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

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.; Donald, K.A.; Dubourg, C.; Eliyahu, A.; Emrick, L.; Engleman, K.; Gonfiantini, M.V.; 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, J.A.; Roulet-Perez, E.; Santani, A.; Santos-Simarro, F.; Pode-Shakked, B.; Skraban, C.; Slaugh, R.; Superti-Furga, A.; Thiffault, I.; van Jaabrsveld, R.H.; Vincent, M.; Wang, H.G.; Zacher, P.; Rush, E.; Pitt, G.S.; Au, PYB; Shashi, V.

doi:10.1038/s41436-021-01232-8

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

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Serval ID

serval:BIB_1C202819AA37

Type

Article: article from journal or magazin.

Collection

Publications

Institution

UNIL/CHUV

Title

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

Journal

Genetics in medicine

Author(s)

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., Donald K.A., Dubourg C., Eliyahu A., Emrick L., Engleman K., Gonfiantini M.V., 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 J.A., Roulet-Perez E., Santani A., Santos-Simarro F., Pode-Shakked B., Skraban C., Slaugh R., Superti-Furga A., Thiffault I., van Jaabrsveld R.H., Vincent M., Wang H.G., Zacher P., Rush E., Pitt G.S., Au PYB, Shashi V.

Working group(s)

Undiagnosed Diseases Network

Contributor(s)

Alejandro M.E., Azamian M.S., Bacino C.A., Balasubramanyam A., Burrage L.C., Chao H.T., Clark G.D., Craigen W.J., Dai H., Dhar S.U., Emrick L.T., Goldman A.M., Hanchard N.A., Jamal F., Karaviti L., Lalani S.R., Lee B.H., Lewis R.A., Marom R., Moretti P.M., Murdock D.R., Nicholas S.K., Orengo J.P., Posey J.E., Potocki L., Rosenfeld J.A., Samson S.L., Scott D.A., Tran A.A., Vogel T.P., Wangler M.F., Yamamoto S., Eng C.M., Liu P., Ward P.A., Behrens E., Deardorff M., Falk M., Hassey K., Sullivan K., Vanderver A., Goldstein D.B., Cope H., McConkie-Rosell A., Schoch K., Shashi V., Smith E.C., Spillmann R.C., Sullivan J.A., Tan Q.K., Walley N.M., Agrawal P.B., Beggs A.H., Berry G.T., Briere L.C., Cobban L.A., Coggins M., Cooper C.M., Fieg E.L., High F., Holm I.A., Korrick S., Krier J.B., Lincoln S.A., Loscalzo J., Maas R.L., MacRae C.A., Pallais J.C., Rao D.A., Rodan L.H., Silverman E.K., Stoler J.M., Sweetser D.A., Walker M., Walsh C.A., Esteves C., Kelley E.G., Kohane I.S., LeBlanc K., McCray A.T., Nagy A., Dasari S., Lanpher B.C., Lanza I.R., Morava E., Oglesbee D., Bademci G., Barbouth D., Bivona S., Carrasquillo O., Chang TCP, Forghani I., Grajewski A., Isasi R., Lam B., Levitt R., Liu X.Z., McCauley J., Sacco R., Saporta M., Schaechter J., Tekin M., Telischi F., Thorson W., Zuchner S., Colley H.A., Dayal J.G., Eckstein D.J., Findley L.C., Krasnewich D.M., Mamounas L.A., Manolio T.A., Mulvihill J.J., LaMoure G.L., Goldrich M.P., Urv T.K., Doss A.L., Acosta M.T., Bonnenmann C., D'Souza P., Draper D.D., Ferreira C., Godfrey R.A., Groden C.A., Macnamara E.F., Maduro V.V., Markello T.C., Nath A., Novacic D., Pusey B.N., Toro C., Wahl C.E., Baker E., Burke E.A., Adams D.R., Gahl W.A., Malicdan MCV, Tifft C.J., Wolfe L.A., Yang J., Power B., Gochuico B., Huryn L., Latham L., Davis J., Mosbrook-Davis D., Rossignol F., Ben Solomon s, MacDowall J., Thurm A., Zein W., Yousef M., Adam M., Amendola L., Bamshad M., Beck A., Bennett J., Berg-Rood B., Blue E., Boyd B., Byers P., Chanprasert S., Cunningham M., Dipple K., Doherty D., Earl D., Glass I., Golden-Grant K., Hahn S., Hing A., Hisama F.M., Horike-Pyne M., Jarvik G.P., Jarvik J., Jayadev S., Lam C., Maravilla K., Mefford H., Merritt J.L., Mirzaa G., Nickerson D., Raskind W., Rosenwasser N., Scott C.R., Sun A., Sybert V., Wallace S., Wener M., Wenger T., Ashley E.A., Bejerano G., Bernstein J.A., Bonner D., Coakley T.R., Fernandez L., Fisher P.G., Fresard L., Hom J., Huang Y., Kohler J.N., Kravets E., Majcherska M.M., Martin B.A., Marwaha S., McCormack C.E., Raja A.N., Reuter C.M., Ruzhnikov M., Sampson J.B., Smith K.S., Sutton S., Tabor H.K., Tucker B.M., Wheeler M.T., Zastrow D.B., Zhao C., Byrd W.E., Crouse A.B., Might M., Nakano-Okuno M., Whitlock J., Brown G., Butte M.J., Dell'Angelica E.C., Dorrani N., Douine E.D., Fogel B.L., Gutierrez I., Huang A., Krakow D., Lee H., Loo S.K., Mak B.C., Martin M.G., Martínez-Agosto J.A., McGee E., Nelson S.F., Nieves-Rodriguez S., Palmer CGS, Papp J.C., Parker N.H., Renteria G., Signer R.H., Sinsheimer J.S., Wan J., Wang L.K., Perry K.W., Woods J.D., Alvey J., Andrews A., Bale J., Bohnsack J., Botto L., Carey J., Pace L., Longo N., Marth G., Moretti P., Quinlan A., Velinder M., Viskochil D., Bayrak-Toydemir P., Mao R., Westerfield M., Bican A., Brokamp E., Duncan L., Hamid R., Kennedy J., Kozuira M., Newman J.H., PhillipsIII J.A., Rives L., Robertson A.K., Solem E., Cogan J.D., Cole F.S., Hayes N., Kiley D., Sisco K., Wambach J., Wegner D., Baldridge D., Pak S., Schedl T., Shin J., Solnica-Krezel L.

ISSN

1530-0366 (Electronic)

ISSN-L

1098-3600

Publication state

Published

Issued date

10/2021

Peer-reviewed

Oui

Volume

Number

Pages

1922-1932

Language

english

Notes

Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish

Abstract

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

OAI-PMH

oai:serval.unil.ch:BIB_1C202819AA37

DOI

10.1038/s41436-021-01232-8

Pubmed

34163037

Web of science

000664809000001

Create date

06/07/2021 14:34