The GOA project (Genetics of Oesophageal Atresia) was based at Addenbrooke’s Hospital, Cambridge, 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) participated in this research project.

The GOA project was 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 withTracheo-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 withinVACTERL 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.

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.

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.

Further information

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

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

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