Title

Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations.

Document Type

Article

Publication Date

10-2021

Identifier

DOI: 10.1038/s41436-021-01232-8

Abstract

PURPOSE: CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype.

METHODS: We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations.

RESULTS: Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism.

CONCLUSION: We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome.

Journal Title

Genetics in medicine : official journal of the American College of Medical Genetics

Volume

23

Issue

10

First Page

1922

Last Page

1932

MeSH Keywords

Autistic Disorder; Calcium Channels, L-Type; Humans; Long QT Syndrome; Phenotype; Syndactyly

Keywords

Autistic Disorder; Calcium Channels, L-Type; Humans; Long QT Syndrome; Phenotype; Syndactyly

Comments

Erratum in

  • Correction: Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations. Rodan LH, Spillmann RC, Kurata HT, Lamothe SM, Maghera J, Jamra RA, Alkelai A, Antonarakis SE, Atallah I, Bar-Yosef O, Bilan F, Bjorgo K, Blanc X, Van Bogaert P, Bolkier Y, Burrage LC, Christ BU, Granadillo JL, Dickson P, Donald KA, Dubourg C, Eliyahu A, Emrick L, Engleman K, Gonfiantini MV, Good JM, Kalser J, Kloeckner C, Lachmeijer G, Macchiaiolo M, Nicita F, Odent S, O'Heir E, Ortiz-Gonzalez X, Pacio-Miguez M, Palomares-Bralo M, Pena L, Platzer K, Quinodoz M, Ranza E, Rosenfeld JA, Roulet-Perez E, Santani A, Santos-Simarro F, Pode-Shakked B, Skraban C, Slaugh R, Superti-Furga A, Thiffault I, van Jaabrsveld RH, Vincent M, Wang HG, Zacher P; Undiagnosed Diseases Network, Rush E, Pitt GS, Au PYB, Shashi V.Genet Med. 2021 Oct;23(10):2016. doi: 10.1038/s41436-021-01306-7.PMID: 34522029 No abstract available.

Grant support

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