Novel De Novo Mutations in CTNND1 Cause a Neurocristopathy Syndrome

Objectives: The aim of this project is to identify pathogenic gene variants in children with multiplex unexplained phenotypes accompanied by cleft lip/palate.

Methods: Family trios are recruited from the South Thames Cleft Unit at St Thomas’ Hospital, London as part of our Cleft-Tooth Anomalies Study (REC16/NI/0026). Following informed consent; a head, neck and oral exam is performed on affected individuals and their parents in a dental setting. A family-tree questionnaire including medical and dental history is then taken by the clinician. Finally, saliva is collected for DNA sequencing from the family trio. Whole exome sequencing (WES) is performed to identify gene variants that may be disease causing.


Results: Whole exome sequencing identified a novel CTNND1 gene variant in our patient with unexplained craniofacial anomalies including cleft lip/palate and oligodontia, cardiac defects, autism (ASD) and other phenotypes suggestive of a yet unexplored syndrome. Moreover, we have identified three other unrelated patients with novel de novo mutations in the CTNND1 gene. These patients were recruited from the Deciphering Developmental Disorders Study (DDD), UK, one of which shares the same variant as our patient. Although CTNND1 is a well-known protein that plays crucial functions developmentally, human variants have not been discovered until recently with a report of three variants in patients with Blepharocheilodontic syndrome (BCD). Otherwise, little is known about the phenotypes that are associated with mutations in this gene. Our functional analysis on model organisms provides evidence on the importance of this protein in craniofacial development.

Conclusions: Our results suggest that CTNND1 may be a new key oral clefting gene, with or without tooth anomalies. Moreover, CTNND1 could also be classified as a neurocristopathy gene due to its effect on structures of neural crest origin.