New genetic causes of cleft lip and palate revealed

Representing approximately 70% of cleft lip and palate cases worldwide, non-syndromic cleft lip and palate usually occurs in isolation without other physical abnormalities. Credit: Getty Images.

A study by an international research team, which included researchers from Seattle Children’s Research Institute, implicates variants in four genes as the primary cause of nonsyndromic cleft lip and palate in humans. The genes, associated for the first time with cleft lip and palate, code for proteins that work together in a network, providing important insight into the biological basis of one of the most common physical malformations.

Representing about 70% of cleft lip and palate cases worldwide, non-syndromic cleft lip and palate usually occur in isolation without other physical abnormalities. This craniofacial malformation has long been thought to be caused by a combination of many common genetic variants and environmental factors, each contributing in a small way to the risk of a child being born with a cleft.

Posted in the American Journal of Human Geneticsthe study provides the first evidence that a significant number of non-syndromic clefts have a single gene base and not a complex base as previously thought.

Studying extended families gives definitive genetic clues

The collaboration between Seattle Children’s, University of Washington School of Medicine, Neuroscience Research Australia (NeuRA), Radboud University Nijmegen and the University of Iowa used next-generation sequencing to study 72 large families in which several people were affected by a non-syndromic cleft. lip and palate.

Dr. Timothy Cox, member of the research institute Center for Developmental Biology and Regenerative Medicine and Seattle Children’s Craniofacial Center co-led the study with Dr Tony Roscioli, Associate Professor of NeuRA, Sydney Children’s Hospital Randwick and UNSW Sydney. Together, they designed a different approach to study the genetic basis of non-syndromic cleft lip and palate.

“Previous studies have focused on using large numbers of affected individuals with no obvious family history, looking for common genetic variants associated with an increased risk of a child being born with a cleft,” Cox said. . “Our new findings indicate that non-syndromic cleft lip and palate occurring in families are more likely to be caused by a rare variant that we can identify using new sequencing technologies available.”

Key cleft lip and palate pathway emerges

Whole-exome sequencing results showed that genetic variants of the four newly implicated genes, plus another gene previously associated with non-syndromic cleft lip and palate, accounted for 15% of families in the study and nearly 3% of a second. , a larger group of small families and isolated cases used to validate the results.

The five functionally linked genes play an important role in regulating a pathway known as the epithelial cadherin-catenin complex. Because this complex connects to other genes previously associated with non-syndromic and syndromic cleft lip and palate, the findings could lead to new diagnostic tests and treatments for cleft lip and palate.

“The genetic pathway that emerged from these data is arguably one of the most significant advances in cleft lip and palate genetics in the past 15 years,” said Cox, who is also a professor of pediatrics at the U.W. School of Medicine. “The pathway provides a target for future studies that explore ways to influence or alter the pathway to prevent cleft lip and palate.”

Future research

Cleft lips and palates are repaired by corrective surgery. Future research will further investigate the biology and link the findings to potential future therapies. These findings will allow geneticists to provide more accurate information to families.

“Importantly, we also showed that some affected individuals in this study had a gene variant that was not inherited from either parent – that is, it likely arose spontaneously in the individual affected early in development – and therefore parents could be reassured of a very low chance of having another affected child,” Roscioli said.

Cox’s lab at Seattle Children’s is also studying how maternal nutritional factors interact with genes to control the formation of the unborn child’s face and how these factors influence the risk of a child being born with a cleft lip and palate. He hopes his research will lead to novel approaches to reduce the severity or incidence of cleft lip and palate in newborns with a genetic predisposition to the birth defect.

“Although not everyone who inherits one of these genetic variants develops cleft lip and palate, it does significantly increase their risk of being affected,” Cox said. “With our continued research, I believe that one day it will be possible to predict the risk of developing cleft and hopefully provide simple dietary modifications to prevent or reduce the severity of the condition.”

This study was supported by grants from the Australian Health & Medical Research Council, the Laurel Endowment for Pediatric Craniofacial Research, the March of Dimes and the National Institutes of Health.


Christine E. Phillips