An Alu-mediated rearrangement causing a 3.2 kb deletion and a novel two base pair deletion in AAAS gene as the cause of triple A syndrome

Triple A syndrome is an autosomal recessive disorder resulting from deleterious mutations in the AAAS gene located on chromosome 12q 13. Typical clinical presentation of this syndrome includes adrenal insufficiency, achalasia, and alacrima. A 10-year-old female was diagnosed with Triple A syndrome at the age of 1 year. Initial analysis of the AAAS gene revealed apparently homozygosity for a novel 2 bp deletion in exon 1. The father of the patient was heterozygous for this mutation but the mother and the maternal grandparents were apparently homozygous for the wild-type. Further studies demonstrated that the patient carried an intragenic 3.2 kb deletion within both 5' and 3' breakpoints located within Alu-repeats. The deletion includes 5'-flanking region, exon 1, intron 1, exon 2, and part of intron 2 sequences of the AAAS gene. This Alu-mediated deletion was inherited from her mother and maternal grandmother. This is the first report that Alu-mediated rearrangement in conjunction with a novel two-bp deletion of the AAAS gene is a cause of Triple A syndrome. The results of our study lead to the hypothesis that an Alu-mediated mechanism may be responsible for large alterations in the AAAS gene. We also stress the importance of studying the family in genetic recessive diseases, such as Triple A syndrome, to avoid incorrect diagnosis and to provide accurate genetic counseling. (c) 2007 Elsevier Inc. All rights reserved.