Unusual Mutations in Btk: An Insertion, a Duplication, an Inversion, and Four Large Deletions

Mutations in Brutonʹs 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 Btk locus has allowed us to characterize these mutations in detail and to identify four different types of alterations. These alterations included a 253-bp retroposon insertion at position +5 within intron 9, an inversion of greater than 48 kb that disrupted Btk between exons 4 and 5, a 12.9-kb duplication including Btk exons 2 to 5, and four deletions ranging from 2.8 to 38 kb in size. The duplication and three of the deletions resulted from unequal crossovers of Alu repeats. Further, three of the deletions terminated within a repeat-rich cluster spanning 30 kb of sequence 3′ of Btk exon 19, suggesting that this region was more susceptible to unequal crossovers than the rest of the Btk gene. These studies describe the first reports of an insertion, an inversion, and a duplication in Btk and demonstrate the utility of large-scale sequencing in the elucidation of disease-causing mutations.