0
Scientific Articles   |    
Exome Sequencing Identifies an MYH3 Mutation in a Family with Distal Arthrogryposis Type 1
David M. Alvarado, PhD1; Jillian G. Buchan, BS1; Christina A. Gurnett, MD, PhD1; Matthew B. Dobbs, MD1
1 Department of Orthopaedic Surgery, Washington University School of Medicine, 1 Children's Place, St. Louis, MO 63110. E-mail address for M.B. Dobbs: dobbsm@wudosis.wustl.edu
View Disclosures and Other Information
Disclosure: One or more of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of an aspect of this work. In addition, one or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by the authors are always available with the online version of this article at jbjs.org.

  • Disclosure statement for author(s): PDF

Investigation performed at Washington University School of Medicine, St. Louis, Missouri

Copyright © 2011 by The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2011 Jun 01;93(11):1045-1050. doi: 10.2106/JBJS.J.02004
5 Recommendations (Recommend) | 3 Comments | Saved by 3 Users Save Case

Abstract

Background: 

Few genes responsible for distal arthrogryposis type 1 are known, although genes coding for the proteins in the sarcomere have been implicated in other types of distal arthrogryposis. Cost-effective sequencing methods are now available to examine all genes in the human genome for the purpose of establishing the genetic basis of musculoskeletal disorders.

Methods: 

A multigenerational family with distal arthrogryposis type 1 characterized by clubfoot and mild hand contractures was identified, and exome sequencing was performed on DNA from one of the affected family members. Linkage analysis was used to confirm whether a genetic variant segregated with distal arthrogryposis.

Results: 

Exome sequencing identified 573 novel variants that were not present in control databases. A missense mutation in MYH3 (a gene coding for the heavy chain of myosin), causing an F437I amino acid substitution, was identified that segregated with distal arthrogryposis in this family. Linkage analysis confirmed that this MYH3 mutation was the only exome variant common to all six affected individuals.

Conclusions: 

Identification of an MYH3 mutation in this family with distal arthrogryposis type 1 broadens the phenotype associated with MYH3 mutations to include distal arthrogryposis types 1, 2A (Freeman-Sheldon syndrome), and 2B (Sheldon-Hall syndrome). Exome sequencing is a useful and cost-effective method to discover causative genetic mutations, although data from extended families may be needed to confirm the importance of the hundreds of identified variants.

Clinical Relevance: 

Distal arthrogryposis type 1 should be considered in the differential diagnosis of isolated clubfoot, particularly when hand contractures are present in any family member or when the clubfoot is severe and resistant to treatment.

Figures in this Article
    Sign In to Your Personal ProfileSign In To Access Full Content
    Not a Subscriber?
    Get online access for 30 days for $35
    New to JBJS?
    Sign up for a full subscription to both the print and online editions
    Register for a FREE limited account to get full access to all CME activities, to comment on public articles, or to sign up for alerts.
    Register for a FREE limited account to get full access to all CME activities
    Have a subscription to the print edition?
    Current subscribers to The Journal of Bone & Joint Surgery in either the print or quarterly DVD formats receive free online access to JBJS.org.
    Forgot your password?
    Enter your username and email address. We'll send you a reminder to the email address on record.

     
    Forgot your username or need assistance? Please contact customer service at subs@jbjs.org. If your access is provided
    by your institution, please contact you librarian or administrator for username and password information. Institutional
    administrators, to reset your institution's master username or password, please contact subs@jbjs.org

    References

    Accreditation Statement
    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
    CME Activities Associated with This Article
    Submit a Comment
    Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
    Comments are moderated and will appear on the site at the discretion of JBJS editorial staff.

    * = Required Field
    (if multiple authors, separate names by comma)
    Example: John Doe





    Related Content
    The Journal of Bone & Joint Surgery
    JBJS Case Connector
    Topic Collections
    Related Audio and Videos
    PubMed Articles
    Clinical Trials
    Readers of This Also Read...
    JBJS Jobs
    12/04/2013
    New York - Icahn School of Medicine at Mount Sinai
    02/28/2014
    District of Columbia (DC) - Children's National Medical Center
    04/02/2014
    W. Virginia - Charleston Area Medical Center
    12/31/2013
    S. Carolina - Department of Orthopaedic Surgery Medical Univerity of South Carlonina