CIDR Whole Exome sequencing of multiplex cleft families

Building upon our previous linkage and association studies, we will use whole exome sequencing studies of second and third degree affected relatives drawn from multiplex families. Our specific aims are: 1) To conduct whole exome sequencing on affected members (2° and 3° relatives) drawn from multiplex cleft families from a consortium to identify novel genes causing non-syndromic oral clefts; 2) To confirm and test the role of rare variants in these novel genes through confirmatory Sanger sequencing, plus linkage information using additional members available in these multiplex families. This whole exome sequencing approach will combine evidence from linkage studies and large scale sequencing to identify novel genes causing oral clefts in multiplex cleft families. ]]>
All affected individuals were identified as having an isolated, non-syndromic oral cleft in the initial recruitment visit, although mis-classification is always possible. All families were reviewed by experienced geneticist(s) and there was no evidence of recognized Mendelian forms of oral clefts (e.g. Vander Woude syndrome), but even this level of phenotypic review can miss some forms of recognized Mendelian syndromes.]]>
We formed an international consortium of cleft researchers from Germany and the US to expand our search for genes influencing risk to oral clefts (cleft lip with/without cleft palate and cleft palate alone) through whole exome sequencing of affected 2° and 3° relatives drawn from multiplex cleft families collected from multiple populations. These families were originally collected for linkage studies from multiple populations, including Germany, Syria, the Philippines, Turkey, China, Central America and Taiwan. For this study, 2° and 3° relatives (avuncular, grandparental, etc. plus first cousins and great-avuncular) were identified and sent to the Center for Inherited Disease Research (CIDR) for whole exome sequencing. All affected individuals were identified as having an isolated, non-syndromic oral cleft in the initial recruitment visit, although the pre-screen testing identified one affected individual with a cleft and trisomy 21. This individual was excluded and a substitute sample from another affected family member was submitted to CIDR. ]]>