Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders.

Congenital cranial dysinnervation disorder cranial nerve eye movement incomitant strabismus sequencing

Journal

Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831

Informations de publication

Date de publication:
17 Jul 2024
Historique:
received: 22 03 2024
revised: 10 07 2024
accepted: 12 07 2024
medline: 21 7 2024
pubmed: 21 7 2024
entrez: 21 7 2024
Statut: aheadofprint

Résumé

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

Identifiants

DOI: 10.1016/j.gim.2024.101216 PMID: 39033378
pubmed: 39033378
pii: S1098-3600(24)00150-3
doi: 10.1016/j.gim.2024.101216
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

101216

Investigateurs

Hugo Abarca-Barriga (H)
Christiane Al-Haddad (C)
Jeffrey L Berman (JL)
Erick D Bothun (ED)
Jenina Capasso (J)
Oscar Francisco Chacon-Camacho (OF)
Lan Chang (L)
Stephen P Christiansen (SP)
Maria Laura Ciccarelli (ML)
Monique Cordonnier (M)
Gerald F Cox (GF)
Cynthia J Curry (CJ)
Linda R Dagi (LR)
Thomas Lee Dahm (T)
Karen L David (KL)
Bradley V Davitt (BV)
Teresa De Berardinis (T)
Joseph L Demer (JL)
Julie Désir (J)
Fabiana D'Esposito (F)
Arlene V Drack (AV)
Eric Eggenberger (E)
James E Elder (JE)
Alexandra T Elliott (AT)
K David Epley (KD)
Hagit Baris Feldman (HB)
Carlos R Ferreira (CR)
Maree P Flaherty (MP)
Anne B Fulton (AB)
Christina Gerth-Kahlert (C)
Irene Gottlob (I)
Stephen Grill (S)
Dorothy J Halliday (DJ)
Frank Hanisch (F)
Eleanor Hay (E)
Gena Heidary (G)
Christopher Holder (C)
Jonathan C Horton (JC)
Alessandro Iannaccone (A)
Sherwin J Isenberg (SJ)
Suzanne C Johnston (SC)
Alon Kahana (A)
James A Katowitz (JA)
Melanie Kazlas (M)
Natalie C Kerr (NC)
Virginia Kimonis (V)
Melissa W Ko (MW)
Feray Koc (F)
Dorte Ancher Larsen (DA)
Guillermo Lay-Son (G)
Danielle M Ledoux (DM)
Alex V Levin (AV)
Richard L Levy (RL)
Christopher J Lyons (CJ)
David A Mackey (DA)
Adriano Magli (A)
Iason S Mantagos (IS)
Candice Marti (C)
Isabelle Maystadt (I)
Fiona McKenzie (F)
Manoj P Menezes (MP)
Claudia N Mikail (CN)
David T Miller (DT)
Kathryn Bisceglia Miller (KB)
Monte D Mills (MD)
Kaori Miyana (K)
H U Moller (HU)
Lisa Mullineaux (L)
Julie K Nishimura (JK)
A Gwendolyn Noble (AG)
Pramod Kumar Pandey (PK)
Piero Pavone (P)
Johann Penzien (J)
Robert Petersen (R)
James A Phalen (JA)
Annapurna Poduri (A)
Claudia R Polo (CR)
Lev Prasov (L)
Feliciano J Ramos (FJ)
Maria Ramos-Caceres (M)
Richard M Robb (RM)
Béatrice Rossillion (B)
Mustafa Sahin (M)
Harvey S Singer (HS)
Lois E H Smith (LEH)
Jeffrey A Sorkin (JA)
Janet S Soul (JS)
Sandra E Staffieri (SE)
Heather J Stalker (HJ)
Steven F Stasheff (SF)
Sonya Strassberg (S)
Mitchell B Strominger (MB)
Deepa Ajay Taranath (DA)
Ioan Talfryn Thomas (IT)
Elias I Traboulsi (EI)
Maria Cristina Ugrin (MC)
Deborah K VanderVeen (DK)
Andrea L Vincent (AL)
Marlene C Vogel G (MC)
Bettina Wabbels (B)
Agnes M F Wong (AMF)
C Geoffrey Woods (CG)
Carolyn Wu (C)
Edward Yang (E)
Alison Yeung (A)
Terri L Young (TL)
Juan C Zenteno (JC)
Alexandra A Zubcov-Iwantscheff (AA)
Johan Zwaan (J)

Informations de copyright

Copyright © 2024. Published by Elsevier Inc.

Auteurs

Julie A Jurgens (JA)

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.

Brenda J Barry (BJ)

Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.

Wai-Man Chan (WM)

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.

Sarah MacKinnon (S)

Department of Ophthalmology, Boston Children's Hospital, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.

Mary C Whitman (MC)

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.

Paola M Matos Ruiz (PM)

Department of Neurology, Boston Children's Hospital, Boston, MA, USA.

Brandon M Pratt (BM)

Department of Neurology, Boston Children's Hospital, Boston, MA, USA.

Eleina M England (EM)

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.

Lynn Pais (L)

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.

Gabrielle Lemire (G)

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.

Emily Groopman (E)

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.

Carmen Glaze (C)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Kathryn A Russell (KA)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Moriel Singer-Berk (M)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Silvio Alessandro Di Gioia (SA)

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.

Arthur S Lee (AS)

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.

Caroline Andrews (C)

Department of Neurology, Boston Children's Hospital, Boston, MA, USA.

Sherin Shaaban (S)

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.

Megan M Wirth (MM)

Department of Neurology, Boston Children's Hospital, Boston, MA, USA.

Sarah Bekele (S)

Department of Neurology, Boston Children's Hospital, Boston, MA, USA.

Melissa Toffoloni (M)

Department of Neurology, Boston Children's Hospital, Boston, MA, USA.

Victoria R Bradford (VR)

Department of Neurology, Boston Children's Hospital, Boston, MA, USA.

Emma E Foster (EE)

Department of Neurology, Boston Children's Hospital, Boston, MA, USA.

Lindsay Berube (L)

Department of Neurology, Boston Children's Hospital, Boston, MA, USA.

Cristina Rivera-Quiles (C)

Department of Neurology, Boston Children's Hospital, Boston, MA, USA.

Fiona M Mensching (FM)

Department of Neurology, Boston Children's Hospital, Boston, MA, USA.

Alba Sanchis-Juan (A)

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.

Jack M Fu (JM)

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.

Isaac Wong (I)

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.

Xuefang Zhao (X)

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.

Michael W Wilson (MW)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Ben Weisburd (B)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Monkol Lek (M)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Harrison Brand (H)

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.

Michael E Talkowski (ME)

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.

Daniel G MacArthur (DG)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Anne O'Donnell-Luria (A)

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.

Caroline D Robson (CD)

Division of Neuroradiology, Department of Radiology, Boston Children's Hospital, Boston, MA, USA; Department of Radiology, Harvard Medical School, Boston, MA, USA.

David G Hunter (DG)

Department of Ophthalmology, Boston Children's Hospital, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.

Elizabeth C Engle (EC)

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.

Classifications MeSH