NONSYNDROMIC CLEFT-LIP WITH OR WITHOUT CLEFT-PALATE - EVIDENCE OF LINKAGE TO BCL3 IN 17 MULTIGENERATIONAL FAMILIES

Nonsyndromic cleft lip with or without cleft palate (CL/P) is a common craniofacial developmental defect. Recent segregation analyses have s uggested that major genes play a role in the etiology of CL/P. Linkage to 22 candidate genes was tested in 11 multigenerational families wit h CL/P, and 21 of these candidates were excluded. APOC2, 19q13.1, whic h is linked to the proto-oncogene BCL3, gave suggestive evidence for l inkage to CL/P. The study was expanded to include a total of 39 multig enerational CL/P families. Linkage was tested in all families, using a n anonymous marker, D19S178, and intragenic markers in BCL3 and APOC2. Linkage was rested under two models, autosomal dominant with reduced penetrance and affecteds only. Homogeneity testing on the two-point da ta gave evidence of heterogeneity at APOC2 under the affecteds-only mo del. Both models showed evidence of heterogeneity, with 43% of familie s linked at zero recombination to BCL3 when marker data from BCL3 and APOC2 were included. A maximum multipoint LOD score of 7.00 at BCL3 wa s found among the 17 families that had posterior probabilities greater than or equal to 50% in favor of linkage. The transmission disequilib rium test provided additional evidence for linkage with the 3 allele o f BCL3 more often transmitted to affected children. These results sugg est that BCL3, or a nearby gene, plays a role in the etiology of CL/P in some families.