Unusual mutations in Btk: An insertion, a duplication, an inversion, and four large deletions

Mutations in Bruton's tyrosine kinase (Btk) result in the immunodeficiency X-linked agammaglobulinemia (XLA). In a previous study of 101 patients with presumed XLA, we identified seven patients with large genomic alterations in Btk. The recent completion of 100 kb of contiguous DNA sequence at the B tk locus has allowed us to characterize these mutations in detail and to id entify four different types of alterations. These alterations included a 25 3-bp retroposon insertion at position +5 within intron 9, an inversion of g reater than 48 kb that disrupted Btk between exons 4 and 5, a 12.9-kb dupli cation including Btk exons 2 to 5, and four deletions ranging from 2.8 to 3 8 kb in size. The duplication and three of the deletions resulted from uneq ual crossovers of Alu repeats. Further, three of the deletions terminated w ithin a repeat-rich cluster spanning 30 kb of sequence 3' of Btk exon 19, s uggesting that this region was more susceptible to unequal crossovers than the rest of the Btk gene. These studies describe the first reports of an in sert-ion, an inversion, and a duplication in Btk and demonstrate the utilit y of large-scale sequencing in the elucidation of disease-causing mutations . (C) 1999 Academic Press.