CCDG: Exomes of Orofacial Clefts

Orofacial Clefts (OFCs) are genetically complex structural birth defects caused by genetic factors, environmental exposures, and their interactions. OFCs are the most common craniofacial anomalies in humans. Affect about 1 in 800 newborns, OFCs are also one of the most common structural birth defects worldwide. OFCs can impose a substantial personal cost resulting from the associated emotional and financial burden. On average a child undergoes 6 surgeries, spends 30 days in hospital, receives 5 years of orthodontic treatment, and participates in ongoing speech therapy, leading to an estimated total lifetime treatment cost of about $200,000. Individuals born with an OFC have higher infant mortality (especially in developing countries with limited access to care), higher mortality rates at all other stages of life, increased incidence of mental health problems, and higher risk for other disorders (notably including breast, brain, and colon cancers). Prior genetic studies have focused on the contribution of common genetic variants through genome-wide linkage and association studies. These studies have revealed a significant etiologic heterogeneity. One promising approach to dissect the etiology of OFCs into focus on subclinical phenotypic features present in the non-cleft family members of affected individuals. These subclinical features are subtle phenotypic features that may represent mild manifestations of the same risk genes; thus, their inclusion in family-based studies may clarify the inheritance patterns in OFC families. In this project, we conducted whole exome sequencing in multiplex families with both overt OFCs and subclinical phenotypes to identify high-impact genes causing OFCs. ]]>
Families were included if the child has a cleft lip, cleft palate or both. Parents may or may not be affected. At least one individual in the family had to have an orbicularis oris discontinuity or velopharyngeal dysfunction.]]>
The current study is the result of many years of ongoing collaborations among the study investigators, which began in the 1980's, followed by genome-wide linkage studies in the 1990's-early 2000's, and then genome-wide association studies in the 2010's. A rich phenotyping approach was first added to the consortium in 1999 as a project led by Dr. Mary Marazita under a center grant headed by Dr. Jeff Murray. Additional sites were added throughout the 2000's, until multiple populations and a large number of individuals (~12,000) comprise the current study population for genetic studies of OFCs and related phenotypes. This study selected specific families from the larger study population for whole exome sequencing.]]>