Abstract
Variants in CACNA1A are classically related to episodic ataxia type 2, familial hemiplegic migraine type 1, and spinocerebellar ataxia type 6. Over the years, CACNA1A has been associated with a broader spectrum of phenotypes. Targeted analysis and unbiased sequencing of CACNA1A result not only in clear molecular diagnoses, but also in large numbers of variants of uncertain significance (VUS), or likely pathogenic variants with a phenotype that does not directly match the CACNA1A spectrum. Over the last years, targeted and clinical exome sequencing in our center has identified 41 CACNA1A variants. Ultimately, variants were considered pathogenic or likely pathogenic in 23 cases, with most phenotypes ranging from episodic or progressive ataxia to more complex ataxia syndromes, as well as intellectual disability and epilepsy. In two cases, the causality of the variant was discarded based on non-segregation or an alternative diagnosis. In the remaining 16 cases, the variant was classified as uncertain, due to lack of opportunities for segregation analysis or uncertain association with a non-classic phenotype. Phenotypic variability and the large number of VUS make CACNA1A a challenging gene for neurogenetic diagnostics. Accessible functional read-outs are clearly needed, especially in cases with a non-classic phenotype.
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Acknowledgements
We thank several colleagues from the departments of neurology, pediatric neurology, and human genetics of Radboud university medical center, Nijmegen, the Netherlands for their role in collecting relevant patient data. We would like to thank C. Gilissen (department of human genetics, Radboud university medical center, Nijmegen, the Netherlands) for collecting information on the chance of de novo mutations in CACNA1A.
Funding
M.P. Hommersom, T.H. van Prooije, M. Pennings, M.I. Schouten, H. van Bokhoven and E-J. Kamsteeg report no disclosures. M.P. Hommersom is supported by a grant from the Radboud university medical center and Donders Institute for Brain, Cognition and Behaviour. T.H. van Prooije is supported by a grant from ZonMW. H. van Bokhoven is supported by grants from Radboud university medical center. B. van de Warrenburg is supported by grants from Radboud university medical center, ZonMW, Hersenstichting, uniQure, Gossweiler Foundation, the Michael J Fox Foundation, and has served on scientific advisory boards of uniQure and Vico Therapeutics. Authors of this publication are members of the European Reference Network for Rare Neurological Diseases—Project ID No 739510.
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MPH, THP and BPCW conceptualized the study. MPH and THP drafted the manuscript. MP had a major role in data acquisition. MIS and E-JK interpreted the data. HB, E-JK and BPCW revised the manuscript for intellectual content.
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Hommersom, M.P., van Prooije, T.H., Pennings, M. et al. The complexities of CACNA1A in clinical neurogenetics. J Neurol 269, 3094–3108 (2022). https://doi.org/10.1007/s00415-021-10897-9
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DOI: https://doi.org/10.1007/s00415-021-10897-9