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

NCT03059420 | Recruiting

• 1 other identifier: 05-03-036R
• Study Type: observational
• Target: 20,000
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

CFEOM (Congenital Fibrosis of Extraocular Muscles); CCDD (Congenital Cranial Dysinnervation Disorders); DRS (Duane Retraction Syndrome); DRRS (Duane Radial Ray Syndrome); Strabismus; MGJWS (Marcus Gunn Jaw Winking Syndrome); HGP (Horizontal Gaze Palsy); HGPPS (Horizontal Gaze Palsy with Progressive Scoliosis); Moebius

Outcome Measures

Primary Outcomes (1)

• Identifying and characterizing genes important in normal development and function of the ocular motility system, cranial nerves and brainstem and associated with congenital cranial dysinnervation disorders and related anomalies.

  This is an observational, descriptive study with no interventions geared towards identifying novel genes and characterizing their function, expression and impact on human cranial nerve development and disease. As genes previously undescribed in the human population are identified and characterized, reports regarding these details will be written and published but such timelines are impossible to predict. Also, as new information on previously identified genes is gathered generated, additional reports will be issued through scientific publications. As long as funding is available, the work will proceed in a rolling, ongoing timeline.

  Ongoing

Eligibility Criteria

• Age: 1 Day+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Individuals diagnosed with strabismus, congenital ocular motility disorders, cranial nerve dysfunction, brainstem disorders and other associated anomalies, as well as their similarly affected or unaffected family members. Unaffected individuals are enrolled only if a relative is diagnosed with one of these conditions at least one affected family members is enrolled.

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Boston Children's Hospital: lead
• Howard Hughes Medical Institute: collaborator

Study Sites (1)

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

RECRUITING

Related Publications (18)

• 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.

  PMID: 27181683 BACKGROUND

• 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.

  PMID: 25559402 BACKGROUND

• 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.

  PMID: 24612975 BACKGROUND

• 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.

  PMID: 24091937 BACKGROUND

• 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.

  PMID: 24138051 BACKGROUND

• 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.

  PMID: 20074521 BACKGROUND

• 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.

  PMID: 20034095 BACKGROUND

• 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.

  PMID: 28681861 BACKGROUND

• 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.

  PMID: 28777491 BACKGROUND

• 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.

  PMID: 31211835 BACKGROUND

• 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.

  PMID: 30272120 BACKGROUND

• 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.

  PMID: 30098192 BACKGROUND

• 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.

  PMID: 29887215 BACKGROUND

• 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.

  PMID: 31302631 BACKGROUND

• 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.

  PMID: 31541710 BACKGROUND

• 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.

  PMID: 32328577 BACKGROUND

• 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.

  PMID: 33827624 BACKGROUND

• 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.

  PMID: 33649541 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Following specimens may be submitted: saliva, blood, discarded tissue

MeSH Terms

Conditions

Congenital Cranial Dysinnervation Disorders; Duane Retraction Syndrome; Mobius Syndrome; Ocular Motility Disorders; Marcus Gunn phenomenon; gaze palsy, familial horizontal, with progressive scoliosis; Facial Paralysis; Facial paresis, hereditary, congenital; Oculomotor Nerve Diseases; Trochlear Nerve Diseases; Abducens Nerve Diseases; Synkinesis; Levator-Medial Rectus Synkinesis; Athabaskan brainstem dysgenesis; Glossopharyngeal Nerve Diseases; Bell Palsy; Accessory Nerve Diseases; Hypoglossal Nerve Diseases; congenital fibrosis of the extraocular muscles; Strabismus

Condition Hierarchy (Ancestors)

Cranial Nerve Diseases; Nervous System Diseases; Nervous System Malformations; Eye Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Eye Diseases, Hereditary; Genetic Diseases, Inborn; Facial Nerve Diseases; Mouth Diseases; Stomatognathic Diseases; Abnormalities, Multiple; Infant, Newborn, Diseases; Central Nervous System Diseases; Paralysis; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Dyskinesias; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections

Study Officials

• Elizabeth Engle, MD

  Boston Children's Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Brenda J Barry, MS

CONTACT

617-919-2168; brenda.barry2@childrens.harvard.edu

Engle Admin

CONTACT

617-919-4030; engle.admin@childrens.harvard.edu

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: OTHER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Investigator, Howard Hughes Medical Institute; Professor of Neurology and Ophthalmology, Harvard Medical School

Study Record Dates

• First Submitted: February 15, 2017
• First Posted: February 23, 2017
• Study Start: February 1, 2004
• Primary Completion (Estimated): January 1, 2030
• Study Completion (Estimated): January 1, 2030
• Last Updated: February 11, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)