ). As TS and CRD children survive longer, there is evidence of emerging mortality risks from further syndromic features ( 4 , 20 , 21 ). Epilepsy is prevalent across CRDs, and seizures may be refractory to standard treatments ( 16 , 17 , 20 , 32 ). Individuals with CRDs where there is suspicion of seizure activity should have neurologic evaluation and seizure rescue medication available in their home, work or school environments. Hypoglycaemia has been noted in CRDs ( 3 – 5 ), and recent work has demonstrated that this is through dysregulated glucose homeostasis, absent hyperinsulinism, and defects in glucagon secretion ( 58 ). Individuals with CACNA1C variants are at risk of hypoglycaemia, particularly when in states of physiological stress, including viral illnesses, which may compound with arrhythmias and lower seizure thresholds to increase the risk of sudden death. Those with CRDs (including TS) should therefore monitor blood glucose levels routinely and have rescue kits (e.g. glucose tablets or gel, fruit juice or sugary drinks/candy) available for use in episodes of low blood sugar. Further features of CRDs will require long-term therapies and interventions and are treated symptomatically and individually. Responses to anaesthesia are reportedly abnormal, and care should be taken with all sedation ( 4 ). Many children with CRDs have frequent infections, likely due to altered immunological function ( 3 , 4 ). Abnormal dentition, frequent cavities and small displaced teeth requiring surgical intervention have commonly been reported ( 3 , 4 , 19 ). Gastroesophageal reflux, frequent vomiting and congenital gastrointestinal defects have been reported across CRDs ( 4 , 30 ). Chronic constipation is seen in > 80% of individuals with TS, and anecdotally stated to be a significant issue amongst CRDs ( 3 , 4 ). The majority of children with CRDs will experience some developmental delay, particularly of speech ( 4 , 19 , 20 ). Autism is a highly penetrant phenotypic feature across CRDs, and other neurodevelopmental conditions (e.g. ADHD), neurosensory and neuromuscular features such as hypotonia complicate this presentation. All children with CRDs should be provided with individualised, tailored support in education and work environments. Long-term evolution of features and outcomes, particularly in those without prolonged QT, are not known, although several individuals are now well into mid-life with a range of functional outcomes ( 4 , 20 ). Based on the above guidance, all individuals with a CACNA1C -Related Disorder should have as a minimum standard of care: Annual cardiac and endocrine review including echocardiography (ECG/EKG) Implantable cardioverter-defibrillators in those with prolonged QTc, and loop recorders in those with borderline QTc Annual neurodevelopmental reviews whilst < 18 years of age Periodic home ambulatory EEG to identify potential seizure activity Home glucose monitoring, hypoglycaemia and seizure rescue kits with appropriate training. Conclusions In the thirty years since Keating et al first described a ‘heart-hand’ syndrome, and twenty years since this was formalised as Timothy Syndrome, the landscape of phenotypic features associated with rare pathogenic variants in the CACNA1C gene has changed substantially. TS remains the most severe presentation, but genomic loci linked to this syndromic phenotype have extended beyond the classical p.G406R variant. Meanwhile, a range of cases have been reported with overlapping or contrasting phenotypic features and novel rare CACNA1C variants. Here, through expert consensus and community engagement, we summarise updated phenotypes and features for TS and its associated presentations. We define CACNA1C -Related Disorders, a new umbrella phenotypic syndrome, capturing the range of classical and newly recognised presentations. Finally, we present the first guidelines on standards of diagnostic and clinical care for individuals presenting with a rare CACNA1C gene variant, driven by the evidence that with appropriate interventions, these individuals can live longer, fulfilling lives. Declarations Funding This research was funded in part by the Wellcome Trust (grant number 222849/Z/21/Z). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any author accepted manuscript version arising from this submission. J.F.G.U. is funded by a Wellcome Trust GW4-CAT Clinical Research Fellowship (222849/Z/21/Z), a Hodge Foundation Early Career Clinical Academic grant, and an HEIW Welsh Clinical Academic Training (WCAT) Fellowship. J.H. is supported by the Hodge Centre for Translational Neuroscience. R.J.L. is funded by the Child Neurologist Career Development Program (CNCDP-K12) and a National Institute of Neurological Disorders and Stroke Clinical Research Career Development Award (NINDS K08–1K08NS13677501A1). I.E.D. is supported by a National Institute of Mental Health (NIMH) R01 (R01MH137160) and a National Heart, Lung, and Blood Institute (NHLBI) R01 (R01HL149926). G.S.P. is supported by R01 HL146149, R01 HL151190, and R01 HL160089 (NHLBI). N.A.L.H is supported by the National Institute for Health and Care Research (NIHR) Oxford Health Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the National Health Service, NIHR, or the Department of Health and Social Care. G.S.B. is funded by Instituto de Salud Carlos III (ISCIII), Fondo Investigación Sanitaria-FIS-(PI21/00094) and co-funded by the European Union, Fundació Bosch i Aymerich, IRSJD is a CERCA Programme from Generalitat de Catalunya. Author Contribution J.F.G.U devised the project, with input from R.J.L and K.W.T. All meetings were organised and run by J.F.G.U, with K.W.T., R.J.L, I.E.D., G.S.P., E.M.T., A.B., G.W., N.A.L.H., G.S.B., R.B., D.A. and J.H. inputting into meetings and the Delphi process. Suggestions received input from the CACNA1C community through the TSA and TSF. The manuscript was written by J.F.G.U., with figures and background material from H.T. and E.M.T. All authors reviewed the manuscript. Acknowledgement Early discussions on this topic were contributed to by Dr Andy Golden, who was pivotal to research developments and care for individuals with TS, and sadly passed away before the development of this guideline. Bambino Gesù Children Hospital IRCCS is an HCP for The European Reference Network for rare, low-prevalence, and complex diseases of the heart—ERN GUARD-Heart. The Timothy Syndrome Alliance (TSA) is supported by the Chan-Zuckerberg Initiative (CZI) Rare As One programme. E.M.T. is a full- time employee of Boehringer Ingelheim. Prior to her move into industry, she was in receipt of unrestricted research grants from J&J Innovation, and from Boehringer Ingelheim and Biogen, via the Psychiatry Consortium of the Medicines Discovery Catapult. She also provided consultancy to Boehringer Ingelheim and ONO Pharma. She reports no conflict of interest with the current manuscript. The remaining authors declare that they have no competing interests. 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05:55:06","extension":"png","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":45812,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8058536/v1/35938f266383aef983921c27.png"},{"id":96046697,"identity":"f4dbda10-a483-4d61-88fc-33dfc6a82805","added_by":"auto","created_at":"2025-11-17 05:55:06","extension":"xml","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":166371,"visible":true,"origin":"","legend":"","description":"","filename":"b948b1c7f0b545cc8722fa04135270a61structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8058536/v1/6d5830f7719cf0100ec642e0.xml"},{"id":96046699,"identity":"eea29970-1778-4c57-a4c4-4b710c23fe83","added_by":"auto","created_at":"2025-11-17 05:55:06","extension":"html","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":182637,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8058536/v1/bc2ad70ad2d5e9da14006c7d.html"},{"id":96046685,"identity":"07709ad0-1dd6-4ac4-a5f5-29bb2b908ac8","added_by":"auto","created_at":"2025-11-17 05:55:06","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":207936,"visible":true,"origin":"","legend":"\u003cp\u003ePublished variants in CACNA1C mapped to a model of the Ca\u003csub\u003ev\u003c/sub\u003e1.2 protein\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBased upon review of published variants undertaken to September 2025. See Supplementary Material for list of variants and publications. Created in BioRender. Tunbridge, E. (2026) https://BioRender.com/b078y2i\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8058536/v1/1b7d9364c33e23936d50a19e.png"},{"id":96046692,"identity":"5d0311b3-2b4e-45e3-9731-8217da591b54","added_by":"auto","created_at":"2025-11-17 05:55:06","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":114671,"visible":true,"origin":"","legend":"\u003cp\u003eTimeline of meetings and public engagement of the CACNA1C language consensus group\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThis figure was created in BioRender. Underwood, J. (2026) https://BioRender.com/etvxcc3\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8058536/v1/1418c7b92206af9573065ff2.png"},{"id":96046686,"identity":"fcf6bb1b-8ba7-44b3-a60f-d0db5eb07620","added_by":"auto","created_at":"2025-11-17 05:55:06","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":700102,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart for syndromic interpretation and diagnosis in individuals with pathogenic CACNA1C rare variants\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThis figure was created in BioRender. Underwood, J. (2026) https://BioRender.com/jlnh24q\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8058536/v1/e7fad3902bd7f71fc172151b.png"},{"id":96245613,"identity":"a758177e-ea74-46b0-ae7e-5b532fc614a2","added_by":"auto","created_at":"2025-11-19 07:21:16","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":197950,"visible":true,"origin":"","legend":"\u003cp\u003eEuler diagram of diagnoses and syndromes featuring CACNA1C gene changes\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThis figure was created in BioRender. Underwood, J. (2026) https://BioRender.com/335c7zp\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8058536/v1/e0752b0d96f823f93b74f992.png"},{"id":96915981,"identity":"ba23f81d-9a5e-449a-8784-d0cbc24ba329","added_by":"auto","created_at":"2025-11-27 14:07:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2177306,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8058536/v1/50fdf420-08e3-4563-b4eb-cd8d98b18b20.pdf"},{"id":96046687,"identity":"aff82dc0-b298-4b32-a0fc-2d14b469fd46","added_by":"auto","created_at":"2025-11-17 05:55:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":449696,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8058536/v1/a9dc9e1ab6b97d005e07e924.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Timothy Syndrome and CACNA1C-Related Disorder: First International Language and Management Guidelines Consensus Statement","fulltext":[{"header":"Background","content":"\u003cp\u003eTimothy Syndrome (TS) (Online Mendelian Inheritance in Man (OMIM) entry #601005) is a multisystemic disorder incorporating physical, neurodevelopmental and psychiatric features. It was first described in 1992, through cases of a novel prolonged QT arrhythmia syndrome associated with syndactyly (finger and toe webbing) (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e). It was formally characterised in 2004 through the work of the Keating and Splawski labs (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e), and named after Katherine Wilson Timothy (KWT), Clinical Coordinator and key force behind the search and triangulation of the genetic locus of TS.\u003c/p\u003e\n\u003cp\u003eThe causative locus for TS was isolated to a missense p.G406R variant in the \u003cem\u003eCACNA1C\u003c/em\u003e gene at 12p13.33, encoding the Ca\u003csub\u003eV\u003c/sub\u003e1.2 L-type voltage gated calcium channel (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e). Its ultra-rare presentation was coupled with significant early-life mortality, which has been reduced with the uptake of screening for prolonged QT in infants born with syndactyly. Population prevalence estimates remain unknown, though some affected individuals are now living well into adulthood with proactive healthcare management and monitoring. KWT\u0026rsquo;s 2024 Natural History Study of TS included 87 cases (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e), whilst the Timothy Syndrome Alliance\u0026rsquo;s (TSA\u0026rsquo;s) global \u003cem\u003eCACNA1C\u003c/em\u003e Community Registry includes 104 individuals as of October 2025. Through efforts by KWT, the Timothy Syndrome Foundation (TSF) and the Timothy Syndrome Alliance (TSA) to raise awareness, the number of identified living individuals with \u003cem\u003eCACNA1C\u003c/em\u003e-Related Disorders has risen in the past five years alone from ~\u0026thinsp;40 to \u0026gt;\u0026thinsp;200, with rapid growth coinciding with the inclusion of \u003cem\u003eCACNA1C\u003c/em\u003e in a range of gene-screening panels and clinical implementation of comprehensive non-targeted next-generation (exome or genome) sequencing.\u003c/p\u003e\n\u003cp\u003eSince the first description of Timothy Syndrome, the phenotype has expanded, as further loci and affected organ systems have been identified. An early advance was the recognition that the thirteen children in whom TS was first identified all had the identical p.G406R variant in exon 8A (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e). Exons 8 and 8A can be alternatively spliced in a mutually exclusive manner, and in 2005 a further individual with TS features, most notably an arrhythmia syndrome associated with marked QT prolongation but no syndactyly, was identified (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e). This individual, with a p.G406R variant present in exon 8 and congenital hip dysplasia, was the first of a small number that led to the definition of TS Type II (TS2) linked to p.G406R in exon 8, differentiated from TS Type I (TS1) in exon 8A. An additional case in the same study, of an individual with a p.G402S variant in exon 8 and with a similar phenotype, was also included in TS2, extending the molecular diagnostic criteria to other loci within \u003cem\u003eCACNA1C\u003c/em\u003e for the first time (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e). It should be noted that the exon 8/8A nomenclature is not consistent in the literature, with many early papers referring imprecisely to Timothy Syndrome across exons 8 and 8A. Here, we utilise the nomenclature originally described in Splawski \u003cem\u003eet al\u003c/em\u003e, with TS1 comprising a phenotype including syndactyly, and TS2 featuring hip dysplasia (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eThe initial descriptions of TS invariably included prolongation of the QT interval, a feature which was soon classified as Long QT syndrome type 8 (LQT8). However, non-cardiac phenotypes are more variable. Thus, subsequent work focused on individuals with isolated prolonged QT intervals without the broader range of TS features (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e). Initial studies indicated that these individuals did not exhibit cognitive impairment, facial dysmorphology or other non-cardiac features (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e). LQT8 was observed with pathogenic variants at loci on the gene distinct from TS, for example, p.P857R in Boczek \u003cem\u003eet al\u003c/em\u003e\u0026rsquo;s study of 15 members of a multi-generational family (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e), and p.R858H in Gardner \u003cem\u003eet al\u003c/em\u003e\u0026rsquo;s study of 26 individuals from a family across five generations (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e). Systematic screening of individuals in long QT databases yielded further case series and novel loci amongst cohorts internationally (\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e). Such studies predominantly focused on cardiac manifestations, and reporting of extra-cardiac features was further complicated by cardiac arrest or hypoxic brain injuries causing neurological injury secondary to the primary arrhythmias. Moreover, most of these early studies did not include long-term follow-up evaluation, complicating the assessment of a cardiac-specific phenotype.\u003c/p\u003e\n\u003cp\u003eSome reported cases of novel pathogenic \u003cem\u003eCACNA1C\u003c/em\u003e rare variants have included symptoms that mirror or physiologically-oppose TS or LQT8, such as short QT duration or Brugada ECG patterns. Short QT syndrome (SQTS) and Brugada Syndrome (BrS) were first reported in individuals with \u003cem\u003eCACNA1C\u003c/em\u003e p.A39V and p.G490R variants in 2007, not long after the definition of TS, however the evidence for such variants as a genetic aetiology of SQTS and BrS is disputed (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e). As with LQT8, subsequent case series and reports drawn from clinical cohorts of individuals with established BrS or early repolarisation syndromes have proposed a spread of loci across the \u003cem\u003eCACNA1C\u003c/em\u003e gene linked to a multisystemic phenotype (\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e). These studies, however, are predominantly single cases, lack familial genetic testing pedigrees, and often variants presented occur at relatively common population frequencies. In 2018 the Clinical Genome Resource (ClinGen) re-examined the gene-disease relationship for \u003cem\u003eCACNA1C\u003c/em\u003e and Brugada Syndrome, and classified the evidence supporting a causal role for \u003cem\u003eCACNA1C\u003c/em\u003e in Brugada Syndrome as limited (\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e). Subsequent international meetings held on topics of ultra-rare cardiac diseases have supported this opinion, based on insufficient case-level data and lack of functional validation evidencing an association between \u003cem\u003eCACNA1C\u003c/em\u003e and Brugada Syndrome.\u003c/p\u003e\n\u003cp\u003eBeyond cardiac presentations, rare variants in the \u003cem\u003eCACNA1C\u003c/em\u003e gene have also been implicated as the cause of syndromic presentations in sporadic case series and reports (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e)(\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e). These symptomatically overlap with the original phenotype ascribed to TS, but include some, but not all, features. Neurodevelopmental disorders are frequently observed: developmental delay, intellectual disability, epilepsy, autism, attention-deficit hyperactivity disorder (ADHD), and hypotonia (\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e). Efforts establishing this phenotype over the past five years has led it to be added to multiple reference sources, including OMIM (#620029), Orphanet, Wikipedia and Gene Reviews (\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e). The largest and most rigorous case series and literature reviews now confirm that rare variants in the \u003cem\u003eCACNA1C\u003c/em\u003e gene cause a highly penetrant multisystemic disorder, but no single review examines all potentially implicated phenotypic features (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eAs the literature on rare pathogenic variants in \u003cem\u003eCACNA1C\u003c/em\u003e has expanded, the language and nomenclature used to describe those presentations has become chaotic and confusing. Beyond TS and LQT8, a range of other terms can be found across published literature and public-facing media, including Atypical Timothy Syndrome, Timothy Syndrome Type 3, Timothy Syndrome Variant, Timothy Syndrome-like \u003cem\u003eCACNA1C\u003c/em\u003e Disorder, Cardiac-only Timothy Syndrome, \u003cem\u003eCACNA1C\u003c/em\u003e-Related Disorders, and \u003cem\u003eCACNA1C\u003c/em\u003e-Associated Neurological Disorders. These terms have no clear, established or defined clinical meaning. The number of identified individuals with rare pathogenic \u003cem\u003eCACNA1C\u003c/em\u003e variants is increasing, support groups and communities are growing, and therapeutic treatments are in development (\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e). There is therefore a need for clarity to guide families, researchers and clinicians. In this work, we set out to achieve cohesion through convening an international network of experts and engaging with the leading TS charities. This resulting consensus document outlines a standard language definition for individuals presenting with variants suspected to be pathogenic in \u003cem\u003eCACNA1C\u003c/em\u003e, along with the first guidelines for their diagnosis and management.\u003c/p\u003e\n\u003ch3\u003e\u0026nbsp;\u003c/h3\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eOverview of case series and literature reviews examining Timothy Syndrome, CACNA1C-related disorder and long QT syndrome 8\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\u003ccolgroup\u003e\u003c/colgroup\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eTimothy \u003cem\u003eet al\u003c/em\u003e, A Natural History of Timothy Syndrome, 2024 (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eWalsh \u003cem\u003eet al\u003c/em\u003e, A multicentre study of patients with Timothy syndrome, 2017 (\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eRodan \u003cem\u003eet al\u003c/em\u003e, Phenotypic expansion of \u003cem\u003eCACNA1C\u003c/em\u003e-associated disorders to include isolated neurological manifestations, 2021 (\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eBorb\u0026aacute;s \u003cem\u003eet al\u003c/em\u003e, Geno- and phenotypic characteristics and clinical outcomes of \u003cem\u003eCACNA1C\u003c/em\u003e gene mutation associated Timothy syndrome, \u0026ldquo;cardiac only\u0026rdquo; Timothy syndrome and isolated long QT syndrome 8: A systematic review, 2022 (\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eLevy \u003cem\u003eet al\u003c/em\u003e, A cross-sectional study of the neuropsychiatric phenotype of \u003cem\u003eCACNA1C\u003c/em\u003e-related disorder, 2022 (\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMatthews \u003cem\u003eet al\u003c/em\u003e, International Cohort of Neonatal Timothy Syndrome, 2024 (\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCipriano \u003cem\u003eet al\u003c/em\u003e, Expanding the Phenotype of the \u003cem\u003eCACNA1C\u003c/em\u003e-Associated Neurological Disorders in Children: Systematic Literature Review and Description of a Novel Mutation, 2024 (\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eSample size\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e87\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e59\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e24\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e44\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eProlonged QT interval/ arrhythmia\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eExcluded ^\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eShortened QT interval\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot observed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eExcluded $\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eExcluded ^\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eIntellectual disability\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eDevelopmental delay\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eSyndactyly\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eHip dysplasia\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eStructural cardiac malformations\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eArrhythmia\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eExcluded ^\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eAutism\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eADHD\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eHypoglycaemia\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eHypotonia\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eEpilepsy/ seizures\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eImmune dysfunction\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentified\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNot discussed\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"8\"\u003e\u003cstrong\u003eIdentified\u0026thinsp;=\u0026thinsp;assessed and observed in cases in study; Not discussed\u0026thinsp;=\u0026thinsp;not assessed in cases in study;\u003c/strong\u003e \u003cstrong\u003e$\u003c/strong\u003e \u003cstrong\u003e=\u003c/strong\u003e \u003cstrong\u003eBorb\u0026aacute;s\u003c/strong\u003e \u003cstrong\u003eet al\u003c/strong\u003e \u003cstrong\u003eexcluded case reports on short QT syndrome and Brugada syndrome associated with\u003c/strong\u003e \u003cstrong\u003eCACNA1C\u003c/strong\u003e \u003cstrong\u003efrom their review; ^ = Cipriano\u003c/strong\u003e \u003cstrong\u003eet al\u003c/strong\u003e \u003cstrong\u003eexcluded case reports with \u0026ldquo;\u003c/strong\u003e\u003cstrong\u003edocumented cardiac conduction defects\u003c/strong\u003e\u003cstrong\u003e\u0026rdquo;\u003c/strong\u003e\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e"},{"header":"Methods","content":"\u003cp\u003eDevelopment of the \u003cem\u003eCACNA1C\u003c/em\u003e consensus guideline was modelled on the Delphi Process (\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e), incorporating multiple rounds of expert discussion, followed by engagement and co-production with the TS and \u003cem\u003eCACNA1C\u003c/em\u003e community. The \u003cem\u003eCACNA1C\u003c/em\u003e language consensus group consisted of twelve participants from ten institutions across the USA, UK and Europe, comprising clinicians, clinical scientists and researchers. Discussions occurred via video conference calls, e-mail communications and draft file outcomes exchanges.\u003c/p\u003e\n\u003cp\u003eKey issues for discussion were initially identified following the \u003cem\u003eConnect CACNA1C Global Network Conference\u003c/em\u003e held by the Timothy Syndrome Alliance (TSA) in June 2023. The language consensus group was convened, and after three rounds of discussions from January to August 2024 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e), language options were presented to the TS and \u003cem\u003eCACNA1C\u003c/em\u003e community for input, along with identification of any further relevant issues. Individuals with \u003cem\u003eCACNA1C\u003c/em\u003e variants and their caregivers were contacted through social media, support groups and the Timothy Syndrome Alliance (TSA) community mailing lists, reaching\u0026thinsp;\u0026gt;\u0026thinsp;200 families. The community voted on language options, which were then discussed along with further outcomes to generate consensus recommendations at a further two working group meeting rounds.\u003c/p\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003eClinical Diagnostic Criteria\u003c/h2\u003e\n\u003cdiv id=\"Sec6\" class=\"Section3\"\u003e\n\u003ch2\u003eClinical features of Timothy Syndrome\u003c/h2\u003e\n\u003cp\u003eAs noted, TS Type 1 was defined through cardinal features of prolonged QT interval, cardiac arrhythmia and syndactyly in individuals with a p.G406R gene variant in exon 8A of \u003cem\u003eCACNA1C\u003c/em\u003e (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e). Further features included autism, developmental delay, seizures, baldness at birth, characteristic facies (flattened nasal bridge, low-set ears, small upper jaw, thin upper lip), small teeth, hypoglycaemia, hypothermia, and hypotonia (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e). Inclusion of individuals with p.G406R variants in exon 8 associated with a similar phenotype but featuring hip dysplasia led to the development of TS Type 2 (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e). These remain the classical signs of TS Type 1 (hereafter TS1) and Type 2 (TS2), and our consensus reaffirmed the importance of these diagnostic entities. The p.G406R gene variant is highly penetrant, and we therefore expect individuals with p.G406R variants to present with symptoms of TS1 or TS2, dependent on whether the p.G406R variant is present in exon 8 or 8A (\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eIn Splawski \u003cem\u003eet al\u003c/em\u003e\u0026rsquo;s work defining TS2, they extended the loci to include p.G402S variants, although this appears to have more variable penetrance (\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e). Further case reports and series have presented individuals with the classical phenotypic features of TS, but novel \u003cem\u003ede novo\u003c/em\u003e gene variants, notably p.R324W (\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e), p.V403M (\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e), p.E407G (\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e), p.E407A (\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e), p.C1021R (\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e), p.I1166T (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e), and p.A1473G (\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e). On this basis, TS1 and TS2 diagnoses should be assigned based on phenotypic syndromic features and not be dependent upon the specific p.G406R loci. Any individual with a rare single nucleotide variant within the \u003cem\u003eCACNA1C\u003c/em\u003e gene presenting with the classic dyad of prolonged QT interval and a neurodevelopmental disorder (e.g. developmental delay, intellectual disability, autism) should be diagnosed as TS following appropriate clinical genetic medical evaluation. In Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e below, we outline a flow chart for diagnostic interpretation of \u003cem\u003eCACNA1C\u003c/em\u003e pathogenic rare variants based upon assessment and examination of all potential syndromic features.\u003c/p\u003e\n\u003cp\u003eThese individuals should be further assessed across all potentially affected organ systems, with ongoing follow-up on an annual basis to monitor for further symptoms driven by developmental changes. Of note, individuals with pathogenic variants in \u003cem\u003eCACNA1C\u003c/em\u003e may present solely with bradycardia whilst \u003cem\u003ein utero\u003c/em\u003e, and in the first year of life with bradycardia or hypotonia, prior to the development of other features. Neonates or infants may show prolonged QT intervals on electrocardiography, with or without 2:1 functional atrioventricular block (secondary to the prolonged QT). All individuals identified \u003cem\u003ein utero\u003c/em\u003e or in the first year of life displaying these features should be treated as suspected TS and followed up closely with proactive intervention and management.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eCACNA1C-Related Disorders\u003c/h2\u003e\n\u003cp\u003eIndividuals with other, non-G406R variants in the \u003cem\u003eCACNA1C\u003c/em\u003e gene may also present with some, but not all, features of TS (\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e). Potential diagnostic and nomenclature structures were distilled to two options through the language consensus working group meetings, which were presented to the \u003cem\u003eCACNA1C\u003c/em\u003e community. 31 individuals with \u003cem\u003eCACNA1C\u003c/em\u003e variants or their families responded to requests for input, voting by 26 to 3 for the adoption of a new CACNA1C-Related Disorders diagnostic term (with two individuals suggesting further options). This new definition provides an umbrella term for all individuals with pathogenic rare variants in \u003cem\u003eCACNA1C\u003c/em\u003e beyond those with TS1 or TS2 phenotypes, as laid out in Figs.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e and \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e. This serves to bring those with LQT8 into the wider community, and to include those individuals who previously did not have a formal diagnosis, allowing them improved access to medical care and therapies. Within the CACNA1C-Related Disorders (CRDs) umbrella, syndromic presentations of pathogenic \u003cem\u003eCACNA1C\u003c/em\u003e rare variant with multiple organ system involvement fitting published literature but inconsistent with TS can be diagnosed with CACNA1C-Related Disorder (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). CACNA1C-Related Disorder (CRD) aligns the \u003cem\u003eCACNA1C\u003c/em\u003e gene with the movement towards gene-based nomenclature, which has been observed across the field and particularly in channelopathies, e.g., CACNA1A-related disease (\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e), SCN2A-related disorders (\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e), and SCN8A-related disorders (\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eCardiac presentations of CACNA1C-Related Disorders\u003c/h3\u003e\n\u003cp\u003eIndividuals may initially present with isolated cardiac features, encompassing a range of phenotypes featuring isolated prolonged QT interval, arrhythmias, hypertrophic cardiomyopathy, congenital heart disease, sinus node disease and congenital structural cardiac abnormalities (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). The symptomatic presentation of LQT8 in individuals with rare \u003cem\u003eCACNA1C\u003c/em\u003e variants has been robustly demonstrated (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e). Further cardiac phenotypes have previously been linked with \u003cem\u003eCACNA1C\u003c/em\u003e rare variants, including Brugada Syndrome (BrS) (\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e), short QT syndrome (SQTS) (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e), and hypertrophic cardiomyopathy, congenital heart disease and sinus node disease (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e), overlapping and characterised as cardiac-only TS (\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e). For BrS and SQTS studies provide only limited support for a link between \u003cem\u003eCACNA1C\u003c/em\u003e and those phenotypes, and the causal relationship is disputed (\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e), as further evidenced by ClinGen\u0026rsquo;s re-evaluation of the literature (\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e). We recognise that there is no consensus on this evidence, with a need for further in-depth assessments and functional analyses of posited loci.\u003c/p\u003e\n\u003cp\u003eMany existing case reports on individuals with LQT8 are limited to only cardiovascular symptom profiling; therefore, concern was raised throughout the consensus group meetings that this may represent under-reporting or under-assessment of non-cardiac phenotypic features. These single organ-system presentations may be due to splice variation, mosaicism, or decreased penetrance, but all individuals presenting in such a manner require a full, holistic, multisystemic medical work-up. Individuals presenting with single organ system presentations of a pathogenic \u003cem\u003eCACNA1C\u003c/em\u003e rare variant (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e), for example LQT8, fall within the CACNA1C-Related Disorders umbrella term. Individuals identified via single organ-system presentations early in childhood often present later in development with further symptoms as \u003cem\u003eCACNA1C\u003c/em\u003e expression regulation changes (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e), and therefore, ongoing observation and follow-up is advised. In those with \u003cem\u003eCACNA1C\u003c/em\u003e variants, each individual\u0026rsquo;s QT intervals can be highly variable with wide ranges, and cardiac risk does not clearly correlate with observed QT duration (\u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e). Furthermore, some patients may initially present with borderline QT prolongation, which may evolve to LQT8 or place them at risk for acquired long QT syndromes. This evolution of symptoms further supports the umbrella term of CACNA1C-Related Disorders for all patients presenting with a pathogenic \u003cem\u003eCACNA1C\u003c/em\u003e variant, and the need for regular cardiac monitoring as a baseline standard of care.\u003c/p\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n\u003ch2\u003eMolecular Diagnostic Criteria\u003c/h2\u003e\n\u003cdiv id=\"Sec12\" class=\"Section3\"\u003e\n\u003ch2\u003eFunctional interpretation\u003c/h2\u003e\n\u003cp\u003eThe initial novel missense p.G406R variant first identified in exon 8A results in a gain-of-function, manifesting as significant changes in channel activation, voltage-dependent inactivation (VDI) and calcium-dependent inactivation (CDI)(\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e). Electrophysiological studies have demonstrated that this combination of effects is not isolated to the p.G406R variant, but the TS phenotype appears associated pathophysiologically with specific changes in the electrophysiological properties and functions of the Ca\u003csub\u003ev\u003c/sub\u003e1.2 channel. These include hyperpolarised left-shifts of activation curves coupled to altered CDI and VDI, with notable differences observable within this grouping between individual variants such as p.G406R and p.G402S (\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e). Subsequent work has shown that these variants have further effects, including decreased synaptic inhibition, defects in cortical differentiation, altered long-term potentiation, and altered cortical interneuron migration (\u003cspan class=\"CitationRef\"\u003e46\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e). Variant function can therefore be understood to be more complex than simple \u0026lsquo;gain- or loss-of-function\u0026rsquo;, and many variants result in changes with mixed effects, as recently reviewed by Bauer \u003cem\u003eet al\u003c/em\u003e (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eFurther complicating this picture is evidence of both non-linear relationships between \u003cem\u003eCACNA1C\u003c/em\u003e variants and Ca\u003csub\u003eV\u003c/sub\u003e1.2 expression profiles (\u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e). Variants may show increased cell surface expression due to decreased degradation (\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e), while some variants (notably p.G406R) increase basal transcription through excitation-transcription coupling (\u003cspan class=\"CitationRef\"\u003e49\u003c/span\u003e), or alter neuronal gene expression (\u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e), with enhanced activation of the Ca\u003csub\u003ev\u003c/sub\u003e1.2 channel driving multiple pathological mechanisms at both the cellular and network level (\u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e51\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e52\u003c/span\u003e). Expression of Ca\u003csub\u003ev\u003c/sub\u003e1.2 and development of symptoms at a system or organ level are subsequently dependent on transcription of the pathological variant. Ca\u003csub\u003ev\u003c/sub\u003e1.2 is widely expressed in almost all tissues and is critical for development (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e53\u003c/span\u003e). Evidence from long-read sequencing suggests that \u003cem\u003eCACNA1C\u003c/em\u003e incorporates at least 47 constituent exons, with \u0026gt;\u0026thinsp;240 novel transcripts, and those transcripts demonstrate developmental stage and tissue-specific splicing, which are predicted to alter channel function (\u003cspan class=\"CitationRef\"\u003e54\u003c/span\u003e). These mechanisms, in combination with germline mosaicism, are hypothesised to drive the irregular penetrance and phenotypic variability seen across CRDs (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eDue to this complexity, clinical pathogenicity should not be extrapolated based upon inferred gain- or loss-of-function. We recommend supporting clinical variant interpretation with functional testing of the variant in established model systems. Tools and literature supporting variant interpretation are predicted to evolve, and therefore we advise periodic re-testing and re-evaluation utilising updated evidence. This guidance supports the recommendation that diagnoses should be made on a syndromic basis, and pathogenicity cannot yet be inferred from gain- or loss-of-function descriptors alone.\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n\u003ch2\u003eGuidelines for Clinical Care\u003c/h2\u003e\n\u003cp\u003eDue to the widespread but variable expression and mixed effects of \u003cem\u003eCACNA1C\u003c/em\u003e gene variants, presentations are individual specific but frequently multisystemic. All individuals with a \u003cem\u003eCACNA1C\u003c/em\u003e pathogenic or likely pathogenic variant require a full multidisciplinary team clinical work-up, to include, at a minimum cardiac, neurodevelopmental, musculoskeletal and endocrine reviews. We expect individuals to show an evolution of risk and development of new syndromic features over time, secondary to changes in expression of \u003cem\u003eCACNA1C\u003c/em\u003e and the Ca\u003csub\u003ev\u003c/sub\u003e1.2 channel over the lifespan, necessitating consistent follow-up. For individuals with variants of unknown or uncertain significance (VUS) in the \u003cem\u003eCACNA1C\u003c/em\u003e gene, it is reasonable to clinically screen for other organ involvement to determine if there is additional clinical evidence of a CRD.\u003c/p\u003e\n\u003cp\u003eCardiac features of CRDs including TS, as the most reported and historically most lethal phenotypic presentation, have received significant therapeutic study (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e). Recent reviews and case series have demonstrated that beta-blocker medication and implantable cardioverter-defibrillators (ICDs) are the most effective current treatments (\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e55\u003c/span\u003e). Surgical interventions, through left cardiac sympathetic denervation to attenuate heterogeneous sympathetic myocardial innervation, have also demonstrated efficacy (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e56\u003c/span\u003e). Calcium-channel blockers, perhaps counterintuitively, are not effective in the management of any CRDs (including TS) due to the complex gating changes in Ca\u003csub\u003ev\u003c/sub\u003e1.2 (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e57\u003c/span\u003e). Implantation of an ICD early in life decreases mortality risk, and this change in practice has led to a dramatic increase in life expectancy of TS children since the syndrome was first described (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e57\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eNo other comprehensive organ-level systematic reviews have been undertaken in TS or more broadly across CRDs. Timothy \u003cem\u003eet al\u003c/em\u003e\u0026rsquo;s 2024 Natural History Study of TS covers a broad range of phenotypic features in depth, including discussion of key areas for clinical concern (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e). As TS and CRD children survive longer, there is evidence of emerging mortality risks from further syndromic features (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e). Epilepsy is prevalent across CRDs, and seizures may be refractory to standard treatments (\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e). Individuals with CRDs where there is suspicion of seizure activity should have neurologic evaluation and seizure rescue medication available in their home, work or school environments. Hypoglycaemia has been noted in CRDs (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e), and recent work has demonstrated that this is through dysregulated glucose homeostasis, absent hyperinsulinism, and defects in glucagon secretion (\u003cspan class=\"CitationRef\"\u003e58\u003c/span\u003e). Individuals with \u003cem\u003eCACNA1C\u003c/em\u003e variants are at risk of hypoglycaemia, particularly when in states of physiological stress, including viral illnesses, which may compound with arrhythmias and lower seizure thresholds to increase the risk of sudden death. Those with CRDs (including TS) should therefore monitor blood glucose levels routinely and have rescue kits (e.g. glucose tablets or gel, fruit juice or sugary drinks/candy) available for use in episodes of low blood sugar.\u003c/p\u003e\n\u003cp\u003eFurther features of CRDs will require long-term therapies and interventions and are treated symptomatically and individually. Responses to anaesthesia are reportedly abnormal, and care should be taken with all sedation (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e). Many children with CRDs have frequent infections, likely due to altered immunological function (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e). Abnormal dentition, frequent cavities and small displaced teeth requiring surgical intervention have commonly been reported (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e). Gastroesophageal reflux, frequent vomiting and congenital gastrointestinal defects have been reported across CRDs (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e). Chronic constipation is seen in \u0026gt;\u0026thinsp;80% of individuals with TS, and anecdotally stated to be a significant issue amongst CRDs (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e). The majority of children with CRDs will experience some developmental delay, particularly of speech (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e). Autism is a highly penetrant phenotypic feature across CRDs, and other neurodevelopmental conditions (e.g. ADHD), neurosensory and neuromuscular features such as hypotonia complicate this presentation. All children with CRDs should be provided with individualised, tailored support in education and work environments.\u003c/p\u003e\n\u003cp\u003eLong-term evolution of features and outcomes, particularly in those without prolonged QT, are not known, although several individuals are now well into mid-life with a range of functional outcomes (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e). Based on the above guidance, all individuals with a \u003cem\u003eCACNA1C\u003c/em\u003e-Related Disorder should have as a minimum standard of care:\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n\u003cul\u003e\n\u003cli\u003eAnnual cardiac and endocrine review including echocardiography (ECG/EKG)\u003c/li\u003e\n\u003cli\u003eImplantable cardioverter-defibrillators in those with prolonged QTc, and loop recorders in those with borderline QTc\u003c/li\u003e\n\u003cli\u003eAnnual neurodevelopmental reviews whilst\u0026thinsp;\u0026lt;\u0026thinsp;18 years of age\u003c/li\u003e\n\u003cli\u003e\u003cem\u003ePeriodic home ambulatory EEG to identify potential seizure activity\u003c/em\u003e\u003c/li\u003e\n\u003cli\u003e\u003cem\u003eHome glucose monitoring, hypoglycaemia and seizure rescue kits with appropriate training.\u003c/em\u003e\u003c/li\u003e\n\u003c/ul\u003e\n\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn the thirty years since Keating \u003cem\u003eet al\u003c/em\u003e first described a \u0026lsquo;heart-hand\u0026rsquo; syndrome, and twenty years since this was formalised as Timothy Syndrome, the landscape of phenotypic features associated with rare pathogenic variants in the \u003cem\u003eCACNA1C\u003c/em\u003e gene has changed substantially. TS remains the most severe presentation, but genomic loci linked to this syndromic phenotype have extended beyond the classical p.G406R variant. Meanwhile, a range of cases have been reported with overlapping or contrasting phenotypic features and novel rare \u003cem\u003eCACNA1C\u003c/em\u003e variants. Here, through expert consensus and community engagement, we summarise updated phenotypes and features for TS and its associated presentations. We define \u003cem\u003eCACNA1C\u003c/em\u003e-Related Disorders, a new umbrella phenotypic syndrome, capturing the range of classical and newly recognised presentations. Finally, we present the first guidelines on standards of diagnostic and clinical care for individuals presenting with a rare \u003cem\u003eCACNA1C\u003c/em\u003e gene variant, driven by the evidence that with appropriate interventions, these individuals can live longer, fulfilling lives.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis research was funded in part by the Wellcome Trust (grant number 222849/Z/21/Z). For the purpose of Open Access, the author has applied a CC BY public copyright licence to any author accepted manuscript version arising from this submission. J.F.G.U. is funded by a Wellcome Trust GW4-CAT Clinical Research Fellowship (222849/Z/21/Z), a Hodge Foundation Early Career Clinical Academic grant, and an HEIW Welsh Clinical Academic Training (WCAT) Fellowship. J.H. is supported by the Hodge Centre for Translational Neuroscience. R.J.L. is funded by the Child Neurologist Career Development Program (CNCDP-K12) and a National Institute of Neurological Disorders and Stroke Clinical Research Career Development Award (NINDS K08\u0026ndash;1K08NS13677501A1). I.E.D. is supported by a National Institute of Mental Health (NIMH) R01 (R01MH137160) and a National Heart, Lung, and Blood Institute (NHLBI) R01 (R01HL149926). G.S.P. is supported by R01 HL146149, R01 HL151190, and R01 HL160089 (NHLBI). N.A.L.H is supported by the National Institute for Health and Care Research (NIHR) Oxford Health Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the National Health Service, NIHR, or the Department of Health and Social Care. G.S.B. is funded by Instituto de Salud Carlos III (ISCIII), Fondo Investigaci\u0026oacute;n Sanitaria-FIS-(PI21/00094) and co-funded by the European Union, Fundaci\u0026oacute; Bosch i Aymerich, IRSJD is a CERCA Programme from Generalitat de Catalunya.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJ.F.G.U devised the project, with input from R.J.L and K.W.T. All meetings were organised and run by J.F.G.U, with K.W.T., R.J.L, I.E.D., G.S.P., E.M.T., A.B., G.W., N.A.L.H., G.S.B., R.B., D.A. and J.H. inputting into meetings and the Delphi process. Suggestions received input from the CACNA1C community through the TSA and TSF. The manuscript was written by J.F.G.U., with figures and background material from H.T. and E.M.T. All authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eEarly discussions on this topic were contributed to by Dr Andy Golden, who was pivotal to research developments and care for individuals with TS, and sadly passed away before the development of this guideline. Bambino Ges\u0026ugrave; Children Hospital IRCCS is an HCP for The European Reference Network for rare, low-prevalence, and complex diseases of the heart\u0026mdash;ERN GUARD-Heart. The Timothy Syndrome Alliance (TSA) is supported by the Chan-Zuckerberg Initiative (CZI) Rare As One programme. E.M.T. is a full- time employee of Boehringer Ingelheim. Prior to her move into industry, she was in receipt of unrestricted research grants from J\u0026amp;J Innovation, and from Boehringer Ingelheim and Biogen, via the Psychiatry Consortium of the Medicines Discovery Catapult. She also provided consultancy to Boehringer Ingelheim and ONO Pharma. She reports no conflict of interest with the current manuscript. The remaining authors declare that they have no competing interests. Figures 1-4 in this manuscript were generated using Biorender.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMarks ML, Whisler SL, Clericuzio C, Keating M. A new form of long QT syndrome associated with syndactyly. J Am Coll Cardiol. 1995;25(1):59\u0026ndash;64. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/0735-1097(94)00318-k\u003c/span\u003e\u003cspan address=\"10.1016/0735-1097(94)00318-k\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eReichenbach H, Meister EM, Theile H. [The heart-hand syndrome. A new variant of disorders of heart conduction and syndactylia including osseous changes in hands and feet]. 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J Mol Cell Cardiol. 2022;173:92\u0026ndash;100. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.yjmcc.2022.10.003\u003c/span\u003e\u003cspan address=\"10.1016/j.yjmcc.2022.10.003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMatsui M, Lynch LE, Distefano I, Galante A, Gade AR, Wang H-G, et al. Multiple beta cell-independent mechanisms drive hypoglycemia in Timothy syndrome. Nat Commun. 2024;15(1):8980. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41467-024-52885-3\u003c/span\u003e\u003cspan address=\"10.1038/s41467-024-52885-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Timothy Syndrome, CACNA1C-Related Disorders, Long QT, cardiac arrhythmia, syndactyly, developmental delay.","lastPublishedDoi":"10.21203/rs.3.rs-8058536/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8058536/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTimothy 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 \u003cem\u003eCACNA1C\u003c/em\u003e gene, which encodes the widely expressed Ca\u003csub\u003ev\u003c/sub\u003e1.2 voltage-gated calcium channel. Since it\u0026rsquo;s characterisation in 2004, the spread of variants in \u003cem\u003eCACNA1C\u003c/em\u003e associated with Timothy Syndrome has expanded. With advances in sequencing and the inclusion of \u003cem\u003eCACNA1C\u003c/em\u003e 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 \u003cem\u003eCACNA1C\u003c/em\u003e, developed by an international panel of experts through Delphi consensus with the involvement of the \u003cem\u003eCACNA1C\u003c/em\u003e community. We formalise the language around syndromic presentations linked to \u003cem\u003eCACNA1C\u003c/em\u003e variants, reassert and demarcate the classical Timothy Syndrome phenotype, and define a new syndrome, 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.\u003c/p\u003e","manuscriptTitle":"Timothy Syndrome and CACNA1C-Related Disorder: First International Language and Management Guidelines Consensus Statement","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-17 05:55:01","doi":"10.21203/rs.3.rs-8058536/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b8dca790-154e-469d-ba74-3016fe4ab329","owner":[],"postedDate":"November 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-25T19:23:12+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-17 05:55:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8058536","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8058536","identity":"rs-8058536","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}