## **TIMOTHY SYNDROME ALLIANCE (TSA)** ## **ANNUAL REPORT** **FOR FINANCIAL PERIOD 1 DECEMBER 2021 TO 30 NOVEMBER 2022** ## **2022** **www.timothysyndrome.org** **Charity Registration Number: 1185523** ## **WELCOME** ## **Vision:** Our vision is a world where shared knowledge and understanding lead to a cure for everyone with a CACNA1C genetic variant. ## **Mission:** Our mission is to improve the diagnosis, treatment and care of individuals with CACNA1C-related disorders including Timothy Syndrome and LongQT8, and to support the families and carers of those diagnosed. ## **How we work** In following our mission our focus is on each of these five inter dependable areas of activity – raising awareness, improving diagnosis treatment and care, supporting the global community, providing information and advice, and driving research and clinical development. Through collaborations globally we are stronger together. We will build our community and support it with sustainable growth. Our values combine to form a solid foundation for how we do things and what we believe in. We are determined, supportive, empowering, and a community. **----- Start of picture text -----**
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1 ## **CACNA1C** ## **What is CACNA1C?** CACNA1C is a gene that provides the code for a protein found in cells throughout the body. This protein manages the movement of calcium in and out of the cell, which is critical for many cells’ functions. Changes to the gene can cause changes to the protein and its ability to manage calcium movement, making it work more, less, or not at all. ## **What is Timothy Syndrome?** Timothy Syndrome (TS) is caused by specific changes to the CACNA1C gene. There are two types of TS: TS1 and TS2. The most common symptoms include abnormal heart function, irregular heartbeat, abnormal heart structure, neuronal developmental delays, immunodeficiencies, endocrinological dysfunction, gastrointestinal concerns, effects on smooth muscle, effects on skeletal muscle, facial anomalies, syndactyly (joined fingers or toes), mild dental, skin, eye, and hair anomalies. Some individuals have significant episodes of low blood sugar levels (hypoglycemia), seizures, and/or an unusually low body temperature (hypothermia). ## **What is a CACNA1C-related disorder (CRD)?** A novel variant in the CACNA1C gene - individuals have some but not all symptoms typical of Timothy Syndrome. Some affected individuals may present with multisystem health concerns that overlap entirely with Timothy Syndrome. ## **What is Non-syndromic LongQT8?** Non-syndromic LongQT8 overlaps with Timothy Syndrome in that the affected individual has LongQT (a prolonged QT interval on an ECG). There are many variants throughout the CACNA1C gene that appear to cause non-syndromic LongQT8. ## **Prevalence** CRDs are rare and their prevalence is unknown.There are <100 cases of TS diagnosed worldwide. Prevalence is unknown due to the rarity and recent identification of CRDs. 2 ## **IMPACT IN NUMBERS** **2** New genomic test analysis panels **2** New films in **+24** development New members in our Support Group **2** New films in production **50%** Increase in social media followers **1** New Wikipedia page **1** Presentation to leading NHS Hand Surgeons **~500** New website visitors per month **1** 4 hour Brain Research Conference transcribed into Brazilian Portuguese **2** Award-winning films **1** Best Research Partnership Award **+12** Increase in individuals with CRD / TS / LQT8 **1** Published study of the Neuropsychiatric Phenotype of CACNA1C-Related Disorder **1** 'Connect CACNA1C Global Network Conference' 2023 in the planning **1** Scientific Advisory Board **130** Countries visited our website **1** CACNA1C Community Registry **1** 'Mind the Gap' Parental Resilience Programme **1** Psychosocial impact study 2 ## **ACHIEVEMENTS AND PERFORMANCE** ## **Raising Awareness** We have made two award-winning films to date; ‘Timothy Syndrome Alliance’ which highlights the challenges faced by families and how peer support and the friendship and information that brings can make a huge difference, and ‘Rare Strikes Back’ a Rare Disease Day film made with puppets that balances the reality of living with a rare condition with the hope of the Rare Disease Community. Both continue to raise awareness and can be found on our social media channels, website, and The Disorder Channel (available through Roku or Amazon Fire TV). The films have also successfully signposted families to TSA to connect with the CACNA1C Community for knowledge and support. To widen our audience further we enter film festivals. This year Rare Strikes Back won the Gold award at the Charity Film Awards 2022 (£0 - £100,000 Turnover Category) and we were welcomed for a virtual Q&A session at the Health in Focus Film Festival, School of Public Health, Boston University. More filming and interviews have been underway for the making of ‘The Rare Disease Research Journey’, a film demonstrating the importance of public engagement in research. The project is a collaboration between the Neuroscience and Mental Health Innovation Institute (NMHII) University of Cardiff and TSA and is anticipated to be ready for release in early 2023. 3 ## **ACHIEVEMENTS AND PERFORMANCE** Rare Disease Day is observed every year on 28 February (or 29 in leap years) – the rarest day of the year. It is a day when we join together and help build awareness for the 7000 rare diseases affecting 300 million individuals worldwide. Rare Disease Day 2022 was very successful for TSA this year with many social media posts being shared globally by our community and supporters. We were part of a Genetic Alliance Twitter takeover and also involved in a recorded interview with Abcam, a manufacturer of protein research tools for life scientists, helping to expand our audience reach. Awareness Day on 1st October also involved much activity on social media including takeovers of both Rare Revolution Magazine and Genetic Alliance UK channels. The day was also marked with the release of a 2-minute trailer for The Rare Disease Research Journey which was well received with regard to views and engagement. The TSA website continues to grow in users (on average 500 new visitors per month) as well as updated content. Our website is frequently accessed in the German language via the simple flag click and has received visits from all over the world - in June we posted on social media a collage detailing the flags of the 130 countries that have visited our website since it launched 19 months ago. Additional signposting to our website has been successful through our collaborations, press articles, and partnerships with ERN-GUARD Heart, Neurological Alliance, EURORDIS, Rare Diseases International, and Global Genes to name a few. Social media performance on all channels has increased over the year with engagement and 'follows' up by 50% on some platforms. Everything we post uses the same core signposts #CACNA1C #TimothySyndrome #LongQT8. 4 ## **ACHIEVEMENTS AND PERFORMANCE** **Improving diagnosis, treatment and care** Over this last year, we have been working with OPEN Health (a leading global healthcare communications agency with extensive scientific expertise) and members of our community to co-create a pathway-focused educational interactive guide for healthcare professionals. This resource will ensure different stakeholders understand their roles and responsibilities along the patient journey for an individual identified with a CACNA1C gene change. It is anticipated that this will be ready to launch during 2023. Our application has been approved for CACNA1C to be included as a gene within the Genetic Epilepsy syndromes genomic test listed in the NHS National Genomic Test Directory (PanelApp). 'CACNA1C-related disorders' has also been added to the phenotype list for all CACNA1C panels – this includes Intellectual disability, Long QT syndrome, Short QT syndrome, Fetal Anomalies, DDG2P (Developmental Disorders Genotype-to-Phenotype), Hypertrophic cardiomyopathy and Paediatric or syndromic cardiomyopathy. This means CACNA1C variants, other than the Timothy Syndrome causing variant (G406R), are analysed as part of the diagnostic pathway. Update: In January 2023 our application for Timothy Syndrome and CACNA1C-related disorders was approved for the Congenital hyperinsulinism panel. PanelApp is an open platform and as such this knowledgebase of evidence for gene-disease associations is used by the wider global scientific community. 5 ## **ACHIEVEMENTS AND PERFORMANCE** Working further afield TSA has been collaborating with several genetic sequencing companies across the world. We are ensuring that resources are available for patients and families when they receive testing through their laboratories and have been identified to have variants in CACNA1C/a diagnosis of Timothy Syndrome. This support and signposting to our community are an important part of the rare disease journey. In July we were delighted to join ERN GUARD-Heart Patient Advocacy Board (ePAG). European Reference Networks (ERNs) are virtual networks involving healthcare providers across Europe. They aim to tackle complex or rare diseases and conditions that require highly specialised treatment and concentration of knowledge and resources. No country alone has the knowledge and capacity to treat all rare and complex diseases. ERNs offer the potential to give patients and doctors across Europe access to the best expertise and timely exchange of life-saving knowledge without having to travel to another country. There are 24 European Reference Networks that bring together nearly 1,500 Expert centres located in the 27 EU Member States and Norway. Each Network focuses on a different group of diseases (e.g. Rare heart diseases). The mission of ERN GUARD-Heart is to facilitate access to diagnosis and treatment of rare and complex diseases of the heart in adult and paediatric patients across the European Union. ERN GUARD-Heart brings together 44 expert healthcare providers from 16 different Member States committed to patient-centred care and efficient practice based on evidence, knowledge, education, and translational research. September involved in-person discussions and a presentation to leading NHS hand surgeons in Birmingham on the links between syndactyly, Timothy Syndrome Type 1, prolonged QT, and the additional anaesthesia risks to those who may not have been diagnosed pre-corrective surgery. A bonus was the opportunity to present to hand surgeons in Dubai and Amsterdam virtually at the same time. 6 ## **ACHIEVEMENTS AND PERFORMANCE** ## **Supporting our global community** Following a taster session and establishment of need from our community, we launched ‘Mind the Gap’. This Building Parental Resilience Programme with Rareminds, an organisation (CIC) that specialises in providing counselling and emotional wellbeing services for the rare disease community, consisted of 1 x 8-week closed group sessions allowing for a maximum of 10 participants. Held on Zoom the timings made the sessions accessible for as many global time zones as possible. An anonymous feedback questionnaire at the end of the 8 weeks confirmed the following: **100%** 100% of participants responded Yes to 'After this group I feel more positive' **100%** 100% of participants responded Yes to 'After this group I feel more resilient' **100%** 100% of participants responded Yes to 'After this group I feel less isolated' **100%** 100% of participants responded Yes when asked 'Would you recommend this group to others?' **100%** 100% of participants responded Yes when asked 'Would you like to attend further groups of this sort?' Comments included "Absolutely!" "Yes 100%" "Definitely" “I didn’t realise that I needed this group but I did, thank you.” 7 ## **ACHIEVEMENTS AND PERFORMANCE** TSA administrates an online private Facebook Support Group for individuals and families of CACNA1C-related disorders including Timothy Syndrome and LongQT8, offering 24/7 access to emotional and practical support and information via our families. The benefits of this are huge. It enables: - meeting and befriending other people with the same rare disorder and similar experiences from across the world learning about CACNA1C - giving and receiving emotional support - having a place to speak openly about the impact of CACNA1C and one's thoughts and feelings learning coping skills feeling empowered and hopeful advocating to improve healthcare “I am actually over here in tears reading your welcome note to the group. I have been so isolated through this whole ordeal” Many people find it comforting and helpful to talk to someone who has experienced the same things they are facing when they or their child have a health problem. Having a rare condition can often be extremely isolating due to the lack of people with the same condition. It can be just as challenging to be a parent to someone with a rare disease. Rare disease support groups are an important source of emotional and practical support. 'The use of such advocacy-based coping may help patients to foster a sense of empowerment, efficacy, and hope' (Ayme et al., 2008) **+ 24** Total increase in support group members joining between 1 December 2021 and 30 November 2022 Representing **12** individuals with CACNA1C-related disorders including Timothy Syndrome and LongQT8 8 ## **ACHIEVEMENTS AND PERFORMANCE** As our community continues to grow in size so does the spectrum of affectedness of those living with these conditions. In August TSA ran a survey to find out how long it can take to receive an accurate diagnosis. Average years until diagnosis = 4.6 **----- Start of picture text -----**
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Survey completed by 34 individuals representing a total of 37 CACNA1C individuals The huge project to transcribe and translate our 4-hour Brain Research Conference 2021 to Brazilian Portuguese was completed by volunteers at Charity Translators and shared with our community. "I loved the initiative, and congratulations to the volunteers, the translation of videos and online dialogues, yes they are important because I don't know how to say almost anything and I don't understand much." Charity Translators' work with important epilepsy healthcare surveys has also been immensely helpful this year ensuring reliable and accurate recording of specific health concerns. 9 ## **ACHIEVEMENTS AND PERFORMANCE** ## **Providing information and advice** Alongside information provision on our website and social media platforms TSA also administrates an online private Patient Advisory Board for individuals and families of CACNA1C-related disorders including Timothy Syndrome and LongQT8. It is here that TSA updates our community on advocacy, ongoing research, and published papers of interest - in fact, anything that would be of interest to our community relating to CACNA1C and our mission, thus ensuring that the Support Group remains for support only. Accurate and trusted information elsewhere on the internet is not easy to find. CACNA1C-related disorders is a newly characterised disorder. We are delighted to be working with scientists at Healx who are supporting us with Wikipedia updates on the Timothy Syndrome page and the creation of a brand new CACNA1C-related disorders Wikipedia page. Update: this page has been approved which means the growing CACNA1C community now have an accurate and validated Wikipedia source to learn from and enhance with their own insights and citations. TSA continues to advocate with authoritative knowledgebased websites and reference portals to ensure CACNA1C information is up-to-date and accurate. This includes OMIM, Orphanet, and ICD-11. 10 ## **ACHIEVEMENTS AND PERFORMANCE** ## **Driving research and clinical development** TSA is integrated and co-producing research at a number of levels with teams at Cardiff University and Stanford University. This includes co-production of research aims and goals, designing of studies, recruitment, and engagement to feedback results. We have further links to Oxford University (transcription and clinical translation) and the Earlham Institute. Research areas include clinical phenotyping and cell lines for lab work, with further grants towards public engagement. TSA and NMHII were successful in selection to attend ‘Collaborating for Change’ a Rare Neurology/CNS Partnering Event held at The Royal Society of Medicine, London. The event was focused on building collaborations around rare neurological/ central nervous system disorders between patient groups and companies that have assets, technology, and interest in this space. In a new awards ceremony focused entirely on genetic conditions TSA and NMHII Cardiff University received the award for Best Research Partnership. Gene People Awards commemorate outstanding individuals and groups who have achieved incredible things in genetic conditions, whether across the genetic community or for a specific condition. These awards focused on achievements from 2020 and 2021, including campaigns that took place during the pandemic. 11 ## **ACHIEVEMENTS AND PERFORMANCE** A dissertation study undertaken as part of MSc Genetic & Genomic Counselling at Cardiff University has now been completed with the student, Bhavna Vadukul, receiving a Distinction. ‘Exploring the psychosocial impact of Timothy Syndrome and CACNA1C-related disorders on affected individuals and their families’ was a study undertaken by UK families. To date, no other research has been conducted on the lived experience of affected individuals and their families living with these conditions. Medical professionals require further knowledge about these conditions in order to provide appropriate support to affected individuals and families. There is a general lack of research on the psychosocial impact of rare and ultra-rare conditions such as Timothy Syndrome and CACNA1C-related disorders. A summary of Bhavna's work can be found under the research tab on our website. People are unique genetically and even though everyone in our community has the same gene in common, not everyone has the same genetic variant, it may be different from someone else in the next state or the next country. Genetic variants are not the same, they don't necessarily act in the same way and they might have different mechanisms in terms of how they are treated. Our CACNA1C Community Registry, accessible worldwide, launched in June. This is a vitally important research tool in which all families and individuals with an identified CACNA1C gene change (this includes CRD, TS, LQT8, duplications, and deletions) are encouraged to participate. Parents/carers may register on behalf of children and there are appropriate questionnaires to represent those who are sadly no longer with us. 12 ## **ACHIEVEMENTS AND PERFORMANCE** The CACNA1C Community Registry has been designed with the input of clinical researchers to identify information and issues relevant to families and pertinent to developing translational research. As variants in CACNA1C are so rare clinicians may only see one or two individuals in their lifetime, and therefore gathering global data is vital to understanding the natural history and features of the condition. The information being collected will be reviewed by the TSA Scientific Advisory Board, and make available high quality clinical data for research. In the new year, we will have a Scientific Advisory Board to help steer the research efforts of the charity offering expertise on scientific and clinical developments with regard to CACNA1C. We are fortunate to have internationally leading researchers and medics serving on the board chaired by Dr. Jack Underwood, Cardiff University. Planning has also commenced on the 'Connect CACNA1C Global Network Conference' 2023 an online conference to share with families, healthcare professionals, and researchers the very latest knowledge and understanding of CACNA1C. It is the intention for this to be accessible in several languages with successful funding. Published paper of note: Levy, Rebecca J.; Timothy, Katherine W.; Underwood, Jack F.G.; Hall, Jeremy; Bernstein, Jonathan A.; Pașca, Sergiu P. (January 2023). "A Cross-Sectional Study of the Neuropsychiatric Phenotype of CACNA1C-Related Disorder". Pediatric Neurology. 138: 101–106. doi:10.1016/j.pediatrneurol.2022.10.013. PMID 36436328 Understanding what strengths and challenges may happen for a disorder can help families and their medical providers plan, screen, and treat individuals more effectively. TSA collaborated on this study which focuses on experienced issues in development, as well as symptoms involving mood, learning, and the nervous system. Summary of findings: Many individuals with CACNA1C- 13 ## **ACHIEVEMENTS AND PERFORMANCE** related disorders had delays in learning to walk and talk, as well as other developmental milestones. They also commonly reported neuropsychiatric symptoms such as imbalance, incoordination, difficulty with chewing, learning or cognitive disability, seizures, and symptoms associated with autism spectrum disorder. Whether or not an individual had long QT syndrome did not affect the risk of developmental or neuropsychiatric symptoms, so in CACNA1C-related disorders this risk may be related to brain-specific and not heart-related impacts of the CACNA1C gene. ## **Fundraising** Every donation we receive goes to help fund the vital work that we do as a charity. We are global in our advocacy and support and as such, it is important to ensure that we can be supported globally too. This year TSA was approved as a partner on a crowdfunding platform called GlobalGiving on which we are raising funds for the CACNA1C Community Registry. All donations are taxdeductible for donors who are US taxpayers, and all projects on GlobalGiving.org have been pre-qualified for 501(c)(3) equivalency status. The GlobalGiving project page has functionality similar to Facebook making it simple to create a personalised fundraising page to raise funds. It can also be used to set up a monthly giving program by using the recurring donations feature. Our size (day-to-day management of the charity’s activities is undertaken by the Chair of Trustees) alongside low awareness of rare diseases continues to make fundraising a challenge. Running a small charity with such great ambition is only possible thanks to the people and organisations who help fund our work and support us through internal resources and team member time commitments as well as our volunteers who dedicate time and energy. 14 ## **ACHIEVEMENTS AND PERFORMANCE** Our total income for the year is £10,005 (2020/21: £6,084) Against a backdrop of economic and pandemic-related uncertainty, we are immensely grateful to everyone who so generously donated to TSA this year through one-off and regular donations as well as creating birthday and activitybased fundraisers to support our community and projects. Unrestricted income was £5,405 (previous year: £6,084), including unrestricted grants of £1,100. Restricted income from grants was £4,600 of which £4,000 is allocated towards our Registry platform fees which are due in February 2023. We are encouraged that funders understand and align with our research outlook, focus, and passion for the cause and commitment to improving the information and support for families and individuals with CACNA1C changes. Our total expenditure for the year is £4,706 (2020/21: £3,226) ## **Income £10,005** Voluntary receipts Restricted income - grants Unrestricted income - grants ## **Expenditure £4,706** Charitable activities Fundraising, support and governance costs We would like to thank the following Trusts and Foundations for their support during this financial year: Arnold Clark Community Fund Blakemore Foundation St. James's Place Charitable Foundation The Souter Charitable Trust 15 ## **THANK YOU** Thank you, to those we have mentioned throughout this report, plus volunteers Dmitry Kran for website building, Zoe Shaked for German translations, Peter Gardiner for database diving, Rob Bradshaw for adding the extra spark to our films and so many others. We would also like to say a heartfelt thank you to our CACNA1C families and individuals who allow us to share their photos and stories on our website and social media. This makes a huge difference in letting our supporters know how their donation has helped whilst also helping us reach new families and individuals who need support and community. https://www.facebook.com/timothysyndromealliance https://www.instagram.com/timothysyndromealliance https://twitter.com/tsa_charity https://www.tiktok.com/@timothysyndromealliance https://www.linkedin.com/company/timothy-syndrome-alliance https://www.justgiving.com/campaign/timothysyndromealliance This Annual Report was designed and created in house at no cost to TSA 15 The trustees present their report for the period 1 December 2021 to 30 November 2022. TIMOTHY SYNDROME ALLIANCE (TSA) TRUSTEES' REPORT General Information REGISTERED CHARITY NUMBER: 1185523 TRUSTEES: Galina Gardiner Katherine W Timothy Meg Mcloughlin Andy Golden (Until March 2022) Nick Muir Sally Johns (Until June 2022) REGISTERED OFFICE: Objectives: To relieve the needs of those affected by CACNA1C-related disorders including Timothy Syndrome and LQT8, their families, friends, and carers. Promote a greater understanding of the causes, symptoms, and treatment. Raise public awareness of the symptoms, needs, and related medical conditions. Structure, governance, and management: Timothy Syndrome Alliance (TSA) is a registered charity number 1185523, governed by the Charities Act 2006. The charity is a Charitable Incorporated Organisation registered on 27 September 2019 under the Foundation Governing Document. New trustees are appointed by the serving trustees, considering the skills required by the board. Public Benefit: The Trustees confirm that they referred to the Charity Commission's general guidance on public benefit when reviewing the Charity's aims and objectives for the year. Public benefit has been achieved as per the activities outlined in the Achievements and Performance section of this report. Reserves Policy and Going Concern: The trustees regularly monitor income and re-plan expenditures. To ensure a sound infrastructure and financial base trustees will identify our level of reserves as we begin to develop long-term commitments. The trustees have reviewed the circumstances of the Charity and consider that adequate resources continue to be available to fund its activities for the foreseeable future. The trustees are of the view that the Charity is a going concern. ## Trustees' responsibilities statement The trustees are responsible for preparing the trustees' report and the financial statements in accordance with applicable law and United Kingdom Accounting Standards (United Kingdom Generally Accepted Accounting Practice). The trustees are required to prepare accounts for each financial year, which reflect the receipts and payments of the charity and the surplus or deficit of income against payments for the year. The trustees are responsible for: • keeping proper accounting records which disclose with reasonable accuracy at any time the financial position of the charity; and • safeguarding the assets of the charity and hence taking reasonable steps for prevention and detection of fraud and other irregularities. The trustee's annual report was approved on ........................ and signed on behalf of 26 April 2023 the board of trustees by Sophie Muir Chair of Trustees 16 CHARITY COMMISSIO FOR ENGLAND ANO WAIt nM(￿Y 8￿mI10M• ￿lIaTr¢• If8A) Recelpts and pa ments accounts CC16a 0111Y2021 To 30111r2022 Section A Receipts and payments Unr•8trlct•d lund¥ ioth• nMr• R•strlcl•d fund$ Endowm•nt nd¥ T¢rtal lunds L•8t ￿lf A1 RK•l Vol tota AR) 10.OOS •,0 n¥ Totsl 10.006 A3Pa •nt• 701 3321 Sub tot•1 J3 A4 Ag••t •nd Inw•tm•nt Sub total 706 3,226 Net of recelpW(payments) A5 Tran81•rn b•tw••n funds Ca•h lund• l••t ￿*r C•sh luntts th1$ y••r •nd 1858 1858 Sectlon B Statement of assets and Ilabllltles at the end of the perlod Unr•¥trict•d lund• R•strlcl•d fun EndDwm•nl nds Caiigdr. lo Mw••t£ rbMrn•t £ B1 Cagh lundg Total c48h funds 1,299 UrY••trlct•d RMtrlct•d lunds fun io rwwt£ EDdowm•nt lund* Doialls FWMI to f*hkh Dotalll Co* l0OloMI OMI Fund to ¥thkh ••ib CurT•Trl Ootalls Com Iowi(n 84 A•s•ts r•tsln•d for th• chwws own wrtd Doiall$ on 86 U•bllltl•s aaa Slgn8d by on8 or tntst••s on b•harf ol •ll th• ￿u¥l• Date ol roval SwJnatu Pn"nt Name 26 A ril 2023