Introduction
The GOA project (Genetics of Oesophageal Atresia) is based in Cambridge, at Addenbrooke’s Hospital and the Wellcome Trust Sanger Institute (a specialist genetics research centre).
Project lead Dr Charles Shaw-Smith has a particular interest in Oesophageal Atresia and related birth defects. Families of children born with OA/TOF (or adult individuals who were born with OA/TOF) will be able to participate in his research project.
The GOA project is funded by The Wellcome Trust, TOFS and the Addenbrooke’s Hospital Charities Committee.
Dr Shaw-Smith spoke at the 2007 TOFS Conference in Birmingham, and reports on both his talk and workshop were published in the Winter 2007 issue of Chew.
What causes Oesophageal Atresia?
Oesophageal Atresia (OA) is a congenital anomaly occurring in approximately 1 in every 3,500 births, usually in association with Tracheo-Oesophageal Fistula (TOF). Babies born with OA/TOF require corrective surgery and follow-up at a specialist paediatric surgical centre.
It is not known what causes isolated Oesophageal Atresia (where OA/TOF is a child’s only birth defect). Data from family studies suggests that genetic factors do NOT play a major role. This is supported by the observation that where Oesophageal Atresia occurs in twins, most frequently only one of the pair is affected.
Around half of all the children born with Oesophageal Atresia also have other anomalies however; this is termed ‘Syndromic Oesophageal Atresia’. Most commonly the other problems are those described within VACTERL association, in which the child has three or more of the following anomaly groups:
- Vertebral (spine) problems
- Anal (back passage) problems
- Cardiac (heart) problems
- Tracheal (airway) problems
- Esophageal (American spelling of oesophageal) problems
- Renal (kidney) problems
- Limb problems (usually but not always affecting the bones of the forearm)
No specific gene has been associated with VACTERL. However, there are other syndromes which involve Oesophageal Atresia for which genes have been identified.
These include:
- Feingold syndrome: microcephaly (small head), digital anomalies (commonly affecting the 2nd and 5th fingers or the toes) and atresias of the gastro-intestinal tract, associated with defects in the gene N-MYC.
- CHARGE syndrome: Coloboma (a specific eye defect), Heart problems, Atresia choanae (a narrowing of the airways at the back of the nose), Retarded growth, Genital hypoplasia (defects in the sex organs) and Ear abnormalities, associated with defects in the gene CHD7.
- Anopthalmia-Esophageal-Genital syndrome (AEG): a rare condition involving the combination of Anophthalmia (no or very small eye(s)), Esophageal and Genital problems, associated with defects in the gene SOX2.
Additionally, certain chromosomal disorders are associated with Oesophageal Atresia. Chromosomes are the structures into which genes are grouped together (see photo below). There are normally 46 chromosomes in every healthy human cell, which are arranged in pairs.
Picture of normal male chromosomes
Sometimes abnormalities can arise in the structure of chromosomes, and this can be associated with problems. The most well-known chromosomal defect associated with Oesophageal Atresia is Down’s Syndrome (Trisomy 21, where there are three copies of chromosome 21 instead of the normal two) but also Trisomy 13 and Trisomy 18. Isolated cases have also been described with more subtle chromosomal imbalances.
The Genetics of Oesophageal Atresia (GOA) project
This project aims to look in detail at the genetics of Oesophageal Atresia, using a two-stranded approach:
1. Human studies
The gene defects associated with Syndromic Oesophageal Atresia were so recently identified that we don’t yet know how common they are. This is important to know because if an individual has faulty copies of these genes then they may pass the defect on to their children. We are screening samples for defects in a small panel of genes by literally decoding the information held in DNA to see if it differs from the normal sequence (this is called gene sequencing).
Also, no attempt has been made to systematically look for more subtle chromosomal defects in this patient group. We are using a recently developed laboratory technique (called arrayCGH) which is able to detect much smaller changes than the techniques currently used in clinical genetics laboratories.
We are keen to collect DNA samples and clinical information from suitable individuals. Results from tests will be fed back to families, potentially providing them with valuable information about the cause of a child’s problems and risks of recurrence in future children. Families will also be able to participate in a project which we hope will result in more accurate information about the causes of Oesophageal Atresia being available in future.
The following type of individual is most suitable for our study:
- Oesophageal Atresia/Tracheo-Oesophageal Fistula patient with features often associated with a chromosomal disorder: unusual facial features (dysmorphism), growth abnormalities or learning disability/developmental delay.
- VACTERL patient (with or without OA/TOF) with unusual facial features (dysmorphism), growth abnormalities or learning disability/developmental delay.
- Patient with OA/TOF and a family history of OA/TOF
The following patients are not suitable for our study:
- Patient with isolated Oesophageal Atresia
- VACTERL patient with normal growth, development and learning.
Would you like to take part?
If you are interested in taking part, or have any questions about the study, please feel free to contact us. If you live in the UK, the route into the study is via your local/regional Clinical Genetics Service http://www.gig.org.uk/services.htm (ask for a referral from your paediatric consultant or GP) who can review your family history and advise you both before sending samples for our study and on receipt of the results. A research study information sheet and consent form will be given to you and, if they have not already been taken and banked, blood samples (to provide us with a DNA sample for testing) will be required.
Research Clinic
Dr Charles Shaw-Smith is also holding a research clinic four times a year at Addenbrooke’s Hospital in Cambridge - families are very welcome to attend.
2. Laboratory-based studies
We are carrying out laboratory work at the Wellcome Trust Sanger Institute to further characterise the specific genes involved in Oesophageal Atresia and related anomalies. Recently developed genetic techniques enable us to manipulate certain areas of the mouse chromosome in order to determine the effects of removing or duplicating specific genes. This work is critical in helping to identify the exact genes involved in congenital abnormalities including Oesophageal Atresia.
Note to referring clinical geneticists
We are always happy to receive queries about the suitability of patients for inclusion in this study. Please email Charles Shaw-Smith [css@sanger.ac.uk] or Vicki Martin [vicki.martin@addenbrookes.nhs.uk]. Participating families/individuals will be asked to read an information sheet and sign a consent form. Clinical information may be provided by completion of a customised study proforma, or potentially by a detailed clinic letter.
Further information
- Chew, Winter 2007 - summary of Dr Charles Shaw-Smith’s talk and workshop at the 2007 TOFS Conference
- Audio files of Dr Shaw-Smith’s talk and workshop at the 2007 TOFS Conference
- Audio file of Dr Shaw-Smith’s talk at the 2005 TOFS Conference
- Review article by Dr Charles Shaw-Smith http://jmg.bmj.com/cgi/content/full/43/7/545
- GOA Project web page associated with the Molecular Medicine Unit of the Institute of Child Health, University College London: http://www.ich.ucl.ac.uk/ich/academicunits/MMU/CustomMenu_01
The GOA team
Dr Charles Shaw-Smith
Wellcome Trust Intermediate Clinical Fellow
Wellcome Trust Sanger Institute/Honorary Consultant in Clinical Genetics, Addenbrooke’s Hospital, Cambridge
TOFS Patron
Email:
Mekayla Storer
Research Assistant (based at the Wellcome Trust Sanger Institute)
Based at the Wellcome Trust Sanger Institute
Vicki Martin
Research Assistant (based at Addenbrooke’s Hospital, Cambridge)
Former TOFS Trustee and Editor of the TOFS newsletter, Chew; Vicki was herself born with OA/TOF as part of VACTERL association.
Based at Addenbrooke’s Hospital, Cambridge
Email:
PICTURE: the GOA team: (left to right) research assistant Mekayla Storer, project leader Charles Shaw-Smith and research assistant Vicki Martin, photographed outside the Sanger Institute
