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J Med Genet 37:785-787 doi:10.1136/jmg.37.10.785
  • Letters to the editor

The mutation spectrum in Holt-Oram syndrome

  1. STEPHEN J CROSS*,
  2. YUNG-HAO CHING*,
  3. QUAN YI LI*,218,
  4. LINDSAY ARMSTRONG-BUISSERET*,
  5. STEPHANIE SPRANGER,
  6. STANISLAW LYONNET,
  7. DAMIEN BONNET§,
  8. MAILA PENTTINEN,
  9. PHILIPPE JONVEAUX**,
  10. BRUNO LEHEUP164,
  11. GEERT MORTIER,
  12. CONNY VAN RAVENSWAAIJ§§,
  13. CAROL-ANNE GARDINER¶¶,
  14. J DAVID BROOK*,
  15. RUTH NEWBURY-ECOB165
  1. *Institute of Genetics, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
  2. †Centre of Human Genetics and Genetic Counseling, University of Bremen, Leobener Street, D-28359 Bremen, Germany
  3. ‡Unité de Recherches sur les Handicaps Génétiques de l'Enfant, Groupe Hospitalier Necker-Enfants Malades, 149 Rue de Sevres, 75743 Paris Cedex 15, France
  4. §Service de Cardiologie Pédiatrique, Groupe Hospitalier Necker-Enfants Malades, 149 Rue de Sevres, 75743 PARIS Cedex 15, France
  5. ¶Turku University Central Hospital, Clinical Genetics Unit, PL 52, 20521 Turku, Finland
  6. **Service de Génétique, Centre Hospitalier, Universitaire de Nancy, rue du Morvan, 54511 Vandoeuvre les Nancy, France
  7. 164Médecine Infantile et Génétique Clinique, Hôpital d'Enfants, Centre Hospitalier Universitaire de Nancy, rue du Morvan, 54511 Vandoeuvre les Nancy, France
  8. ‡Department of Medical Genetics, University Hospital Gent, De Pintelaan 185, B-9000 Gent, Belgium
  9. §§Department of Human Genetics, University Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands
  10. ¶¶Yorkshire Regional Genetic Service, Department of Clinical Genetics, St James's University Hospital, Ashley Wing, Beckett Street, Leeds LS9 7TF, UK
  11. 165Clinical Genetic Service, Institute of Child Health, Bristol Royal Hospital for Sick Children, St Michael's Hill, Bristol BS2 8BJ, UK
  1. Professor Brook,David.Brook{at}nottingham.ac.uk

    Editor—Holt-Oram syndrome (HOS) is a developmental disorder characterised by malformations of the radial ray of the forelimb and by congenital heart disease.1 The syndrome shows a marked variability in phenotype, with radial ray defects ranging from minor thumb abnormality through to severe reduction defect or phocomelia. The cardiac manifestations of HOS are similarly varied, and patients can present with a variety of structural heart abnormalities, atrial septal defects (ASDs) and ventricular septal defects (VSDs) being the most common, or conduction defects evident on ECG profiles. Previous studies have shown no correlation between the severity of a patient's cardiac and skeletal abnormalities.2 Intrafamilial variation can be wide.

    HOS shows autosomal dominant inheritance and mutations in the T box transcription factor gene (TBX5) have been shown previously to be responsible for this disorder.3 4There is also evidence for genetic heterogeneity.5 The mechanism by which mutations in TBX5 cause a dominant phenotype is not understood at present, and it is anticipated that knowledge of the type of mutations causing HOS may shed light on this. Knowledge of a large number of mutations and the relation of a person's genotype to phenotype is also useful for genetic counselling. In the face of a growing demand for a molecular diagnostic test for HOS, it is also helpful to have a quantitative estimate of the ability of current methods to detect mutations inTBX5.

    Twenty five cases with a clinical diagnosis of Holt-Oram syndrome have been tested for this study, bringing to 47 the total number of cases studied by us. Minimal diagnostic criteria were as described previously2: bilateral radial ray defect, plus either cardiac abnormality or family history of cardiac abnormality. Cases were referred by a variety of clinicians and underwent full clinical assessment including …