 Hi, I'm William Gray, and I'm here to talk about our recently published paper in the journal Human Mutation. Our work was first carried out in King's College in London. The story began when the patient was seen in the clinical genetics department at Guy's Hospital. When he presented to Community Pediatricians days of two and a half, he was noted to be a larger stature and had absent speech and was displaying developmental delay and signs of autism. Following investigations by the Community Pediatrician, he loved taking some basic developmental delay screens, which had included fragile legs, and a RayCGH, or Ray-Comparative Genomic Hybridisation, and it was this test which alerted us to the possibility that there could be a chromosomal rearrangement which might actually underline his phenotype. When Louise mentioned this case to me, it reminded me so much of the P27 transgenic models. P27, also known as CDKM1B, is a cycling-dependent kinase inhibitor that specifically inhibits the progression of the cell cycle. The cell cycle is the process by which a cell duplicates its DNA and divides into two identical daughter cells. The cell cycle is especially important in development as stem cells must self renew as well as undergo asymmetric cell division to produce differentiated cells. CDKM1B is important for neurodevelopment and the asymmetric division of neurostem cells as well as the migration of these cells through the cortical layers. It is the migration of these cells that is vitally important for the correct architecture of the mature brain. Knockout models of CDKM1B have been created in mice. The phenotypes include a large body size, a hyperplasia of multiple organs including the brain, abnormal cortical neuron migration. These models have been found to be cancer-prone, particularly with pituitary tumours. When we compare the phenotypes of these knockout models to those we see in our patients, we find clear similarities. Is this linked to a CDKM1B deletion? In the knockout models these phenotypes are linked to a homozygous deletion of CDKM1B. The importance of CDKM1B in tumour predisposition has been investigated. In a healthy individual with no mutations, the two parental allials produce normal mRNA levels and a threshold level of CDKM1B protein. This allows for normal tumour suppression and normal neurodevelopment. Various groups have examined a genetic polymorphism in the CDKM1B gene that is commonly detected in the population. This CDT transversion, 79 base pairs upstream of the ATG, is linked to a predisposition to breast, prostate, thyroid and endometrial cancers and endocrine tumours. Later it was shown that this variant, which is located close to a u-rich region, binds mRNA regulatory factors, controlling protein translation rather than transcription. A single copy of this mutation leads to normal mRNA levels but reduced CDKM1B protein levels. In this case the threshold level of CDKM1B is maintained and normal neurodevelopment proceeds. Upon analysis of the maternal allial in our patient we found a deletion on chromosome 12 encompassing the CDKM1B gene. Further investigation of this deletion in the intellectually normal mother showed reduced mRNA levels. Despite this reduction there was significant CDKM1B protein produced from the normal allial allowing the protein threshold level to be maintained and normal neurodevelopment to proceed. As well as the maternal deletion our patient had a de novo variant on the paternal allial. This G-A transversion is six base pairs downstream of the previously reported C-T transversion and similar to the minus 79 variant we demonstrated experimentally that the minus 73 variant similarly affects protein translation due to its proximity to the u-rich region. When the maternal deletion is combined with the de novo minus 73 variant we find that the combination of reduced mRNA levels and reduced protein translation leads to an overall decrease of protein level. This is in support of a recessive genetic model for the minus 73 variant. Molecularly it has been demonstrated that the KIP Cycling Dependent Carnase Inhibitor Family of Genes including CDKM1B and CDKM1C are involved in neurodevelopment. CDKM1C is implicated in the well-studied overgrowth syndrome, Beckwith-Fiedman syndrome. It remains to be seen whether CDKM1B has a wider role in other overgrowth syndromes.