¹Department of Human Genetics, Free University of Amsterdam, The Netherlands

²Division of Medical and Molecular Genetics, United Medical and Dental Schools of Guy's and St Thomas's Hospitals, London, UK

³Departments of Biochemistry and Human Genetics, Universität Würzburg, Biozentrum, Würzburg, Germany

⁴Servizio di Genetica Medica, IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy

⁵Department of Pediatric Hematology, Hacettepe University, Ankara, Turkey

⁶Institute for Child Health and Hospital for Children, Madras, India

⁷Department of Haematology, Imperial College School of Medicine, London, UK

⁸Department of Haematology, Royal London Hospital, Whitechapel, London, UK

⁹Department of Haematology, St George's Hospital Medical School, London, UK

¹⁰Department of Pediatrics, Leiden University Hospital, The Netherlands

¹¹Hematology and Bone Marrow Transplantation Unit, Hospital Infantil Vall d'Hebron, Barcelona, Spain

¹²2nd Department of Pediatrics, Semmelweis Medical University, Budapest, Hungary

¹³Research Institute for Pediatric Hematology, Moscow, Russia

¹⁴Department of Genetics, National Institute of Mother and Child, Warsaw, Poland

¹⁵Department of Pediatrics, University Hospital, Lund, Sweden

¹⁶Instituto Portugues Oncology, Lisboa, Portugal

¹⁷Institut für Hematologie, Virchow-Klinikum, Berlin, Germany

¹⁸Department of Clinical Genetics, Free University of Amsterdam, The Netherlands

¹⁹Department of Human Genetics, University of the Witwatersrand, Johannesburg, South Africa

²⁰Fédération d'Hématologie, Service de Greffe de Moelle, Hôpital Saint-Louis, Paris, France

^aCorrespondence: Dr C Mathew, Division of Medical and Molecular Genetics UMDS, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK. Tel: +44(0)171 955 4653; Fax: +44(0)171 955 4644; E-mail: c.mathew@umds.ac.uk

Fanconi anaemia (FA) is a genetically heterogeneous autosomal recessive disorder associated with chromosomal fragility, bone-marrow failure, congenital abnormalities and cancer. The gene for complementation group A (FAA), which accounts for 60-65% of all cases, has been cloned, and is composed of an open reading frame of 4.3 kb, which is distributed among 43 exons. We have investigated the molecular pathology of FA by screening the FAA gene for mutations in a panel of 90 patients identified by the European FA research group, EUFAR. A highly heterogeneous spectrum of mutations was identified, with 31 different mutations being detected in 34 patients. The mutations were scattered throughout the gene, and most are likely to result in the absence of the FAA protein. A surprisingly high frequency of intragenic deletions was detected, which removed between 1 and 30 exons from the gene. Most microdeletions and insertions occurred at homopolymeric tracts or direct repeats within the coding sequence. These features have not been observed in the other FA gene which has been cloned to date (FAC) and may be indicative of a higher mutation rate in FAA. This would explain why FA group A is much more common than the other complementation groups. The heterogeneity of the mutation spectrum and the frequency of intragenic deletions present a considerable challenge for the molecular diagnosis of FA. A scan of the entire coding sequence of the FAA gene may be required to detect the causative mutations, and scanning protocols will have to include methods which will detect the deletions in compound heterozygotes.

Fanconi anaemia; FAA gene; mutations