CRANIRARE-2

Anomalies affecting the bones of the skull and the face (craniofacial malformations) that are present at birth have mostly a genetic background. They can occur in isolated form or as part of conditions with symptoms involving also other organ or organ systems, e.g. intellectual disabilities, abnormalities of brain growth, hearing loss, eye and vision disturbances, and major functional problems of breathing, chewing, swallowing or speech. Such syndromes are mostly rare genetic conditions and they require interdisciplinary medical care involving many clinical specialities for diagnosis, counselling, and therapy. It is essential to have a correct diagnosis as early as possible in order to provide prognostic information, to adjust medical care and treatment, and, importantly, to prevent secondary medical complications, but the large number of different syndromes and the high clinical variability of symptoms make it difficult to establish a correct clinical and genetic diagnosis.The CRANIRARE consortium has brought together international specialists in an interdisciplinary, well-coordinated network to gain insights into the fundamental and complex biological processes of craniofacial development, to understand the molecular pathways and the changes in them that lead to various syndromes involving craniofacial malformations and to use these findings to improve the care of patients.

Our network was able to recruit and clinically characterize over 800 patients with various rare craniofacial malformations, which enabled us to start standardization and harmonization of clinical classifications, molecular diagnosis, and genetic counselling for these disorders. We mainly focused on a range of 19 different rare phenotypes. As an example, in an integrated effort involving all partners, we have collected over 170 patients with Kabuki syndrome. Within the CRANIRARE-2 funding period, partners have successfully identified 26 novel causative genes that had not been previously associated with human diseases and extended the spectrum of conditions caused by five previously known genes. These successful gene identification studies allowed us to learn more about molecular pathways and mechanisms important for biological processes of craniofacial development. Partners have also started to translate these research findings into patient care by establishing new molecular diagnostic tests for novel genes identified. The substantial interactions and collaborations between the CRANIRARE-2 partners resulted in 69 scientific publications since 2012 from the overall consortium, many of them co-authored by at least two partners.