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

Lance Rodan (1) , Rebecca Spillmann (2) , Harley Kurata (3) , Shawn Lamothe (3) , Jasmine Maghera (3) , Rami Abou Jamra (4) , Anna Alkelai (5) , Stylianos Antonarakis (6) , Isis Atallah , Omer Bar-Yosef (7) , Frédéric Bilan (8, 9) , Kathrine Bjorgo , Xavier Blanc (10) , Patrick van Bogaert (9) , Yoav Bolkier (7) , Lindsay Burrage (11) , Björn Christ , Jorge Granadillo (12) , Patricia Dickson (12) , Kirsten Donald , Christèle Dubourg (13, 14) , Aviva Eliyahu (7) , Lisa Emrick , Kendra Engleman , Michaela Veronika Gonfiantini (15) , Jean-Marc Good (16) , Judith Kalser (16) , Chiara Kloeckner , Guus Lachmeijer , Marina Macchiaiolo (15) , Francesco Nicita , Sylvie Odent (17, 13) , Emily O’heir (1, 18) , Xilma Ortiz-Gonzalez (19) , Marta Pacio-Miguez (20) , María Palomares-Bralo (20) , Loren Pena , Konrad Platzer , Mathieu Quinodoz , Emmanuelle Ranza , Jill Rosenfeld , Eliane Roulet-Perez (16) , Avni Santani , Fernando Santos-Simarro (20) , Ben Pode-Shakked (7) , Cara Skraban , Rachel Slaugh (12) , Andrea Superti-Furga (16) , Isabelle Thiffault , Richard van Jaabrsveld , Marie Vincent (21, 22) , Hong-Gang Wang , Pia Zacher , Mercedes Alejandro , Mahshid Azamian , Carlos Bacino , Ashok Balasubramanyam , Hsiao-Tuan Chao , Gary Clark , William Craigen , Hongzheng Dai , Shweta Dhar , Alica Goldman , Neil Hanchard , Fariha Jamal , Lefkothea Karaviti , Seema Lalani , Brendan Lee , Richard Lewis , Ronit Marom , Paolo Moretti , David Murdock , Sarah Nicholas , James Orengo , Jennifer Posey , Lorraine Potocki , Susan Samson , Daryl Scott , Alyssa Tran , Tiphanie Vogel , Michael Wangler , Shinya Yamamoto , Christine Eng , Pengfei Liu , Patricia Ward , Edward Behrens , Matthew Deardorff , Marni Falk , Kelly Hassey , Kathleen Sullivan , Adeline Vanderver , David Goldstein , Heidi Cope , Allyn Mcconkie-Rosell , Kelly Schoch , Vandana Shashi (2) , Edward Smith , Jennifer Sullivan , Queenie K.-G. Tan , Nicole Walley , Pankaj Agrawal , Alan Beggs , Gerard Berry , Lauren Briere , Laurel Cobban , Matthew Coggins , Cynthia Cooper , Elizabeth Fieg , Frances High , Ingrid Holm , Susan Korrick , Joel Krier , Sharyn Lincoln , Joseph Loscalzo , Richard Maas , Calum Macrae , J. Carl Pallais , Deepak Rao , Edwin Silverman , Joan Stoler , David Sweetser , Melissa Walker , Chris Walsh , Cecilia Esteves , Emily Kelley , Isaac Kohane , Kimberly Leblanc , Alexa Mccray , Anna Nagy , Surendra Dasari , Brendan Lanpher , Ian Lanza , Eva Morava , Devin Oglesbee , Guney Bademci , Deborah Barbouth , Stephanie Bivona , Olveen Carrasquillo , Ta Chen Peter Chang , Irman Forghani , Alana Grajewski , Rosario Isasi , Byron Lam , Roy Levitt , Xue Zhong Liu , Jacob Mccauley , Ralph Sacco , Mario Saporta , Judy Schaechter , Mustafa Tekin , Fred Telischi , Willa Thorson , Stephan Zuchner , Heather Colley , Jyoti Dayal , David Eckstein , Laurie Findley , Donna Krasnewich , Laura Mamounas , Teri Manolio , John Mulvihill , Grace Lamoure , Madison Goldrich , Tiina Urv , Argenia Doss , Maria Acosta , Carsten Bonnenmann , Precilla D’souza , David Draper , Carlos Ferreira , Rena Godfrey , Catherine Groden , Ellen Macnamara , Valerie Maduro , Thomas Markello , Avi Nath , Donna Novacic , Barbara Pusey , Camilo Toro , Colleen Wahl , Eva Baker , Elizabeth Burke , David Adams , William Gahl , May Christine V. Malicdan , Cynthia Tifft , Lynne Wolfe , John Yang , Bradley Power , Bernadette Gochuico , Laryssa Huryn , Lea Latham , Joie Davis , Deborah Mosbrook-Davis , Francis Rossignol , Ben Solomon , John Macdowall , Audrey Thurm , Wadih Zein , Muhammad Yousef , Margaret Adam , Laura Amendola , Michael Bamshad , Anita Beck , Jimmy Bennett , Beverly Berg-Rood , Elizabeth Blue , Brenna Boyd , Peter Byers , Sirisak Chanprasert , Michael Cunningham , Katrina Dipple , Daniel Doherty , Dawn Earl , Ian Glass , Katie Golden-Grant , Sihoun Hahn , Anne Hing , Fuki Hisama , Martha Horike-Pyne , Gail Jarvik , Jeffrey Jarvik , Suman Jayadev , Christina Lam , Kenneth Maravilla , Heather Mefford , J. Lawrence Merritt , Ghayda Mirzaa , Deborah Nickerson , Wendy Raskind , Natalie Rosenwasser , C. Ron Scott , Angela Sun , Virginia Sybert , Stephanie Wallace , Mark Wener , Tara Wenger , Euan Ashley , Gill Bejerano , Jonathan Bernstein , Devon Bonner , Terra Coakley , Liliana Fernandez , Paul Fisher , Laure Fresard , Jason Hom , Yong Huang , Jennefer Kohler , Elijah Kravets , Marta Majcherska , Beth Martin , Shruti Marwaha , Colleen Mccormack , Archana Raja , Chloe Reuter , Maura Ruzhnikov , Jacinda Sampson , Kevin Smith , Shirley Sutton , Holly Tabor , Brianna Tucker , Matthew Wheeler , Diane Zastrow , Chunli Zhao , William Byrd , Andrew Crouse , Matthew Might , Mariko Nakano-Okuno , Jordan Whitlock , Gabrielle Brown , Manish Butte , Esteban Dell’angelica , Naghmeh Dorrani , Emilie Douine , Brent Fogel , Irma Gutierrez , Alden Huang , Deborah Krakow , Hane Lee , Sandra Loo , Bryan Mak , Martin Martin , Julian Martínez-Agosto , Elisabeth Mcgee , Stanley Nelson , Shirley Nieves-Rodriguez , Christina G.S. Palmer , Jeanette Papp , Neil Parker , Genecee Renteria , Rebecca Signer , Janet Sinsheimer , Jijun Wan , Lee-Kai Wang , Katherine Wesseling Perry , Jeremy Woods , Justin Alvey , Ashley Andrews , Jim Bale , John Bohnsack , Lorenzo Botto , John Carey , Laura Pace , Nicola Longo , Gabor Marth , Aaron Quinlan , Matt Velinder , Dave Viskochil , Pinar Bayrak-Toydemir , Rong Mao , Monte Westerfield , Anna Bican , Elly Brokamp , Laura Duncan , Rizwan Hamid , Jennifer Kennedy , Mary Kozuira , John Newman , John Phillipsiii , Lynette Rives , Amy Robertson , Emily Solem , Joy Cogan , F. Sessions Cole , Nichole Hayes , Dana Kiley , Kathy Sisco , Jennifer Wambach , Daniel Wegner , Dustin Baldridge , Stephen Pak , Timothy Schedl , Jimann Shin , Lilianna Solnica-Krezel , Eric Rush (23, 24, 25) , Geoffrey Pitt (26) , Ping Yee Billie Au (27)

1 Boston Children's Hospital
2 Duke University [Durham]
3 University of Alberta
4 Universität Leipzig [Leipzig]
5 CUMC - Columbia University Medical Center
6 HUG - Geneva University Hospital
7 TAU - Tel Aviv University
8 Service Génétique Médicale [CHU Poitiers]
9 CIMoTHeMA - Cibles moléculaires et thérapeutiques de la maladie d'Alzheimer
10 LJLL (UMR_7598) - Laboratoire Jacques-Louis Lions
11 BCM - Baylor College of Medicine
12 Washington University School of Medicine in St. Louis
13 CHU Pontchaillou [Rennes]
14 IGDR - Institut de Génétique et Développement de Rennes
15 IRCCS - Istituti di Ricovero e Cura a Carattere Scientifico
16 Lausanne University Hospital
17 Centre de référence Maladies Rares CLAD-Ouest [Rennes]
18 BROAD INSTITUTE - Broad Institute of MIT and Harvard
19 CHOP - Children’s Hospital of Philadelphia
20 Hospital Universitario La Paz
21 ITX-lab - Unité de recherche de l'institut du thorax
22 CHU Nantes - Centre hospitalier universitaire de Nantes
23 University of Kansas Medical Center [Kansas City, KS, USA]
24 University of Missouri System
25 Children's Mercy Hospital [Kansas City]
26 Weill Cornell Medicine [New York]
27 University of Calgary

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.

Domains: Life Sciences [q-bio]; Genetics

Lance Rodan, Rebecca Spillmann, Harley Kurata, Shawn Lamothe, Jasmine Maghera, et al.. Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations. Genetics in Medicine, 2021, 23 (10), pp.1922-1932. ⟨10.1038/s41436-021-01232-8⟩. ⟨hal-03519600⟩