Whole exome sequencing and heterologous cellular electrophysiology studies elucidate a novel loss-of-function mutation in the CACNA1A-encoded neuronal P/Q-type calcium channel in a child with congenital hypotonia and developmental delay
Abstract
Background A 4-year-old boy born at 37 weeks' gestation with intrauterine growth retardation presented with developmental delay with pronounced language and gross motor delay, axial hypotonia, and dynamic hypertonia of the extremities. Investigations including the Minnesota Newborn Screen, thyroid stimulating hormone/thyroxin, and inborn errors of metabolism screening were negative. Cerebral magnetic resonance imaging and spectroscopy were normal. Genetic testing was negative for coagulopathy, Smith-Lemli-Opitz, fragile X, and Prader-Willi/Angelman syndromes. Whole genome array analysis was unremarkable.Methods Whole exome sequencing was performed through a commercial testing laboratory to elucidate the underlying etiology for the child's presentation. A de novo mutation was hypothesized. In attempt to establish pathogenicity of our candidate variant, cellular electrophysiologic functional analysis of the putative de novo mutation was performed using patch-clamp technology.Results Whole exome sequencing revealed a p.P1353L variant in the CACNA1A gene, which encodes for the α1-subunit of the brain-specific P/Q-type calcium channel (CaV2.1). This presynaptic high-voltage-gated channel couples neuronal excitation to the vesicular release of neurotransmitter and is implicated in several neurologic disorders. DNA Sanger sequencing confirmed that the de novo mutation was absent in both parents and present in the child only. Electrophysiologic analysis of P1353L-CACNA1A demonstrated near complete loss of function, with a 95% reduction in peak current density.Conclusions Whole exome sequencing coupled with cellular electrophysiologic functional analysis of a de novoCACNA1A missense mutation has elucidated the probable underlying pathophysiologic mechanism responsible for the child's phenotype. Genetic testing of CACNA1A in patients with congenital hypotonia and developmental delay may be warranted.
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Coupling whole exome sequencing with cellular electrophysiologic functional analysis may elucidate the underlying pathophysiologic mechanism responsible for certain phenotypes.
“Coupling whole exome sequencing with cellular electrophysiologic functional analysis may elucidate the underlying pathophysiologic mechanism responsible for certain phenotypes.433”
From European Heart Rhythm Association (EHRA) consensus document on the management of supraventricular arrhythmias, endorsed by Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia (SOLAECE) (2017) · cites this paper as [433]
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Additional file 2 of Calcium channelopathies and intellectual disability: a systematic review
Kessi, M., Chen, B., Peng, J., Yan, F., Yang, L., & Yin, F. (2021) · Figshare · doi:10.6084/m9.figshare.14594115
Additional file 1 of Calcium channelopathies and intellectual disability: a systematic review
Kessi, M., Chen, B., Peng, J., Yan, F., Yang, L., & Yin, F. (2021) · Figshare · doi:10.6084/m9.figshare.14594112
Additional file 3 of Calcium channelopathies and intellectual disability: a systematic review
Kessi, M., Chen, B., Peng, J., Yan, F., Yang, L., & Yin, F. (2021) · Figshare · doi:10.6084/m9.figshare.14594118
- Authors
- Weyhrauch, D. L., Ye, D., Boczek, N. J., Tester, D. J., Gavrilova, R. H., Patterson, M. C., Wieben, E. D., & Ackerman, M. J.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Ackerman, Michael J.
- ORCID
- Venue
- Pediatric Neurology
- Publisher
- Elsevier BV
- Published
- 2016-02
- Volume
- 55
- Pages
- 46-51
- ISSN
- 0887-8994 (ISSN-L)
- OpenAlex
- W2176964840
- Cited by
- 24
- References
- 35
- Citations by year
- 2025: 3 · 2023: 2 · 2022: 1 · 2021: 5 · 2020: 2 · 2019: 4 · 2018: 3 · 2017: 1 · 2016: 3
- FWCI
- 1.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pediatric Neurology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- CACNA1A, P/Q-type calcium channels, Cav2.1, de novo mutations, loss-of-function mutations, congenital hypotonia, developmental delay, developmental coordination disorder, fetal growth restriction, missense mutations, presynaptic neurotransmitter release
- MeSH terms
- Developmental Disabilities, Child, Preschool, Humans, Male, Muscle Hypotonia, Calcium Channels, Patch-Clamp Techniques, Mutation, Missense, Calcium Channels, N-Type, Exome
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