Segregation Analysis of Isolated Cleft Lip in a high-prevalence cluster of South America: uncommon high-risk allele and implications for genetic association studies.

POLETTA F; CASTILLA E; ORIOLI I; MEREB JC; CARVALHO; BRANDON CA; RESICK JM; VIEIRA AR; MARAZITA ML; LOPEZ CAMELO JS

Montreal

Congreso; 12th International Congress of Human Genetics / 61st Annual Meeting of the American Society of Human Genetics; 2011

ASHG

The genetic contribution to the etiology of CL/P is complex and mainly heterogeneous. A CL/P high prevalence area was previously identified in Argentine Patagonia probably associated with Amerindian ancestry and low socioeconomic strata. The aim of this work was to estimate the mode of inheritance and the number of loci involved in CL/P families from Patagonia prior to plan for linkage/association studies. The sample included 117 extended pedigrees (2,835 total people) ascertained from CL/P probands registered by ECLAMC (The Latin-American Collaborative Study of Congenital Malformations) hospitals in Patagonia. Family Risk Ratios (FRR) were estimated for first-, second-, and third-degree relatives of CL/P probands and Complex Segregation Analyses (CSA) were conducted using Pointer and SAGE software. CSA excluded the Sporadic, Environmental and Multifactorial threshold models, and provided evidence that CL/P is most likely determined by a dominant major gene with incomplete penetrance and with residual familial effects on affection status. Furthermore, FRR for relatives equate well with a major gene (or multiple additive or independent loci). One or two loci interacting epistatically with an poligenic background is shown to be a plausible alternative. The high-risk allele frequency estimates (1 to 9%) has important implications with regards to the feasibility of identifying causative loci in this population through the typical commercial platforms and methods used in genome-wide association studies. Newer methodological approaches including customized genotyping platforms and analysis methods for association involving rare variants should be taken into account for future association studies to be conducted in this population. The identification of susceptibility genes associated with the occurrence of oral clefts in this high-prevalence cluster will eventually provide practical advice for genetic counseling of these families that will be more accurate than the current empiric recurrence risk estimates used.