Breakpoints around the HOXD cluster result in various limb malformations.

Background: Characterisation of disease associated balanced
chromosome rearrangements is a promising starting point in the
search for candidate genes and regulatory elements. Methods: We
have identified and investigated three patients with limb
abnormalities and breakpoints involving chromosome 2q31. Patient 1
with severe brachydactyly and syndactyly, mental retardation,
hypoplasia of the cerebellum, scoliosis, and ectopic anus, carries
a balanced t(2;10)(q31.1;q26.3) translocation. Patient 2, with
translocation t(2;10)(q31.1;q23.33), has aplasia of the ulna,
shortening of the radius, finger anomalies, and scoliosis. Patient
3 carries a pericentric inversion of chromosome 2, inv(2)(p15q31).
Her phenotype is characterised by bilateral aplasia of the fibula
and the radius, bilateral hypoplasia of the ulna, unossified carpal
bones, and hypoplasia and dislocation of both tibiae. Results: By
fluorescence in situ hybridisation, we have mapped the breakpoints
to intervals of approximately 170 kb or less. None of the three
2q31 breakpoints, which all mapped close to the HOXD cluster,
disrupted any known genes. Conclusions: Hoxd gene expression in the
mouse is regulated by cis-acting DNA elements acting over distances
of several hundred kilobases. Moreover, Hoxd genes play an
established role in bone development. It is therefore very likely
that the three rearrangements disturb normal HOXD gene regulation
by position effects.