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

Lance H Rodan; Rebecca C Spillmann; Harley T Kurata; Shawn M Lamothe; Jasmine Maghera; Rami Abou Jamra; Anna Alkelai; Stylianos E Antonarakis; Isis Atallah; Omer Bar-Yosef; Frédéric Bilan; Kathrine Bjorgo; Xavier Blanc; Patrick Van Bogaert; Yoav Bolkier; Lindsay C Burrage; Björn U Christ; Jorge L Granadillo; Patricia Dickson; Kirsten A Donald; Christèle Dubourg; Aviva Eliyahu; Lisa Emrick; Kendra Engleman; Michaela Veronika Gonfiantini; Jean-Marc Good; Judith Kalser; Chiara Kloeckner; Guus Lachmeijer; Marina Macchiaiolo; Francesco Nicita; Sylvie Odent; Emily O'Heir; Xilma Ortiz-Gonzalez; Marta Pacio-Miguez; María Palomares-Bralo; Loren Pena; Konrad Platzer; Mathieu Quinodoz; Emmanuelle Ranza; Jill A Rosenfeld; Eliane Roulet-Perez; Avni Santani; Fernando Santos-Simarro; Ben Pode-Shakked; Cara Skraban; Rachel Slaugh; Andrea Superti-Furga; Isabelle Thiffault; Richard H van Jaabrsveld

doi:10.1038/s41436-021-01232-8

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

Lance H Rodan, Rebecca C Spillmann, Harley T Kurata, Shawn M Lamothe, Jasmine Maghera, Rami Abou Jamra, Anna Alkelai, Stylianos E Antonarakis, Isis Atallah, Omer Bar-Yosef, Frédéric Bilan, Kathrine Bjorgo, Xavier Blanc, Patrick Van Bogaert, Yoav Bolkier, Lindsay C Burrage, Björn U Christ, Jorge L Granadillo, Patricia Dickson, Kirsten A DonaldChristèle Dubourg, Aviva Eliyahu, Lisa Emrick, Kendra Engleman, Michaela Veronika Gonfiantini, Jean-Marc Good, Judith Kalser, Chiara Kloeckner, Guus Lachmeijer, Marina Macchiaiolo, Francesco Nicita, Sylvie Odent, Emily O'Heir, Xilma Ortiz-Gonzalez, Marta Pacio-Miguez, María Palomares-Bralo, Loren Pena, Konrad Platzer, Mathieu Quinodoz, Emmanuelle Ranza, Jill A Rosenfeld, Eliane Roulet-Perez, Avni Santani, Fernando Santos-Simarro, Ben Pode-Shakked, Cara Skraban, Rachel Slaugh, Andrea Superti-Furga, Isabelle Thiffault, Richard H van Jaabrsveld,

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1922-1932
Number of pages	11
Journal	Genetics in medicine : official journal of the American College of Medical Genetics
Volume	23
Issue number	10
DOIs	https://doi.org/10.1038/s41436-021-01232-8
Publication status	Published - Oct 2021

Keywords

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

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10.1038/s41436-021-01232-8

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Rodan, L. H., Spillmann, R. C., Kurata, H. T., Lamothe, S. M., Maghera, J., Jamra, R. A., Alkelai, A., Antonarakis, S. E., Atallah, I., Bar-Yosef, O., Bilan, F., Bjorgo, K., Blanc, X., Van Bogaert, P., Bolkier, Y., Burrage, L. C., Christ, B. U., Granadillo, J. L., Dickson, P. (2021). Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations. Genetics in medicine : official journal of the American College of Medical Genetics, 23(10), 1922-1932. https://doi.org/10.1038/s41436-021-01232-8

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title = "Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations",

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.",

keywords = "Autistic Disorder/genetics, Calcium Channels, L-Type/genetics, Humans, Long QT Syndrome, Phenotype, Syndactyly",

author = "Rodan, {Lance H} and Spillmann, {Rebecca C} and Kurata, {Harley T} and Lamothe, {Shawn M} and Jasmine Maghera and Jamra, {Rami Abou} and Anna Alkelai and Antonarakis, {Stylianos E} and Isis Atallah and Omer Bar-Yosef and Fr{\'e}d{\'e}ric Bilan and Kathrine Bjorgo and Xavier Blanc and {Van Bogaert}, Patrick and Yoav Bolkier and Burrage, {Lindsay C} and Christ, {Bj{\"o}rn U} and Granadillo, {Jorge L} and Patricia Dickson and Donald, {Kirsten A} and Christ{\`e}le Dubourg and Aviva Eliyahu and Lisa Emrick and Kendra Engleman and Gonfiantini, {Michaela Veronika} and Jean-Marc Good and Judith Kalser and Chiara Kloeckner and Guus Lachmeijer and Marina Macchiaiolo and Francesco Nicita and Sylvie Odent and Emily O'Heir and Xilma Ortiz-Gonzalez and Marta Pacio-Miguez and Mar{\'i}a Palomares-Bralo and Loren Pena and Konrad Platzer and Mathieu Quinodoz and Emmanuelle Ranza and Rosenfeld, {Jill A} and Eliane Roulet-Perez and Avni Santani and Fernando Santos-Simarro and Ben Pode-Shakked and Cara Skraban and Rachel Slaugh and Andrea Superti-Furga and Isabelle Thiffault and {van Jaabrsveld}, {Richard H}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.",

year = "2021",

month = oct,

doi = "10.1038/s41436-021-01232-8",

language = "English",

volume = "23",

pages = "1922--1932",

journal = "Genetics in medicine : official journal of the American College of Medical Genetics",

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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, J-M, 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 2021, 'Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations', Genetics in medicine : official journal of the American College of Medical Genetics, vol. 23, no. 10, pp. 1922-1932. https://doi.org/10.1038/s41436-021-01232-8

Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations. / Rodan, Lance H; Spillmann, Rebecca C; Kurata, Harley T et al.
In: Genetics in medicine : official journal of the American College of Medical Genetics, Vol. 23, No. 10, 10.2021, p. 1922-1932.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations

AU - Rodan, Lance H

AU - Spillmann, Rebecca C

AU - Kurata, Harley T

AU - Lamothe, Shawn M

AU - Maghera, Jasmine

AU - Jamra, Rami Abou

AU - Alkelai, Anna

AU - Antonarakis, Stylianos E

AU - Atallah, Isis

AU - Bar-Yosef, Omer

AU - Bilan, Frédéric

AU - Bjorgo, Kathrine

AU - Blanc, Xavier

AU - Van Bogaert, Patrick

AU - Bolkier, Yoav

AU - Burrage, Lindsay C

AU - Christ, Björn U

AU - Granadillo, Jorge L

AU - Dickson, Patricia

AU - Donald, Kirsten A

AU - Dubourg, Christèle

AU - Eliyahu, Aviva

AU - Emrick, Lisa

AU - Engleman, Kendra

AU - Gonfiantini, Michaela Veronika

AU - Good, Jean-Marc

AU - Kalser, Judith

AU - Kloeckner, Chiara

AU - Lachmeijer, Guus

AU - Macchiaiolo, Marina

AU - Nicita, Francesco

AU - Odent, Sylvie

AU - O'Heir, Emily

AU - Ortiz-Gonzalez, Xilma

AU - Pacio-Miguez, Marta

AU - Palomares-Bralo, María

AU - Pena, Loren

AU - Platzer, Konrad

AU - Quinodoz, Mathieu

AU - Ranza, Emmanuelle

AU - Rosenfeld, Jill A

AU - Roulet-Perez, Eliane

AU - Santani, Avni

AU - Santos-Simarro, Fernando

AU - Pode-Shakked, Ben

AU - Skraban, Cara

AU - Slaugh, Rachel

AU - Superti-Furga, Andrea

AU - Thiffault, Isabelle

AU - van Jaabrsveld, Richard H

PY - 2021/10

Y1 - 2021/10

N2 - 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.

AB - 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.

KW - Autistic Disorder/genetics

KW - Calcium Channels, L-Type/genetics

KW - Humans

KW - Long QT Syndrome

KW - Phenotype

KW - Syndactyly

UR - http://www.scopus.com/inward/record.url?scp=85109046823&partnerID=8YFLogxK

U2 - 10.1038/s41436-021-01232-8

DO - 10.1038/s41436-021-01232-8

M3 - Article

C2 - 34163037

SN - 1098-3600

VL - 23

SP - 1922

EP - 1932

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

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

IS - 10

ER -

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

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Keywords

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