Genetic Studies of Strabismus, Congenital Cranial Dysinnervation Disorders (CCDDs), and Their Associated Anomalies

NCT ID: NCT03059420

Last Updated: 2026-02-11

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 20000 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2004-02-01
• Study Completion Date: 2030-01-31

Brief Summary

The purpose of this study is to identify genes associated with impaired development and function of the cranial nerves and brainstem, which may result in misalignment of the eyes (strabismus) and related conditions.

Detailed Description

If left untreated or unrecognized, strabismus or misalignment of the eyes, can impair the development of normal vision and is recognized to be an inherited trait in some families. The Engle Lab has investigated the genetics of complex and common strabismus and eyelid movement disorders for over 10 years and the lab's interests have expanded to include Congenital Cranial Dysinnervation Disorders (CCDDs) which are neurological disorders affecting one or more of the 12 cranial nerves. Cranial nerves control bodily functions such as movement of the eyes, transmission of visual information, smell, facial sensation, facial expression, blinking, hearing, balance, taste, chewing and swallowing.

Based on genetic studies on individuals with eye movement and eyelid disorders, the lab learned that some individuals have additional ocular defects, vascular, limb and other abnormalities. In addition, in some families relatives who carry the gene mutation may manifest the familial syndrome by having only some additional features but NOT the oculomotility disorder. Therefore, to gain greater understanding of the spectrum of the disorders being investigated, we may also enroll individuals without eye movement or lid defects who have symptoms associated with mutations in congenital cranial dysinnervation disorder (CCDD) genes.

Conditions

Congenital Fibrosis of Extraocular Muscles; Duane Retraction Syndrome; Duane Radial Ray Syndrome; Mobius Syndrome; Brown Syndrome; Marcus Gunn Syndrome; Strabismus Congenital; Horizontal Gaze Palsy; Horizontal Gaze Palsy With Progressive Scoliosis; Facial Palsy; Facial Paresis, Hereditary, Congenital; Third Nerve Palsy; Fourth Nerve Palsy; Sixth Nerve Palsy; Synkinesis; Ocular Motility Disorders; Levator-Medial Rectus Synkinesis; Athabaskan Brainstem Dysgenesis; Tongue Paralysis; Ninth Nerve Disorder; Fifth Nerve Palsy; Seventh Nerve Palsy; Eleventh Nerve Disorder; Twelfth Nerve Disorder; Vagus Nerve Paralysis; Moebius Sequence

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: OTHER

Eligibility Criteria

Inclusion Criteria

• The Engle Lab is very interested in enrolling individuals with congenital conditions related to eye movement, cranial nerve and brainstem-based dysfunction, often broadly referred to as congenital cranial dysinnervation disorders (CCDDs).

Exclusion Criteria

• Individuals with cranial nerve disorders associated with known disorders, such as Saethre-Chotzen associated with established genetic mutations, or acquired conditions including trauma, stroke, tumor or spinal cord injuries.

• Minimum Eligible Age: 1 Day
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Howard Hughes Medical Institute

OTHER

Sponsor Role: collaborator

Boston Children's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Elizabeth Engle

Investigator, Howard Hughes Medical Institute; Professor of Neurology and Ophthalmology, Harvard Medical School

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Elizabeth Engle, MD

Role: PRINCIPAL_INVESTIGATOR

Boston Children's Hospital

Locations

Boston Children's Hospital

Boston, Massachusetts, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Brenda J Barry, MS

Role: CONTACT

brenda.barry2@childrens.harvard.edu

617-919-2168

Engle Admin

Role: CONTACT

engle.admin@childrens.harvard.edu

617-919-4030

References

Park JG, Tischfield MA, Nugent AA, Cheng L, Di Gioia SA, Chan WM, Maconachie G, Bosley TM, Summers CG, Hunter DG, Robson CD, Gottlob I, Engle EC. Loss of MAFB Function in Humans and Mice Causes Duane Syndrome, Aberrant Extraocular Muscle Innervation, and Inner-Ear Defects. Am J Hum Genet. 2016 Jun 2;98(6):1220-1227. doi: 10.1016/j.ajhg.2016.03.023. Epub 2016 May 12.

Reference Type: BACKGROUND

PMID: 27181683 (View on PubMed)

Balasubramanian R, Chew S, MacKinnon SE, Kang PB, Andrews C, Chan WM, Engle EC. Expanding the phenotypic spectrum and variability of endocrine abnormalities associated with TUBB3 E410K syndrome. J Clin Endocrinol Metab. 2015 Mar;100(3):E473-7. doi: 10.1210/jc.2014-4107. Epub 2015 Jan 5.

Reference Type: BACKGROUND

PMID: 25559402 (View on PubMed)

MacKinnon S, Oystreck DT, Andrews C, Chan WM, Hunter DG, Engle EC. Diagnostic distinctions and genetic analysis of patients diagnosed with moebius syndrome. Ophthalmology. 2014 Jul;121(7):1461-8. doi: 10.1016/j.ophtha.2014.01.006. Epub 2014 Mar 6.

Reference Type: BACKGROUND

PMID: 24612975 (View on PubMed)

Shaaban S, Ramos-Platt L, Gilles FH, Chan WM, Andrews C, De Girolami U, Demer J, Engle EC. RYR1 mutations as a cause of ophthalmoplegia, facial weakness, and malignant hyperthermia. JAMA Ophthalmol. 2013 Dec;131(12):1532-40. doi: 10.1001/jamaophthalmol.2013.4392.

Reference Type: BACKGROUND

PMID: 24091937 (View on PubMed)

Graeber CP, Hunter DG, Engle EC. The genetic basis of incomitant strabismus: consolidation of the current knowledge of the genetic foundations of disease. Semin Ophthalmol. 2013 Sep-Nov;28(5-6):427-37. doi: 10.3109/08820538.2013.825288.

Reference Type: BACKGROUND

PMID: 24138051 (View on PubMed)

Tischfield MA, Baris HN, Wu C, Rudolph G, Van Maldergem L, He W, Chan WM, Andrews C, Demer JL, Robertson RL, Mackey DA, Ruddle JB, Bird TD, Gottlob I, Pieh C, Traboulsi EI, Pomeroy SL, Hunter DG, Soul JS, Newlin A, Sabol LJ, Doherty EJ, de Uzcategui CE, de Uzcategui N, Collins ML, Sener EC, Wabbels B, Hellebrand H, Meitinger T, de Berardinis T, Magli A, Schiavi C, Pastore-Trossello M, Koc F, Wong AM, Levin AV, Geraghty MT, Descartes M, Flaherty M, Jamieson RV, Moller HU, Meuthen I, Callen DF, Kerwin J, Lindsay S, Meindl A, Gupta ML Jr, Pellman D, Engle EC. Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. Cell. 2010 Jan 8;140(1):74-87. doi: 10.1016/j.cell.2009.12.011.

Reference Type: BACKGROUND

PMID: 20074521 (View on PubMed)

Miyake N, Andrews C, Fan W, He W, Chan WM, Engle EC. CHN1 mutations are not a common cause of sporadic Duane's retraction syndrome. Am J Med Genet A. 2010 Jan;152A(1):215-7. doi: 10.1002/ajmg.a.33168. No abstract available.

Reference Type: BACKGROUND

PMID: 20034095 (View on PubMed)

Di Gioia SA, Connors S, Matsunami N, Cannavino J, Rose MF, Gilette NM, Artoni P, de Macena Sobreira NL, Chan WM, Webb BD, Robson CD, Cheng L, Van Ryzin C, Ramirez-Martinez A, Mohassel P, Leppert M, Scholand MB, Grunseich C, Ferreira CR, Hartman T, Hayes IM, Morgan T, Markie DM, Fagiolini M, Swift A, Chines PS, Speck-Martins CE, Collins FS, Jabs EW, Bonnemann CG, Olson EN; Moebius Syndrome Research Consortium; Carey JC, Robertson SP, Manoli I, Engle EC. A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome. Nat Commun. 2017 Jul 6;8:16077. doi: 10.1038/ncomms16077.

Reference Type: BACKGROUND

PMID: 28681861 (View on PubMed)

Telegrafi A, Webb BD, Robbins SM, Speck-Martins CE, FitzPatrick D, Fleming L, Redett R, Dufke A, Houge G, van Harssel JJT, Verloes A, Robles A, Manoli I, Engle EC; Moebius Syndrome Research Consortium; Jabs EW, Valle D, Carey J, Hoover-Fong JE, Sobreira NLM. Identification of STAC3 variants in non-Native American families with overlapping features of Carey-Fineman-Ziter syndrome and Moebius syndrome. Am J Med Genet A. 2017 Oct;173(10):2763-2771. doi: 10.1002/ajmg.a.38375. Epub 2017 Aug 4.

Reference Type: BACKGROUND

PMID: 28777491 (View on PubMed)

Whitman MC, Miyake N, Nguyen EH, Bell JL, Matos Ruiz PM, Chan WM, Di Gioia SA, Mukherjee N, Barry BJ, Bosley TM, Khan AO, Engle EC. Decreased ACKR3 (CXCR7) function causes oculomotor synkinesis in mice and humans. Hum Mol Genet. 2019 Sep 15;28(18):3113-3125. doi: 10.1093/hmg/ddz137.

Reference Type: BACKGROUND

PMID: 31211835 (View on PubMed)

Grant PE, Im K, Ahtam B, Laurentys CT, Chan WM, Brainard M, Chew S, Drottar M, Robson CD, Drmic I, Engle EC. Altered White Matter Organization in the TUBB3 E410K Syndrome. Cereb Cortex. 2019 Jul 22;29(8):3561-3576. doi: 10.1093/cercor/bhy231.

Reference Type: BACKGROUND

PMID: 30272120 (View on PubMed)

Shaaban S, MacKinnon S, Andrews C, Staffieri SE, Maconachie GDE, Chan WM, Whitman MC, Morton SU, Yazar S, MacGregor S, Elder JE, Traboulsi EI, Gottlob I, Hewitt AW; Strabismus Genetics Research Consortium; Hunter DG, Mackey DA, Engle EC. Genome-Wide Association Study Identifies a Susceptibility Locus for Comitant Esotropia and Suggests a Parent-of-Origin Effect. Invest Ophthalmol Vis Sci. 2018 Aug 1;59(10):4054-4064. doi: 10.1167/iovs.18-24082.

Reference Type: BACKGROUND

PMID: 30098192 (View on PubMed)

Di Gioia SA, Shaaban S, Tuysuz B, Elcioglu NH, Chan WM, Robson CD, Ecklund K, Gilette NM, Hamzaoglu A, Tayfun GA, Traboulsi EI, Engle EC. Recessive MYF5 Mutations Cause External Ophthalmoplegia, Rib, and Vertebral Anomalies. Am J Hum Genet. 2018 Jul 5;103(1):115-124. doi: 10.1016/j.ajhg.2018.05.003. Epub 2018 Jun 7.

Reference Type: BACKGROUND

PMID: 29887215 (View on PubMed)

Thomas MG, Maconachie GDE, Constantinescu CS, Chan WM, Barry B, Hisaund M, Sheth V, Kuht HJ, Dineen RA, Harieaswar S, Engle EC, Gottlob I. Congenital monocular elevation deficiency associated with a novel TUBB3 gene variant. Br J Ophthalmol. 2020 Apr;104(4):547-550. doi: 10.1136/bjophthalmol-2019-314293. Epub 2019 Jul 13.

Reference Type: BACKGROUND

PMID: 31302631 (View on PubMed)

Heidary G, Mackinnon S, Elliott A, Barry BJ, Engle EC, Hunter DG. Outcomes of strabismus surgery in genetically confirmed congenital fibrosis of the extraocular muscles. J AAPOS. 2019 Oct;23(5):253.e1-253.e6. doi: 10.1016/j.jaapos.2019.05.018. Epub 2019 Sep 18.

Reference Type: BACKGROUND

PMID: 31541710 (View on PubMed)

Sadeghi N, Hutchinson E, Van Ryzin C, FitzGibbon EJ, Butman JA, Webb BD, Facio F, Brooks BP, Collins FS, Jabs EW, Engle EC, Manoli I, Pierpaoli C; Moebius Syndrome Research Consortium. Brain phenotyping in Moebius syndrome and other congenital facial weakness disorders by diffusion MRI morphometry. Brain Commun. 2020;2(1):fcaa014. doi: 10.1093/braincomms/fcaa014. Epub 2020 Feb 14.

Reference Type: BACKGROUND

PMID: 32328577 (View on PubMed)

Webb BD, Manoli I, Engle EC, Jabs EW. A framework for the evaluation of patients with congenital facial weakness. Orphanet J Rare Dis. 2021 Apr 7;16(1):158. doi: 10.1186/s13023-021-01736-1.

Reference Type: BACKGROUND

PMID: 33827624 (View on PubMed)

Jurgens JA, Barry BJ, Lemire G, Chan WM, Whitman MC, Shaaban S, Robson CD, MacKinnon S, England EM, McMillan HJ, Kelly C, Pratt BM; Care4Rare Canada Consortium; O'Donnell-Luria A, MacArthur DG, Boycott KM, Hunter DG, Engle EC. Novel variants in TUBA1A cause congenital fibrosis of the extraocular muscles with or without malformations of cortical brain development. Eur J Hum Genet. 2021 May;29(5):816-826. doi: 10.1038/s41431-020-00804-7. Epub 2021 Mar 1.

Reference Type: BACKGROUND

PMID: 33649541 (View on PubMed)

Other Identifiers

05-03-036R

Identifier Type: -

Identifier Source: org_study_id