Heterogeneous spectrum of mutations in the Fanconi anaemia group A gene

Fanconi anaemia (FA) is a genetically heterogeneous autosomal recessive dis order associated with chromosomal fragility, bone-marrow failure, congenita l abnormalities and cancer. The gene for complementation group A (FAA), whi ch 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 m utations in a panel of 90 patients identified by the European FA research g roup, EUFAR, A highly heterogeneous spectrum of mutations was identified, w ith 31 different mutations being detected in 34 patients. The mutations wer e scattered throughout the gene, and most are likely to result in the absen ce of the FAA protein. A surprisingly high frequency of intragenic deletion s was detected, which removed between 1 and 30 exons from the gene. Most mi crodeletions and insertions occurred at homopolymeric tracts or direct repe ats,within the coding sequence. These features have not been observed in th e other FA gene which has been cloned to date (FAC) and may be indicative o f a higher mutation rate in I;AA. This would explain why FA group A is much more common than the other complementation groups. The heterogeneity of th e mutation spectrum and the frequency of intragenic deletions present a con siderable 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 mu tations, and scanning protocols will have to include methods which will det ect the deletions in compound heterozygotes.