Journal article
Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders
Genetics in medicine, Vol.27(4), 101216
04/2025
DOI: 10.1016/j.gim.2024.101216
PMCID: PMC11739428
PMID: 39033378
Abstract
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.
Details
- Title: Subtitle
- Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders
- Creators
- Julie A. Jurgens - Broad InstituteArlene V. DrackOcular CCDD Phenotyping ConsortiumBrenda J. Barry - Boston Children's HospitalWai-Man Chan - Boston Children's HospitalSarah MacKinnon - Boston Children's HospitalMary C. Whitman - Boston Children's HospitalPaola M. Matos Ruiz - Boston Children's HospitalBrandon M. Pratt - Boston Children's HospitalEleina M. England - Broad InstituteLynn Pais - Broad InstituteGabrielle Lemire - Broad InstituteEmily Groopman - Broad InstituteCarmen Glaze - Broad InstituteKathryn A. Russell - Broad InstituteMoriel Singer-Berk - Broad InstituteSilvio Alessandro Di Gioia - RegeneronArthur S. Lee - Broad InstituteCaroline Andrews - Boston Children's HospitalSherin Shaaban - Boston Children's HospitalMegan M. Wirth - Boston Children's HospitalSarah Bekele - Boston Children's HospitalMelissa Toffoloni - Boston Children's HospitalVictoria R. Bradford - Boston Children's HospitalEmma E. Foster - Boston Children's HospitalLindsay Berube - Boston Children's HospitalCristina Rivera-Quiles - Boston Children's HospitalFiona M. Mensching - Boston Children's HospitalAlba Sanchis-Juan - Broad InstituteJack M. Fu - Broad InstituteIsaac Wong - Broad InstituteXuefang Zhao - Broad InstituteMichael W. Wilson - Broad InstituteBen Weisburd - Broad InstituteMonkol Lek - Broad InstituteHugo Abarca-BarrigaChristiane Al-HaddadJeffrey L. BermanOscar Francisco Chacon-CamachoErick D. BothunJenina CapassoLan ChangStephen P. ChristiansenMaria Laura CiccarelliMonique CordonnierGerald F. CoxCynthia J. CurryLinda R. DagiThomas Lee DahmKaren L. DavidBradley V. DavittTeresa De BerardinisJoseph L. DemerJulie DésirFabiana D’EspositoEric EggenbergerJames E. ElderAlexandra T. ElliottK. David EpleyHagit Baris FeldmanCarlos R. FerreiraMaree P. FlahertyAnne B. FultonChristina Gerth-KahlertIrene GottlobStephen GrillDorothy J. HallidayFrank HanischEleanor HayGena HeidaryChristopher HolderJonathan C. HortonAlessandro IannacconeSherwin J. IsenbergSuzanne C. JohnstonAlon KahanaJames A. KatowitzMelanie KazlasNatalie C. KerrVirginia KimonisMelissa W. KoFeray KocDorte Ancher LarsenGuillermo Lay-SonDanielle M. LedouxAlex V. LevinRichard L. LevyChristopher J. LyonsDavid A. MackeyAdriano MagliIason S. MantagosCandice MartiIsabelle MaystadtFiona McKenzieManoj P. MenezesClaudia N. MikailDavid T. MillerKathryn Bisceglia MillerMonte D. MillsKaori MiyanaH.U. MollerLisa MullineauxJulie K. NishimuraA. Gwendolyn NoblePramod Kumar PandeyPiero PavoneJohann PenzienRobert PetersenJames A. PhalenAnnapurna PoduriClaudia R. PoloLev PrasovFeliciano J. RamosMaria Ramos-CaceresRichard M. RobbBéatrice RossillionMustafa SahinHarvey S. SingerLois E.H. SmithJeffrey A. SorkinJanet S. SoulSandra E. StaffieriHeather J. StalkerSteven F. StasheffSonya StrassbergMitchell B. StromingerDeepa Ajay TaranathIoan Talfryn ThomasElias I. TraboulsiMaria Cristina UgrinDeborah K. VanderVeenAndrea L. VincentMarlene C. Vogel GBettina WabbelsAgnes M.F. WongC. Geoffrey WoodsCarolyn WuEdward YangAlison YeungTerri L. YoungJuan C. ZentenoAlexandra A. Zubcov-IwantscheffJohan ZwaanHarrison Brand - Massachusetts General HospitalMichael E. Talkowski - Broad InstituteDaniel G. MacArthur - Broad InstituteAnne O’Donnell-Luria - Broad InstituteCaroline D. Robson - Boston Children's HospitalDavid G. Hunter - Boston Children's HospitalElizabeth C. Engle - Harvard University
- Resource Type
- Journal article
- Publication Details
- Genetics in medicine, Vol.27(4), 101216
- DOI
- 10.1016/j.gim.2024.101216
- PMID
- 39033378
- PMCID
- PMC11739428
- NLM abbreviation
- Genet Med
- ISSN
- 1098-3600
- eISSN
- 1530-0366
- Publisher
- Elsevier Inc
- Language
- English
- Electronic publication date
- 07/17/2024
- Date published
- 04/2025
- Academic Unit
- Stead Family Department of Pediatrics; Ophthalmology and Visual Sciences
- Record Identifier
- 9984687779802771
Metrics
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