Four genes have been identified that work together to cause cleft lip and palate, in an international research collaboration with researchers from UNSW Sydney and the University of Washington.

The genes, associated for the first time with cleft lip and palate, encode proteins that work together in a network, providing important insights into the biological basis of one of the most common physical malformations. The NHMRC-funded project was led by Associate Professor Tony Roscioli from Neuroscience Research Australia (NeuRA), UNSW Sydney, and Sydney Children’s Hospital, Randwick; and Professor Timothy Cox, from Seattle Children’s Research Institute and the University of Washington School of Medicine in the USA.

Representing about 70% of cleft lip and palate cases worldwide, non-syndromic cleft lip and palate typically occur in isolation without other physical abnormalities. This craniofacial malformation has long been considered to be caused by a combination of many common genetic variants and environmental factors, each contributing a small amount to the risk of a child being born with a cleft. Using next-generation sequencing, the research team identified variants in four new genes, each representing a primary cause of non-syndromic cleft lip and palate. These genes are known to encode proteins that work together in a network, providing important insight into the biological basis of the cleft lip and palate.

Variants in these genes were found to account for 15% of the families who took part in the study and in nearly 3% of a second, larger group of smaller families and isolated cases. Published in the American Journal of Human Genetics, the study provides the first evidence that a significant number of non-syndromic clefts have a single gene basis and not a complex basis as previously thought.

Associate Professor Tony Roscioli said cleft lip/palate is one of the most common human malformations, occurring in 1 in 800 children.

“That equates to about 250 Australian children each year and one affected child born every 3 minutes worldwide,” said Roscioli.

“What we were seeking to identify in this study was whether single genes could cause a cleft lip or palate in families where there were multiple affected people.”

“Knowing the genes and the way these impact lip and palate formation opens the door for further research to understand how these genes work and to develop treatments.”