Phenotypic Characterization of Timothy Syndrome Caused by the
            <i>CACNA1C</i>
            p.Gly402Ser Variant

Delinière, Antoine; Haddad, Christelle; Herrera-Siklódy, Claudia; Hermida, Alexis; Pruvot, Étienne; Bressieux-Degueldre, Sabrina; Millat, Gilles; Janin, Alexandre; Hermida, Jean‐Sylvain; Asatryan, Babken; Chevalier, Philippe

doi:10.1161/circgen.122.004010

Cited by 4 publications

(2 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our case showed a gingival hyperplasia and abnormal tooth shape. Although dental defects as well as gingival hyperplasia have been reported in few previous CACNA1C case descriptions, these clinical characteristics have been found only in association with Timothy syndrome phenotype [40][41][42]. Ion channels are well known for being involved in tooth formation [43], additionally, defects in gene encoding L-type calcium channels have been associated with abnormal dentition [44,45].…”

Section: Discussionmentioning

confidence: 99%

Expanding the Phenotype of the CACNA1C-Associated Neurological Disorders in Children: Systematic Literature Review and Description of a Novel Mutation

Cipriano,

Piscopo,

Aiello

et al. 2024

Children

View full text Add to dashboard Cite

CACNA1C gene encodes the alpha 1 subunit of the CaV1.2 L-type Ca2+ channel. Pathogenic variants in this gene have been associated with cardiac rhythm disorders such as long QT syndrome, Brugada syndrome and Timothy syndrome. Recent evidence has suggested the possible association between CACNA1C mutations and neurologically-isolated (in absence of cardiac involvement) phenotypes in children, giving birth to a wider spectrum of CACNA1C-related clinical presentations. However, to date, little is known about the variety of both neurological and non-neurological signs/symptoms in the neurologically-predominant phenotypes. Methods and results: We conducted a systematic review of neurologically-predominant presentations without cardiac conduction defects, associated with CACNA1C mutations. We also reported a novel de novo missense pathogenic variant in the CACNA1C gene of a children patient presenting with constructional, dressing and oro-buccal apraxia associated with behavioral abnormalities, mild intellectual disability, dental anomalies, gingival hyperplasia and mild musculoskeletal defects, without cardiac conduction defects. Conclusions: The present study highlights the importance of considering the investigation of the CACNA1C gene in children’s neurological isolated syndromes, and expands the phenotype of the CACNA1C related conditions. In addition, the present study highlights that, even in absence of cardiac conduction defects, nuanced clinical manifestations of the Timothy syndrome (e.g., dental and gingival defects) could be found. These findings suggest the high variable expressivity of the CACNA1C gene and remark that the absence of cardiac involvement should not mislead the diagnosis of a CACNA1C related disorder.

show abstract

Section: Discussionmentioning

confidence: 99%

Expanding the Phenotype of the CACNA1C-Associated Neurological Disorders in Children: Systematic Literature Review and Description of a Novel Mutation

Cipriano,

Piscopo,

Aiello

et al. 2024

Children

View full text Add to dashboard Cite

show abstract

“…Similarly, mutations in CACNA1C alter L-type voltage-gated Ca 2+ -channels and are associated with long QT and short QT syndromes. An example is Timothy syndrome, the complex congenital syndrome caused by CACNA1C mutations (Delinière et al 2023), which involves cardiac manifestations such as long QT, along with one or more non-cardiac phenotypes such as skeletal, facial, and neurodevelopmental abnormalities (Borbás et al 2022).…”

Section: Dreamer Pipelinementioning

confidence: 99%

DREAMER: Exploring Common Mechanisms of Adverse Drug Reactions and Disease Phenotypes through Network-Based Analysis

Firoozbakht,

Elkjaer,

Handy

et al. 2024

Preprint

View full text Add to dashboard Cite

Adverse drug reactions (ADRs) are a major concern in clinical healthcare, significantly affecting patient safety and drug development. The need for a deeper understanding of ADR mechanisms is crucial for improving drug safety profiles in drug design and drug repurposing. This study introduces DREAMER (Drug adverse REAction Mechanism ExplaineR), a novel network-based method for exploring the mechanisms underlying adverse drug reactions and disease phenotypes at a molecular level by leveraging a comprehensive knowledge graph obtained from various datasets. By considering drugs and diseases that cause similar phenotypes, and investigating their commonalities regarding their impact on specific modules of the protein-protein interaction network, DREAMER can robustly identify protein sets associated with the biological mechanisms underlying ADRs and unravel the causal relationships that contribute to the observed clinical outcomes. Applying DREAMER to 649 ADRs, we identified proteins associated with the mechanism of action for 67 ADRs across multiple organ systems, e.g., ventricular arrhythmia, metabolic acidosis, and interstitial pneumonitis. In particular, DREAMER highlights the importance of GABAergic signaling and proteins of the coagulation pathways for personality disorders and intracranial hemorrhage, respectively. We further demonstrate the application of DREAMER in drug repurposing and propose sotalol (targeting KCNH2), ranolazine (targeting SCN5A, currently under clinical trial), and diltiazem (indicated drug targeting CACNA1C and SCN3A) as candidate drugs to be repurposed for cardiac arrest. In summary, DREAMER effectively detects molecular mechanisms underlying phenotypes emphasizing the importance of network-based analyses with integrative data for enhancing drug safety and accelerating the discovery of novel therapeutic strategies.

show abstract

Management of ultrarare inherited arrhythmia syndromes

Roston,

Bezzerides,

Roberts

et al. 2024

Heart Rhythm

View full text Add to dashboard Cite

Phenotypic Characterization of Timothy Syndrome Caused by the CACNA1C p.Gly402Ser Variant

Cited by 4 publications

References 4 publications

Expanding the Phenotype of the CACNA1C-Associated Neurological Disorders in Children: Systematic Literature Review and Description of a Novel Mutation

Expanding the Phenotype of the CACNA1C-Associated Neurological Disorders in Children: Systematic Literature Review and Description of a Novel Mutation

DREAMER: Exploring Common Mechanisms of Adverse Drug Reactions and Disease Phenotypes through Network-Based Analysis

Management of ultrarare inherited arrhythmia syndromes

Contact Info

Product

Resources

About