Genotype–phenotype Correlations of cacna1a Non-expansion Variants Associated with Paroxysmal and Degenerative Neurological Disorders
Abstract number :
3.119
Submission category :
12. Genetics / 12A. Human Studies
Year :
2024
Submission ID :
169
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Shih-An Tang, MD – 1 Division of Epilepsy, Neurological Institute, Taipei Veteran General Hospital; 2 School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
Yo-Tsen Liu, MD, PhD – Division of Epilepsy, Neurological Institute, Taipei Veteran General Hospital
Rationale: CACNA1A, which encodes the voltage-dependent P/Q-type calcium channel subunit alpha-1A, is known to cause spinocerebellar ataxia type 6 (SCA6) and paroxysmal neurological disorders (PND), such as developmental and epileptic encephalopathy (DEE), familial hemiplegic migraine (FHM) and episodic ataxia (EA). With the advancement of next-generation sequencing, more CACNA1A non-expansion variants than expected have been identified in a wide range of PNDs, including paroxysmal dystonia and tremor. Understanding the clinical significance of these variants relies on a comprehensive delineation of the genotype-phenotype correlation. In this study, we reported 13 CACNA1A non-expansion variants, including five novel variants, associated with SCA6 or PNDs. This study expands the phenotypic spectrum of CACNA1A variants and contributes to the determination their pathogenicity.
Methods: Ninety-three unrelated patients with molecularly unassigned spinocerebellar ataxia (after exclusion of CAG repeat expansion), and 192 unrelated patients diagnosed as idiopathic epilepsy, paroxysmal kinesigenic dyskinesia (PKD), EA or FHM, were submitted for whole exome sequencing. The diagnoses were reviewed by senior neurologists at the Neurological Institute of Taipei Veterans General Hospital. For the identified genomic variations, Sanger sequencing was performed for validation, and intrafamilial segregation was conducted if family members were available.
Results: A total of 13 CACNA1A variants were identified from 13 unrelated probands, including 5 novel variants (p.Gln735Arg, p.Lys837fsX, p.Met1886Ile, p.Ala1957Ser, p.Glu2200Lys), 5 pathogenic variants (p.Arg279Cys, p.Cys287Tyr, p.Arg582Gln, p.Gln680fsX, p.Val1392Met) , and 3 variants of uncertain significance (p.Gly636Ser, p.Arg2154Trp, c.6545-4C >T). p.Gln735Arg, p.Val1392Met, p.Met1886Ile, p.Ala1957Ser, and p.Arg2154Trp were identified from patient of idiopathic epilepsy with a mean onset age of 2.25 years. All the patients had drug-resistant epilepsy, but only one had developmental delay. Four were detected in patients of other PNDs with a mean onset at 17.25 years old: p.Cys287Tyr in EA, p.Gly636Ser in FHM, and p.Glu2200Lys and c.6545-4C >T in PKD. p.Arg279Cys, p.Arg582Gln, p.Gln680fsX, and p.Lys837fsX were identified from SCA6 patients with a mean onset at 30.25 years old.
Conclusions: This study revealed high phenotypic heterogeneity in CACNA1A-related disorders. For example, CACNA1A-related epilepsy may not be limited to DEE. We also reported typical PKD cases associated with CACNA1A variants. Incomplete penetrance and lack of electrophysiological impacts usually set the difficulty in determining the pathogenicity of a CACNA1A variant. Our results revealed a significant correlation between age of onset and the clinical syndrome, providing a potential clue for phenotype-genotype correlation. Although some CACNA1A variants are currently categorized as uncertain, they remain the most suitable genetic etiology for the observed phenotypes. We expect that our report will serve as a valuable addition to the existing database.
Funding: No funding was received.
Genetics