WashU weekly Neuroscience publications

Group characterization of impact-induced, in vivo human brain kinematics
(2021) Journal of the Royal Society, Interface, 18 (179), p. 20210251. 

Gomez, A.D.^a , Bayly, P.V.^b , Butman, J.A.^c , Pham, D.L.^d , Prince, J.L.^e , Knutsen, A.K.^d

^a School of Medicine, Department of Neurology, Johns Hopkins University, 200 Carnegie Hall, MD, 600 North Wolfe Street, Baltimore, United States
^b Department of Mechanical Engineering and Materials Science, Washington University in St Louis, MI, 1 Brookings Drive, Box 1185, Saint Louis, United States
^c Clinical Center, National Institutes of Health, MD, Bethesda, United States
^d Center for Neuroscience and Regenerative Medicine, Henry M Jackson Foundation for the Advancement of Military Medicine Inc, MD, Bethesda, United States
^e Department of Electrical and Computer Engineering, Johns Hopkins University, MD, Baltimore, United States

Abstract
Brain movement during an impact can elicit a traumatic brain injury, but tissue kinematics vary from person to person and knowledge regarding this variability is limited. This study examines spatio-temporal brain-skull displacement and brain tissue deformation across groups of subjects during a mild impact in vivo. The heads of two groups of participants were imaged while subjected to a mild (less than 350 rad s-2) impact during neck extension (NE, n = 10) and neck rotation (NR, n = 9). A kinematic atlas of displacement and strain fields averaged across all participants was constructed and compared against individual participant data. The atlas-derived mean displacement magnitude was 0.26 ± 0.13 mm for NE and 0.40 ± 0.26 mm for NR, which is comparable to the displacement magnitudes from individual participants. The strain tensor from the atlas displacement field exhibited maximum shear strain (MSS) of 0.011 ± 0.006 for NE and 0.017 ± 0.009 for NR and was lower than the individual MSS averaged across participants. The atlas illustrates common patterns, containing some blurring but visible relationships between anatomy and kinematics. Conversely, the direction of the impact, brain size, and fluid motion appear to underlie kinematic variability. These findings demonstrate the biomechanical roles of key anatomical features and illustrate common features of brain response for model evaluation.

Author Keywords
dynamic magnetic resonance imaging;  finite strain;  head impact;  traumatic brain injury

Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia
(2021) Brain, 144 (5), pp. 1422-1434. 

Wiessner, M.^a , Maroofian, R.^b , Ni, M.-Y.^c , Pedroni, A.^d , Müller, J.S.^e , Stucka, R.^a , Beetz, C.^e , Efthymiou, S.^b , Santorelli, F.M.^g , Alfares, A.A.^h , Zhu, C.^i j k , Uhrova Meszarosova, A.^l , Alehabib, E.^m , Bakhtiari, S.ⁿ , Janecke, A.R.^o p , Otero, M.G.^q , Chen, J.Y.H.^r , Peterson, J.T.^s , Strom, T.M.^t , De Jonghe, P.^u v w , Deconinck, T.^x , De Ridder, W.^u v w , De Winter, J.^u v w , Pasquariello, R.^g , Ricca, I.^g , Alfadhel, M.^y , Van De Warrenburg, B.P.^z , Portier, R.^aa , Bergmann, C.^ab ac , Ghasemi Firouzabadi, S.^ad , Jin, S.C.^ae , Bilguvar, K.^af ag , Hamed, S.^ah , Abdelhameed, M.^ah , Haridy, N.A.^b ah , Maqbool, S.^ai , Rahman, F.^ai , Anwar, N.^ai , Carmichael, J.^aj , Pagnamenta, A.^ak , Wood, N.W.^b al , Tran Mau-Them, F.^am , Haack, T.^an , Di Rocco, M.^ao , Ceccherini, I.^ap , Iacomino, M.^aq , Zara, F.^aq ar , Salpietro, V.^ar as , Scala, M.^ar as , Rusmini, M.^ap , Xu, Y.ⁱ , Wang, Y.^at , Suzuki, Y.^au , Koh, K.^av , Nan, H.^av , Ishiura, H.^aw , Tsuji, S.^ax , Lambert, L.^ay , Schmitt, E.^az , Lacaze, E.^ba , Küpper, H.^bb , Dredge, D.^r , Skraban, C.^bc bd , Goldstein, A.^s bd , Willis, M.J.H.^be , Grand, K.^bf , Graham, J.M.^bf , Lewis, R.A.^bg , Millan, F.^bh , Duman, Ö.^bi , Dündar, N.^bj , Uyanik, G.^bk bl , Schöls, L.^bm bn , Nürnberg, P.^bo , Nürnberg, G.^bo , Catala Bordes, A.^l , Seeman, P.^l , Kuchar, M.^bp , Darvish, H.^bq , Rebelo, A.^br , Bouçanova, F.^d bs , Medard, J.-J.^d bs , Chrast, R.^d bs , Auer-Grumbach, M.^bt , Alkuraya, F.S.^bu , Shamseldin, H.^bu , Al Tala, S.^bv , Rezazadeh Varaghchi, J.^bw , Najafi, M.^f bx , Deschner, S.^by , Gläser, D.^by , Hüttel, W.^bz , Kruer, M.C.ⁿ , Kamsteeg, E.-J.^bx , Takiyama, Y.^av , Züchner, S.^br , Baets, J.^u v w , Synofzik, M.^bm bn , Schüle, R.^bm bn , Horvath, R.^e , Houlden, H.^b , Bartesaghi, L.^d bs , Lee, H.-J.^c , Ampatzis, K.^d , Pierson, T.M.^f q bg ca , Senderek, J.^a , Genomics England Research Consortium, PREPARE network^cb

^a Friedrich-Baur-Institute, Department of Neurology, LMU Munich, Munich, Germany
^b Department of Neuromuscular Disorders, Institute of Neurology, University College London, London, United Kingdom
^c Department of Biochemistry, National Defense Medical Center, Neihu, Taipei, Taiwan
^d Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
^e Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
^f Center for the Undiagnosed Patient, Cedars-Sinai Medical Center, Los Angeles, CA, United States
^g Molecular Medicine Unit, IRCCS Fondazione Stella Maris, Pisa, Italy
^h Department of Pediatrics, College of Medicine, Qassim University, Qassim, Saudi Arabia
ⁱ Henan Key Laboratory of Child Brain Injury, Institute of Neuroscience, Third Affliated Hospital of Zhengzhou University, Zhengzhou, China
^j Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Göteborg, Sweden
^k Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
^l DNA Laboratory, Department of Paediatric Neurology, Second Faculty of Medicine, Charles University, University Hospital Motol, Prague, Czech Republic
^m Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
ⁿ Barrow Neurological Institute, Phoenix Children’s Hospital, University of Arizona College of Medicine, Phoenix, United States
^o Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria
^p Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
^q Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
^r Neurology Department, Massachusetts General Hospital, Boston, MA, United States
^s Mitochondrial Medicine Frontier Program, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^t Institute of Human Genetics, Technische Universität Mänchen, Munich, Germany
^u Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerpen, Belgium
^v Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium
^w Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerpen, Belgium
^x Center of Medical Genetics, University of Antwerp, Antwerp University Hospital, Antwerpen, Belgium
^y Genetics Division, Department of Pediatrics, King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia
^z Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Nijmegen, Netherlands
^aa Polikliniek Neurologie Enschede, Medisch Spectrum Twente, Enschede, Netherlands
^ab Medizinische Genetik Mainz, Limbach Genetics, Mainz, Germany
^ac Department of Medicine, Nephrology, University Hospital Freiburg, Germany
^ad Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
^ae Department of Genetics, Washington University School of Medicine, St. Louis, United States
^af Department of Genetics, Yale University School of Medicine, New Haven, CT, United States
^ag Yale Center for Genome Analysis, Yale University, New Haven, CT, United States
^ah Department of Neurology and Psychiatry, Assiut University Hospital, Assiut, Egypt
^ai Development and Behavioural Paediatrics Department, Institute of Child Health, The Children Hospital, Lahore, Pakistan
^aj Oxford Regional Clinical Genetics Service, Northampton General Hospital, Northampton, United Kingdom
^ak NIHR Oxford BRC, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
^al The National Hospital for Neurology and Neurosurgery, London, United Kingdom
^am Unité Fonctionnelle 6254 d’Innovation en Diagnostique Génomique des Maladies Rares, Pôle de Biologie, CHU Dijon Bourgogne, Dijon, France
^an Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
^ao Rare Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
^ap Genetics and Genomics of Rare Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
^aq Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
^ar Dep. of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy
^as Pediatric Neurology and Neuromuscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
^at Department of Pediatrics, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
^au Department of Pediatric Neurology, Osaka Women’s and Children’s Hospital, Osaka, Japan
^av Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan
^aw Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
^ax Institute of Medical Genomics, International University of Health and Welfare, Chiba, Japan
^ay Department of Clinical Genetics, CHRU Nancy, UMR-S INSERM N-GERE 1256, Université de Lorraine, Faculté de Médecine, Nancy, France
^az Department of Neuroradiology, CHRU Nancy, Nancy, France
^ba Department of Medical Genetics, Le Havre Hospital, Le Havre, France
^bb Department of Pediatric Neurology, University Children’s Hospital Tübingen, Tübingen, Germany
^bc Roberts Individualized Medical Genetics Center, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^bd Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^be Department of Pediatrics, Naval Medical Center San Diego, San Diego, CA, United States
^bf Department of Pediatrics, Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, CA, United States
^bg Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
^bh GeneDx, Gaithersburg, MD, United States
^bi Department of Pediatric Neurology, Akdeniz University Hospital, Antalya, Turkey
^bj Department of Pediatric Neurology, Izmir Katip Celebi University, Izmir, Turkey
^bk Center for Medical Genetics, Hanusch Hospital, Vienna, Austria
^bl Medical School, Sigmund Freud Private University, Vienna, Austria
^bm Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen, Tübingen, Germany
^bn German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany
^bo Cologne Center for Genomics, Faculty of Medicine, Cologne University Hospital, University of Cologne, Cologne, Germany
^bp Department of Paediatric Neurology, Liberec Hospital, Liberec, Czech Republic
^bq Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
^br Dr. John T. Macdonald Foundation, Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, United States
^bs Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
^bt Department of Orthopaedics and Traumatology, Medical University of Vienna, Vienna, Austria
^bu Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
^bv Department of Pediatrics, Genetic Unit, Armed Forces Hospital, Khamis Mushayt, Saudi Arabia
^bw Hasti Genetic Counseling Center of Welfare Organization of Southern Khorasan, Birjand, Iran
^bx Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands
^by genetikum, Center for Human Genetics, Neu-Ulm, Germany
^bz Institut für Pharmazeutische Wissenschaften, Albert-Ludwigs-Universität Freiburg, Freibug, Germany
^ca Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, United States

Abstract
Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays. © 2021 The Author(s).

Author Keywords
autosomal recessive;  hereditary spastic paraplegia;  HPDL;  HSP;  mitochondrial disorder

Funding details
01GM1511
MAB-108-070
01GM1607, 01GM1905
National Institute of Neurological Disorders and StrokeNINDSR01NS072248
Japan Agency for Medical Research and DevelopmentAMED19ek0109279h0003
Wellcome TrustWTWT093205, WT104033AIA
Newton FundMR/ N027302/1
Ministerio de Sanidad, Consumo y Bienestar SocialMISAN441409627, EJP RD COFUND-EJP N 825575
Medical Research CouncilMRC109915/Z/15/Z, MR/N025431/1
Deutsche ForschungsgemeinschaftDFG
Ministry of Education, Culture, Sports, Science and TechnologyMonbusho
ZonMw
Bundesministerium für Bildung und ForschungBMBF
Fonds Wetenschappelijk OnderzoekFWO1805016N
Ministero della SaluteRC5X1000, RF-2016- 02361610
Ministerstvo Zdravotnictví Ceské RepublikyMZCRAZV NU20-04- 00279, DRO 00064203
Ministry of Health, Labour and WelfareMHLWJP18K07495
VetenskapsrådetVR2018-02667, 717791
Ministry of Science and Technology, TaiwanMOST107-2320-B-016-014
Horizon 2020779257
Major Science and Technology Project of Hainan Province171100310200
Research Committee for Ataxic Disease

Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations
(2021) Genetics in Medicine, . 

Rodan, L.H.^a b , Spillmann, R.C.^c , Kurata, H.T.^d , Lamothe, S.M.^d , Maghera, J.^d , Jamra, R.A.^e , Alkelai, A.^f , Antonarakis, S.E.^g , Atallah, I.^h , Bar-Yosef, O.^i j , Bilan, F.^k , Bjorgo, K.^l , Blanc, X.^g , Van Bogaert, P.^m , Bolkier, Y.^j n , Burrage, L.C.^o , Christ, B.U.^p , Granadillo, J.L.^q , Dickson, P.^q , Donald, K.A.^p , Dubourg, C.^r s , Eliyahu, A.^j t u , Emrick, L.^o , Engleman, K.^v , Gonfiantini, M.V.^w , Good, J.-M.^x , Kalser, J.^x , Kloeckner, C.^e , Lachmeijer, G.^y , Macchiaiolo, M.^w , Nicita, F.^z , Odent, S.^aa , O’Heir, E.^a ab , Ortiz-Gonzalez, X.^ac , Pacio-Miguez, M.^ad , Palomares-Bralo, M.^ad , Pena, L.^ae af , Platzer, K.^e , Quinodoz, M.^ag ah , Ranza, E.^g , Rosenfeld, J.A.^o , Roulet-Perez, E.^x , Santani, A.^ai aj , Santos-Simarro, F.^ad , Pode-Shakked, B.^j ak , Skraban, C.^aj al , Slaugh, R.^q , Superti-Furga, A.^x , Thiffault, I.^v , van Jaabrsveld, R.H.^y , Vincent, M.^am , Wang, H.-G.^an , Zacher, P.^ao , Alejandro, M.E.^at , Azamian, M.S.^at , Bacino, C.A.^at , Balasubramanyam, A.^at , Burrage, L.C.^at , Chao, H.-T.^at , Clark, G.D.^at , Craigen, W.J.^at , Dai, H.^at , Dhar, S.U.^at , Emrick, L.T.^at , Goldman, A.M.^at , Hanchard, N.A.^at , Jamal, F.^at , Karaviti, L.^at , Lalani, S.R.^at , Lee, B.H.^at , Lewis, R.A.^at , Marom, R.^at , Moretti, P.M.^at , Murdock, D.R.^at , Nicholas, S.K.^at , Orengo, J.P.^at , Posey, J.E.^at , Potocki, L.^at , Rosenfeld, J.A.^at , Samson, S.L.^at , Scott, D.A.^at , Tran, A.A.^at , Vogel, T.P.^at , Wangler, M.F.^au , Yamamoto, S.^au , Eng, C.M.^av , Liu, P.^av , Ward, P.A.^av , Behrens, E.^aw , Deardorff, M.^aw , Falk, M.^aw , Hassey, K.^aw , Sullivan, K.^aw , Vanderver, A.^aw , Goldstein, D.B.^ax , Cope, H.^ay , McConkie-Rosell, A.^ay , Schoch, K.^ay , Shashi, V.^ay , Smith, E.C.^ay , Spillmann, R.C.^ay , Sullivan, J.A.^ay , Tan, Q.K.-G.^ay , Walley, N.M.^ay , Agrawal, P.B.^az , Beggs, A.H.^az , Berry, G.T.^az , Briere, L.C.^az , Cobban, L.A.^az , Coggins, M.^az , Cooper, C.M.^az , Fieg, E.L.^az , High, F.^az , Holm, I.A.^az , Korrick, S.^az , Krier, J.B.^az , Lincoln, S.A.^az , Loscalzo, J.^az , Maas, R.L.^az , MacRae, C.A.^az , Pallais, J.C.^az , Rao, D.A.^az , Rodan, L.H.^az , Silverman, E.K.^az , Stoler, J.M.^az , Sweetser, D.A.^az , Walker, M.^az , Walsh, C.A.^az , Esteves, C.^ba , Kelley, E.G.^ba , Kohane, I.S.^ba , LeBlanc, K.^ba , McCray, A.T.^ba , Nagy, A.^ba , Dasari, S.^bb , Lanpher, B.C.^bb , Lanza, I.R.^bb , Morava, E.^bb , Oglesbee, D.^bb , Bademci, G.^bc , Barbouth, D.^bc , Bivona, S.^bc , Carrasquillo, O.^bc , Chang, T.C.P.^bc , Forghani, I.^bc , Grajewski, A.^bc , Isasi, R.^bc , Lam, B.^bc , Levitt, R.^bc , Liu, X.Z.^bc , McCauley, J.^bc , Sacco, R.^bc , Saporta, M.^bc , Schaechter, J.^bc , Tekin, M.^bc , Telischi, F.^bc , Thorson, W.^bc , Zuchner, S.^bc , Colley, H.A.^bd , Dayal, J.G.^bd , Eckstein, D.J.^bd , Findley, L.C.^bd , Krasnewich, D.M.^bd , Mamounas, L.A.^bd , Manolio, T.A.^bd , Mulvihill, J.J.^bd , LaMoure, G.L.^bd , Goldrich, M.P.^bd , Urv, T.K.^bd , Doss, A.L.^bd , Acosta, M.T.^be , Bonnenmann, C.^be , D’Souza, P.^be , Draper, D.D.^be , Ferreira, C.^be , Godfrey, R.A.^be , Groden, C.A.^be , Macnamara, E.F.^be , Maduro, V.V.^be , Markello, T.C.^be , Nath, A.^be , Novacic, D.^be , Pusey, B.N.^be , Toro, C.^be , Wahl, C.E.^be , Baker, E.^bf , Burke, E.A.^bg , Adams, D.R.^bg , Gahl, W.A.^bg , Malicdan, M.C.V.^bg , Tifft, C.J.^bg , Wolfe, L.A.^bg , Yang, J.^bg , Power, B.^bg , Gochuico, B.^bg , Huryn, L.^bg , Latham, L.^bg , Davis, J.^bg , Mosbrook-Davis, D.^bg , Rossignol, F.^bg , Ben Solomon^bg , MacDowall, J.^bg , Thurm, A.^bg , Zein, W.^bg , Yousef, M.^bg , Adam, M.^bh , Amendola, L.^bh , Bamshad, M.^bh , Beck, A.^bh , Bennett, J.^bh , Berg-Rood, B.^bh , Blue, E.^bh , Boyd, B.^bh , Byers, P.^bh , Chanprasert, S.^bh , Cunningham, M.^bh , Dipple, K.^bh , Doherty, D.^bh , Earl, D.^bh , Glass, I.^bh , Golden-Grant, K.^bh , Hahn, S.^bh , Hing, A.^bh , Hisama, F.M.^bh , Horike-Pyne, M.^bh , Jarvik, G.P.^bh , Jarvik, J.^bh , Jayadev, S.^bh , Lam, C.^bh , Maravilla, K.^bh , Mefford, H.^bh , Merritt, J.L.^bh , Mirzaa, G.^bh , Nickerson, D.^bh , Raskind, W.^bh , Rosenwasser, N.^bh , Scott, C.R.^bh , Sun, A.^bh , Sybert, V.^bh , Wallace, S.^bh , Wener, M.^bh , Wenger, T.^bh , Ashley, E.A.^bi , Bejerano, G.^bi , Bernstein, J.A.^bi , Bonner, D.^bi , Coakley, T.R.^bi , Fernandez, L.^bi , Fisher, P.G.^bi , Fresard, L.^bi , Hom, J.^bi , Huang, Y.^bi , Kohler, J.N.^bi , Kravets, E.^bi , Majcherska, M.M.^bi , Martin, B.A.^bi , Marwaha, S.^bi , McCormack, C.E.^bi , Raja, A.N.^bi , Reuter, C.M.^bi , Ruzhnikov, M.^bi , Sampson, J.B.^bi , Smith, K.S.^bi , Sutton, S.^bi , Tabor, H.K.^bi , Tucker, B.M.^bi , Wheeler, M.T.^bi , Zastrow, D.B.^bi , Zhao, C.^bi , Byrd, W.E.^bj , Crouse, A.B.^bj , Might, M.^bj , Nakano-Okuno, M.^bj , Whitlock, J.^bj , Brown, G.^bk , Butte, M.J.^bk , Dell’Angelica, E.C.^bk , Dorrani, N.^bk , Douine, E.D.^bk , Fogel, B.L.^bk , Gutierrez, I.^bk , Huang, A.^bk , Krakow, D.^bk , Lee, H.^bk , Loo, S.K.^bk , Mak, B.C.^bk , Martin, M.G.^bk , Martínez-Agosto, J.A.^bk , McGee, E.^bk , Nelson, S.F.^bk , Nieves-Rodriguez, S.^bk , Palmer, C.G.S.^bk , Papp, J.C.^bk , Parker, N.H.^bk , Renteria, G.^bk , Signer, R.H.^bk , Sinsheimer, J.S.^bk , Wan, J.^bk , Wang, L.-K.^bk , Perry, K.W.^bk , Woods, J.D.^bk , Alvey, J.^bl , Andrews, A.^bl , Bale, J.^bl , Bohnsack, J.^bl , Botto, L.^bl , Carey, J.^bl , Pace, L.^bl , Longo, N.^bl , Marth, G.^bl , Moretti, P.^bl , Quinlan, A.^bl , Velinder, M.^bl , Viskochil, D.^bl , Bayrak-Toydemir, P.^bm , Mao, R.^bm , Westerfield, M.^bn , Bican, A.^bo , Brokamp, E.^bo , Duncan, L.^bo , Hamid, R.^bo , Kennedy, J.^bo , Kozuira, M.^bo , Newman, J.H.^bo , PhillipsIII, J.A.^bo , Rives, L.^bo , Robertson, A.K.^bo , Solem, E.^bo , Cogan, J.D.^bo , Cole, F.S.^bp , Hayes, N.^bp , Kiley, D.^bp , Sisco, K.^bp , Wambach, J.^bp , Wegner, D.^bp , Baldridge, D.^bp , Pak, S.^bp , Schedl, T.^bp , Shin, J.^bp , Solnica-Krezel, L.^bp , Rush, E.^ap aq ar , Pitt, G.^an , Au, P.Y.B.^as , Shashi, V.^c , Undiagnosed Diseases Network^bq

^a Division of Genetics and Genomics, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, United States
^b Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
^c Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC, United States
^d Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
^e Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
^f Institute for Genomic Medicine, Columbia University Medical Center, New York, NY, United States
^g Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland
^h Division of Genetic Medicine, Lausanne University Hospital, Lausanne, Switzerland
ⁱ Pediatric Neurology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Hahsomer, Israel
^j Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
^k CHU de Poitiers, Service de Génétique, EA3808 NEUVACOD, Poitiers, France
^l Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
^m CHU d’Angers, Service de Pédiatrie, EA3808 NEUVACOD, Angers, France
ⁿ Pediatric Cardiology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Hahsomer, Israel
^o Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, United States
^p Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital, University of Cape Town, Cape Town, SA, South Africa
^q Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^r Service de Génétique Moléculaire et Génomique, CHU, Rennes, France
^s University of Rennes, CNRS, IGDR, UMR 6290, Rennes, France
^t The Danek Gertner Insitute of Human Genetics, Sheba Medical Center, Tel-Hahsomer, Israel
^u Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Hahsomer, Israel
^v Center for Pediatric Genomic Medicine, Children’s Mercy Hospital, Kansas City, MO, United States
^w Rare Diseases and Medical Genetic Unit, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
^x Pediatric Neurology, Lausanne University Hospital, Lausanne, Switzerland
^y Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands
^z Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neurosciences and Neurorehabilitation, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
^aa Service de Génétique Clinique, Centre de référence “Maladies Rares” Anomalies du développement CLAD-Ouest, Hôpital SUD, Échirolles, France
^ab Center for Mendelian Genomics and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, United States
^ac Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^ad Instituto de Genética Médica y Molecular (INGEMM), Hospital Universitario La Paz, IdiPAZ, CIBERER, ISCIII, Madrid, Spain
^ae Cincinnati Children’s Hospital and Medical Center Cincinnati, Cincinnati, OH, United States
^af University of Cincinnati College of Medicine Cincinnati, Cincinnati, OH, United States
^ag Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland
^ah Department of Ophthalmology, University of Basel, Basel, Switzerland
^ai Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^aj Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
^ak Institute of Rare Diseases, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Hahsomer, Israel
^al Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^am Service de Génétique Médicale, CHU Nantes, France; Inserm, CNRS, Univ Nantes, l’institut du thorax, Nantes, France
^an Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY, United States
^ao The Saxon Epilepsy Center Kleinwachau, Radeberg, Germany
^ap The Children’s Mercy Hospital, Kansas City, MO, United States
^aq Department of Pediatrics University of Missouri—Kansas City, Kansas City, MO, United States
^ar Department of Internal Medicine, University of Kansas Medical Center, Kansas City, MO, United States
^as Alberta Children’s Hospital Research Institute, Department of Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
^at BCM Clinical, Houston, TX, United States
^au BCM MOSC, Houston, TX, United States
^av BCM Sequencing, Houston, TX, United States
^aw CHOP, Philadelphia, PA, United States
^ax Columbia University, New York, NY, United States
^ay Duke University, Durham, NC, United States
^az Harvard University, Boston, MA, United States
^ba Harvard CC, Boston, MA, United States
^bb Mayo Clinic, Rochester, MN, United States
^bc Miami, Miami, FL, United States
^bd NIH, Bethesda, MD, United States
^be NIH UDP, Bethesda, MD, United States
^bf NIH UDP, DRM, Bethesda, MD, United States
^bg NIH UDP, NHGRI, Bethesda, MD, United States
^bh PNW, Seattle, WA, United States
^bi Stanford, Stanford, CA, United States
^bj UAB CC, Birmingham, AL, United States
^bk UCLA, Los Angeles, CA, United States
^bl University of Utah, Salt Lake City, UT, United States
^bm University of Utah/ARUP, Salt Lake City, UT, United States
^bn UO MOSC, Eugene, OR, United States
^bo Vanderbilt, Nashville, TN, United States
^bp Washington University Clinical, St. Louis, MO, United States

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. © 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.

Funding details
B2017/BMD-3721
U01HG007709
National Institutes of HealthNIH
National Human Genome Research InstituteNHGRIR01 HG009141, UM1 HG008900
Duke University1RO1HD090132-01A1
Cornell UniversityCU
Baylor College of MedicineU01HG007672
Rare Disease FoundationRDF
Canadian Institutes of Health ResearchCIHRMOP-97988
University of AlbertaUofA