Recurrent inversion events at 17q21.31 microdeletion locus are linked to the MAPT H2 haplotype

The chromosomal band 17q21.31, containing the microtubule-associated protein tau (MAPT) gene, is a hotspot for chromosomal rearrangements. It is known to contain a common inversion polymorphism of approximately 900 kb in populations with European ancestry. The inverted configuration is linked to a distinct MAPT haplotype, H2, which is relatively common in Europeans but nearly absent in Asian and African populations. Recent studies have demonstrated that the H2 haplotype is ancestral in hominoids, and under positive selection in Europeans. This haplotype is also linked to events leading to the 17q21.31 microdeletion syndrome, one of the most common causes of 'idiopathic' mental retardation in people of European descent. We performed direct analysis of the chromosome structure by fluorescence in situ hybridization and observed heterozygosity of the inversion status for the H2 chromosomes, but not for the H1 haplotype. Inversion heterozygosity was also observed in a mother homozygous for the H2 haplotype, who transmitted the chromosome with the deletion to a proband with 17q21.31 microdeletion syndrome. Our results highlight an allele-specific sensitivity to chromosome rearrangements and suggest that it is the heterozygosity of inversion status that predisposes to the 17q21.31 microdeletion syndrome.