Three siblings, born with cleft lip and palate, were identified, and also a common gene mutation associated with the birth defect, that they share.
The gene intraflagellar transport 88 (IFT88) ensures that transportation antennae (cilia) on embryonic cells travel to the right place, enabling the development of cartilage, bone and smooth muscle in the face and skull.
‘Identifying the underlying causes of craniofacial disorders can reduce the severity of the birth defect, lessening the associated social, emotional and financial burden faced by the families.’
Cilia play critical tissue-specific roles in craniofacial development.
"Finding this birth defect in every single child in a family is like catching lightning in a bottle because it allowed us to pinpoint the gene mutation that is probably responsible," said Yang Chai, senior author of the study and director of the Center for Craniofacial Molecular Biology at the Herman Ostrow School of Dentistry of USC.
"Our finding that the gene IFT88 is involved in cleft lip and palate is unlikely to be mere coincidence." Chai added.
The study involved three siblings,two boys and a girl, who were born with cleft lip and palate. Their mother did not have the congenital disorder, but their father did. Their orofacial abnormality was repaired through surgery.
Cleft lip and palate is the most common birth defect in the U.S, according to data from the Centers for Disease Control and Prevention. Around 7,000 children are born with this condition annually.
"Although most people are not familiar with cleft lip and palate, it is a common congenital anomaly that impacts survival, feeding, speech and has long-term implications if not repaired early and correctly," said Pedro Sanchez, a co-author of the study, a medical geneticist at CHLA and an assistant professor of clinical pathology and pediatrics at the Keck School of Medicine. "It occurs in approximately 1 in 1000 live births.
In order to identify the gene IFT88, researchers went through 32,061 unique gene variations.
"If someone carries this mutation, they may have a higher chance of giving birth to children with cleft lip and palate," said Chai, associate dean of the Ostrow School. "Doctors can provide consultations to these patients before they give birth, so parents can have surgery lined up and seek out proper care for their newborns."
Other congenital diseases tied to a genetic disorder of cilia on embryonic cells include retinal degeneration, hearing defects, polydactyly (extra fingers or toes at birth) and brain malformations.
The research team also examined mice which had a mutation in IFT88 gene and found that they exhibited severe craniofacial defects including cleft lip and palate and tongue agenesis.
"In our study, however, the animal model and the human mutation match," Chai said. "In the animal model, there is no doubt. We have shown that 100 percent of the mice who have a single mutation in IFT88 have cleft lip and palate."
Since this study involved only three children, more investigation is needed to validate the findings.
The study was a collaborative effort between the Ostrow School of Dentistry, the Keck School of Medicine of USC, Children's Hospital Los Angeles and the nonprofit Operation Smile and the results are published in the journal Human Molecular Genetics
- Yang Chai et al. Intraflagellar transport 88 (IFT88) is crucial for craniofacial development in mice and is a candidate gene for human cleft lip and palate. Human Molecular Genetics; (2017) DOI: 10.1093/hmg/ddx002