CRANIRARE

The CRANIRARE project aimed to analyse the molecular and pathophysiological mechanisms of rare craniofacial malformations and to transmit the results into improved patient care. CRANIRARE work on the molecular basis and gene identification of 13 selected rare craniofacial malformations. An large number of patients including several large and unique families were clinically characterized and included into the CRANIRARE studies. In order to improve patient care and therapeutic strategies, it was essential to (i) further understand the fundamental and complex biological processes underlying craniofacial development, (ii) to elucidate conserved molecular pathways during development, (iii) to identify the molecular and pathogenic mechanisms of these disorders, and (iv) to translate these findings into clinical practice and use this knowledge as basis for the development of new therapies.
During the funding period, the network was able to ascertain and clinically characterize a substantial number of patients with various craniofacial malformations, which enabled us to start standardization and harmonization of clinical classifications, molecular diagnosis, and genetic counselling for these disorders. In this context, we prepared a booklet describing clinical and molecular issues for the craniofacial disorders of interest. We now successfully identified eighteen novel causative genes for thirteen different disorders. The gene identifications allowed us to elucidate new conserved molecular pathways and mechanisms important for biological processes of craniofacial development: We were able to show that recessive mutations in ALX1 and ALX4 genes underlie clinically distinct forms of frontonasal dysplasias, reported that Treacher Collins syndrome represent a ribosomopathy and is caused also by mutations in the POLR1C and POLR1D genes, and identified regulatory alterations of SOX9, a novel disease-causing mechanism for craniofacial malformations, as cause of Pierre-Robin syndrome. Moreover, molecular and functional studies provided further evidence that centrosomal dysfunction is responsible for microcephaly and facial dysmorphisms associated with Seckel syndrome, showed that loss of CHSY1 function leads to alterations in BMP signaling causing craniosynostosis. In addition, the CRANIRARE partners identified novel genes for Antley-Bixler syndrome, Crouzon syndrome, acrocallosal syndrome, Hamamy syndrome, and Feingold syndrome. To improve future therapeutic options for patients with craniofacial malformations, we developed novel technologies for local delivery of bioactive agents to induce bone tissue regeneration and tested these technologies in cell systems. These highly successful studies clearly demonstrate the benefit of transnational studies in rare diseases as well as the substantial interactions and collaborations between the CRANIRARE partners.