Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders

Julie A Jurgens; Brenda J Barry; Wai-Man Chan; Sarah MacKinnon; Mary C Whitman; Paola M Matos Ruiz; Brandon M Pratt; Eleina M England; Lynn Pais; Gabrielle Lemire; Emily Groopman; Carmen Glaze; Kathryn A Russell; Moriel Singer-Berk; Silvio Alessandro Di Gioia; Arthur S Lee; Caroline Andrews; Sherin Shaaban; Megan M Wirth; Sarah Bekele; Melissa Toffoloni; Victoria R Bradford; Emma E Foster; Lindsay Berube; Cristina Rivera-Quiles; Fiona M Mensching; Alba Sanchis-Juan; Jack M Fu; Isaac Wong; Xuefang Zhao; Michael W Wilson; Ben Weisburd; Monkol Lek; Ocular CCDD Phenotyping Consortium; Harrison Brand; Michael E Talkowski; Daniel G MacArthur; Anne O'Donnell-Luria; Caroline D Robson; David G Hunter; Elizabeth C Engle

doi:10.1016/j.gim.2024.101216

Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders

Genet Med. 2024 Jul 17:101216. doi: 10.1016/j.gim.2024.101216. Online ahead of print.

Authors

Julie A Jurgens¹, Brenda J Barry², Wai-Man Chan³, Sarah MacKinnon⁴, Mary C Whitman⁵, Paola M Matos Ruiz⁶, Brandon M Pratt⁶, Eleina M England⁷, Lynn Pais⁷, Gabrielle Lemire⁷, Emily Groopman⁷, Carmen Glaze⁸, Kathryn A Russell⁸, Moriel Singer-Berk⁸, Silvio Alessandro Di Gioia⁹, Arthur S Lee¹, Caroline Andrews⁶, Sherin Shaaban¹⁰, Megan M Wirth⁶, Sarah Bekele⁶, Melissa Toffoloni⁶, Victoria R Bradford⁶, Emma E Foster⁶, Lindsay Berube⁶, Cristina Rivera-Quiles⁶, Fiona M Mensching⁶, Alba Sanchis-Juan¹¹, Jack M Fu¹¹, Isaac Wong¹¹, Xuefang Zhao¹¹, Michael W Wilson⁸, Ben Weisburd⁸, Monkol Lek⁸; Ocular CCDD Phenotyping Consortium; Harrison Brand¹², Michael E Talkowski¹³, Daniel G MacArthur⁸, Anne O'Donnell-Luria¹⁴, Caroline D Robson¹⁵, David G Hunter⁴, Elizabeth C Engle¹⁶

Collaborators

Ocular CCDD Phenotyping Consortium:
Hugo Abarca-Barriga, Christiane Al-Haddad, Jeffrey L Berman, Erick D Bothun, Jenina Capasso, Oscar Francisco Chacon-Camacho, Lan Chang, Stephen P Christiansen, Maria Laura Ciccarelli, Monique Cordonnier, Gerald F Cox, Cynthia J Curry, Linda R Dagi, Thomas Lee Dahm, Karen L David, Bradley V Davitt, Teresa De Berardinis, Joseph L Demer, Julie Désir, Fabiana D'Esposito, Arlene V Drack, Eric Eggenberger, James E Elder, Alexandra T Elliott, K David Epley, Hagit Baris Feldman, Carlos R Ferreira, Maree P Flaherty, Anne B Fulton, Christina Gerth-Kahlert, Irene Gottlob, Stephen Grill, Dorothy J Halliday, Frank Hanisch, Eleanor Hay, Gena Heidary, Christopher Holder, Jonathan C Horton, Alessandro Iannaccone, Sherwin J Isenberg, Suzanne C Johnston, Alon Kahana, James A Katowitz, Melanie Kazlas, Natalie C Kerr, Virginia Kimonis, Melissa W Ko, Feray Koc, Dorte Ancher Larsen, Guillermo Lay-Son, Danielle M Ledoux, Alex V Levin, Richard L Levy, Christopher J Lyons, David A Mackey, Adriano Magli, Iason S Mantagos, Candice Marti, Isabelle Maystadt, Fiona McKenzie, Manoj P Menezes, Claudia N Mikail, David T Miller, Kathryn Bisceglia Miller, Monte D Mills, Kaori Miyana, H U Moller, Lisa Mullineaux, Julie K Nishimura, A Gwendolyn Noble, Pramod Kumar Pandey, Piero Pavone, Johann Penzien, Robert Petersen, James A Phalen, Annapurna Poduri, Claudia R Polo, Lev Prasov, Feliciano J Ramos, Maria Ramos-Caceres, Richard M Robb, Béatrice Rossillion, Mustafa Sahin, Harvey S Singer, Lois E H Smith, Jeffrey A Sorkin, Janet S Soul, Sandra E Staffieri, Heather J Stalker, Steven F Stasheff, Sonya Strassberg, Mitchell B Strominger, Deepa Ajay Taranath, Ioan Talfryn Thomas, Elias I Traboulsi, Maria Cristina Ugrin, Deborah K VanderVeen, Andrea L Vincent, Marlene C Vogel G, Bettina Wabbels, Agnes M F Wong, C Geoffrey Woods, Carolyn Wu, Edward Yang, Alison Yeung, Terri L Young, Juan C Zenteno, Alexandra A Zubcov-Iwantscheff, Johan Zwaan

Affiliations

¹ F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA; Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
² Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
³ F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA; Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
⁴ Department of Ophthalmology, Boston Children's Hospital, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
⁵ F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA; Department of Ophthalmology, Boston Children's Hospital, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
⁶ Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
⁷ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁸ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁹ F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA; Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Regeneron Pharmaceuticals, Tarrytown, NY, 10591, USA.
¹⁰ F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA; Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA; Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA.
¹¹ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹² Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, MA, USA.
¹³ Department of Neurology, Harvard Medical School, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁵ Division of Neuroradiology, Department of Radiology, Boston Children's Hospital, Boston, MA, USA; Department of Radiology, Harvard Medical School, Boston, MA, USA.
¹⁶ F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA; Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA; Department of Ophthalmology, Boston Children's Hospital, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA. Electronic address: elizabeth.engle@childrens.harvard.edu.

PMID: 39033378
DOI: 10.1016/j.gim.2024.101216

Abstract

Purpose: To identify genetic etiologies and genotype/phenotype associations for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs).

Methods: We coupled phenotyping with exome or genome sequencing of 467 probands (550 affected and 1108 total individuals) with genetically unsolved oCCDDs, integrating analyses of pedigrees, human and animal model phenotypes, and de novo variants to identify rare candidate single nucleotide variants, insertion/deletions, and structural variants disrupting protein-coding regions. Prioritized variants were classified for pathogenicity and evaluated for genotype/phenotype correlations.

Results: Analyses elucidated phenotypic subgroups, identified pathogenic/likely pathogenic variant(s) in 43/467 probands (9.2%), and prioritized variants of uncertain significance in 70/467 additional probands (15.0%). These included known and novel variants in established oCCDD genes, genes associated with syndromes that sometimes include oCCDDs (e.g., MYH10, KIF21B, TGFBR2, TUBB6), genes that fit the syndromic component of the phenotype but had no prior oCCDD association (e.g., CDK13, TGFB2), genes with no reported association with oCCDDs or the syndromic phenotypes (e.g., TUBA4A, KIF5C, CTNNA1, KLB, FGF21), and genes associated with oCCDD phenocopies that had resulted in misdiagnoses.

Conclusion: This study suggests that unsolved oCCDDs are clinically and genetically heterogeneous disorders often overlapping other Mendelian conditions and nominates many candidates for future replication and functional studies.

Keywords: Congenital cranial dysinnervation disorder; cranial nerve; eye movement; incomitant strabismus; sequencing.

Grants and funding

R01 EY032539/EY/NEI NIH HHS/United States