Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders

• DOI: 10.1016/j.gim.2024.101216
• Publication Date: 2024-07-18T01:20:28Z
• Authors: 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...; Arthur S. Lee; Caroline Andrews; Sherin Shaaban; Megan M. Wirth; Sarah Bekele; Melissa Toffoloni; Victoria R. Bradford; Emma E. Foster; Lindsay Berube; Cristina Rivera-Q...; Fiona M. Mensching; Alba Sanchis-Juan; Jack M. Fu; Isaac Wong; Xuefang Zhao; Michael W. Wilson; Ben Weisburd; Monkol Lek; Hugo Abarca-Barriga; Christiane Al-Haddad; Jeffrey L. Berman; Erick D. Bothun; Jenina Capasso; Oscar Francisco C...; Lan Chang; Stephen P. Christ...; Maria Laura Cicca...; 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-K...; Irene Gottlob; Stephen Grill; Dorothy J. Halliday; Frank Hanisch; Eleanor Hay; Gena Heidary; Christopher Holder; Jonathan C. Horton; Alessandro Iannac...; 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...; 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. Strom...; Deepa Ajay Taranath; Ioan Talfryn Thomas; Elias I. Traboulsi; Maria Cristina Ugrin; Deborah K. Vander...; 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. Zubc...; Johan Zwaan; Harrison Brand; Michael E. Talkowski; Daniel G. MacArthur; Anne O’Donnell-Luria; Caroline D. Robson; David G. Hunter; Elizabeth C. Engle
• Keywords: Phenocopy; Proband; Mendelian inheritance; Pedigree chart; Genome-wide Association Study; Candidate gene; Exome; Medical genetics

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 1108 total individuals) genetically oCCDDs, integrating analyses pedigrees, human animal model phenotypes, de novo variants to rare candidate single nucleotide variants, insertion/deletions, structural disrupting protein-coding regions.Prioritized were classified pathogenicity evaluated correlations. Results:Analyses elucidated phenotypic subgroups, identified pathogenic/likely pathogenic variant(s) in 43/467 (9.2%), prioritized uncertain significance 70/467 additional (15.0%).These included known novel established oCCDD genes, genes associated syndromes that sometimes include oCCDDs (e.g., MYH10, KIF21B, TGFBR2, TUBB6), fit the syndromic component phenotype but had no prior association CDK13, TGFB2), reported phenotypes TUBA4A, KIF5C, CTNNA1, KLB, FGF21), phenocopies resulted misdiagnoses. Conclusion:This study suggests are clinically heterogeneous often overlapping other Mendelian conditions nominates many candidates future replication functional studies.