Juxtaposition of heterochromatic and euchromatic regions by chromosomal translocation mediates a heterochromatic long-range position effect associated with a severe neurological phenotype

FISH mapped the translocation breakpoints (bkps) to 15p11.2 within satellite III and the 16q12.1 euchromatic band within the ITFG1 gene. The expression of the genes located on both sides of the translocation were tested by means of real-time PCR and three, all located on der(16), were found to be variously perturbed: the euchromatic gene NETO2/BTCL2 was silenced, whereas VPS35 and SHCBP1, located within the major heterochromatic block of chromosome 16q11.2, were over-expressed. Pyrosequencing and chromatin immunoprecipitation of NETO2/BTCL2 and VPS35 confirmed the expression findings. Interphase FISH analysis showed that der(16) localised to regions occupied by the beta satellite heterochromatic blocks more frequently than der(15).To the best of our knowledge, this is the first report of a heterochromatic position effect in humans caused by the juxtaposition of euchromatin/heterochromatin as a result of chromosomal rearrangement. The overall results are fully in keeping with the observations in Drosophila and suggest the occurrence of a human heterochromatin position effect associated with the nuclear repositioning of the der(16) and its causative role in the patient's syndromic phenotype.Patients with syndromic clinical phenotypes include an interesting subset of carriers of de novo balanced chromosomal rearrangements with no apparent loss or gain of genetic material. These abnormalities can be explained by the loss of function of a dose-sensitive gene disrupted by one rearrangement breakpoint [1-3]. The breakpoints of the balanced chromosomal rearrangements associated with a clinical phenotype are often molecularly mapped in an attempt to identify the disease-causing genes affected by the abnormality. Although the rearrangements may lead to the direct disruption of one or two genes, this is not always the case. It has also been shown that breakpoints occur outside the genes themselves and affect their regulation by causing a change in their position within the gen