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Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders.
Jurgens, Julie A; Barry, Brenda J; Chan, Wai-Man; MacKinnon, Sarah; Whitman, Mary C; Matos Ruiz, Paola M; Pratt, Brandon M; England, Eleina M; Pais, Lynn; Lemire, Gabrielle; Groopman, Emily; Glaze, Carmen; Russell, Kathryn A; Singer-Berk, Moriel; Di Gioia, Silvio Alessandro; Lee, Arthur S; Andrews, Caroline; Shaaban, Sherin; Wirth, Megan M; Bekele, Sarah; Toffoloni, Melissa; Bradford, Victoria R; Foster, Emma E; Berube, Lindsay; Rivera-Quiles, Cristina; Mensching, Fiona M; Sanchis-Juan, Alba; Fu, Jack M; Wong, Isaac; Zhao, Xuefang; Wilson, Michael W; Weisburd, Ben; Lek, Monkol; Brand, Harrison; Talkowski, Michael E; MacArthur, Daniel G; O'Donnell-Luria, Anne; Robson, Caroline D; Hunter, David G; Engle, Elizabeth C.
  • 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.
  • Barry BJ; Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  • 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
  • MacKinnon S; Department of Ophthalmology, Boston Children's Hospital, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
  • 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.
  • Matos Ruiz PM; Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
  • Pratt BM; Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
  • 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.
  • 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.
  • 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.
  • 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.
  • Glaze C; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Russell KA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Singer-Berk M; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 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, Tarr
  • 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.
  • Andrews C; Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
  • 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
  • Wirth MM; Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
  • Bekele S; Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
  • Toffoloni M; Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
  • Bradford VR; Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
  • Foster EE; Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
  • Berube L; Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
  • Rivera-Quiles C; Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
  • Mensching FM; Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
  • 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.
  • 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.
  • 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.
  • 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.
  • Wilson MW; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Weisburd B; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Lek M; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 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.
  • 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.
  • MacArthur DG; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 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.
  • Robson CD; Division of Neuroradiology, Department of Radiology, Boston Children's Hospital, Boston, MA, USA; Department of Radiology, Harvard Medical School, Boston, MA, USA.
  • Hunter DG; Department of Ophthalmology, Boston Children's Hospital, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
  • 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
Genet Med ; : 101216, 2024 Jul 17.
Article en En | MEDLINE | ID: mdl-39033378
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.
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Texto completo: 1 Banco de datos: MEDLINE Idioma: En Año: 2024 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Idioma: En Año: 2024 Tipo del documento: Article