An Alu-mediated rearrangement causing a 3.2kb 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 12q13. 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 2bp 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 3.2kb 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.