 About ten years ago, I received a call from the late Dr. David Bush who was testing cells from patients suspected of having Xeroderma pigmentosum and he found the cells from a patient who was a young boy with melanoma who had defective DNA repair. We brought him to the National Institutes of Health to study when he was twelve years old and we realized he did not have Xeroderma pigmentosum but he had unusual features of pigmented lesions and deafness. When we examined him two years later we found that he had developed a melanoma behind his ear and the genetic counselor examined him and thought that he might have features of the George syndrome so we did a karyotype and discovered that he had a translocation between chromosomes nine and twenty-two. We then embarked on a study to do more clinical examination of the patient and detailed laboratory studies that they form the basis of this paper. We had the opportunity to perform high resolution MR imaging of this patient's inner ear apparatus and in contrast to the normal inner ear there were a number of developmental abnormalities including incomplete winding of the cochlea with a much reduced number of turns. In addition the vestibule and semicircular canals were incompletely formed. Now with the presence of a cochlea one might consider the ability to augment hearing with a cochlear implant but a detailed examination of the internal auditory canals reveals the presence of only the facial nerve and a complete absence of the cochlear nerve as well as an absence of the vestibular nerves so one nerve within the canal as opposed to the normal complement of four nerves. Ken Kramer brought this case to my attention which had a very interesting translocation that was not easy to map. We had tried by array CGH but the deletion wasn't apparent so we turned to physically separating the partnered chromosomes in the reciprocal translocation. To do that we used the skills of Gary Stone who had expertise in chromosome flow sorting that allowed us to physically separate the two chromosomes and precisely map the break points using high resolution CGH arrays. From that information it was pretty much possible to go ahead and map the precise break point at the nucleotide resolution. I've worked on this project for five years. In this study we made a great effort to map the break point. Since the break point on chromosome 22 lies in the unclone number gap. Using hundreds pairs of the primer and cloned back clones and the probes we finally localized the break point on chromosome 22. At the break point, the HPAS PETR 22 is allowed us to find a new gene FAM 238 and identify a chimeric transcriptor which is a negative regulator for P14-R and the TBX1. We made a summary model to explain that our findings the translocation between chromosome 9 and 22 produced a chimeric message that part of 9 and part of 22 this produced a dominant negative repression of the untranslocated chromosome 9 and the TBX1 and chromosome 22 resulting in reduced DNA repair and abnormal formation of the inner ear. Experimentally we were able to use SI RNA to reduce the expression of this chimeric and reversed some of these abnormalities showing increased level of P14-ARF and increased DNA repair and so we think this is a model of dominant negative repression induced by the translocation.