Evidence of linkage in a Hispanic cohort with a Class III dentofacial phenotype

Abstract

Despite the prevalence of craniofacial disorders, the genetic contribution remains poorly understood. Class III malocclusion represents a specific craniofacial problem that can be handicapping, both functionally and socially. We hypothesized that the Class III phenotype is genetically linked to specific loci that regulate maxillary or mandibular growth. To determine the region linked to the Class III phenotype in four Hispanic families, we performed a genome-wide scan and linkage analysis using 500 microsatellite markers. Pedigree and linkage analyses revealed that the Class III phenotype (primarily maxillary deficiency) segregates in an autosomal-dominant manner, and that 5 loci (1p22.1, 3q26.2, 11q22, 12q13.13, and 12q23) are suggestive of linkage. Candidate genes within the 12q23 region (ZLR=2.93) include IGF1, HOXC, and COL2A1. Chromosome 1 results (ZLR=2.92) were similar to those reported previously in an Asian cohort with mandibular prognathism, suggesting that a common upstream genetic element may be responsible for both mandibular prognathism and maxillary deficiency.

Figures

Figure 1.

Pedigrees of four families showing segregation of the Class III phenotype as indicated by darkened (affected) circles or squares. Squares indicate male; circles indicate female; diagonal line indicates deceased.

Figure 2.

Cephalometric tracing showing summary of selected linear and angular cephalometric measurements used in study. Co-ANS (mm), maxillary unit length; Co-Gn (mm), mandibular unit length; Co-Gn :: Co-ANS (mm), maxillary and mandibular difference; Go-Gn (mm), mandibular corpus length; S-N (mm), anteroposterior length of cranial base; ANS-Me (mm), lower facial height; Co-Go (mm), posterior facial height; Wits (mm), length of distance AO-BO (AO, intersection between perpendicular line dropped from Point A and occlusal plane; BO, intersection between perpendicular line dropped from Point B and occlusal plane); ANB, anteroposterior relation of maxilla and mandible; SNA, anteroposterior maxillary position to anterior cranial plane; SNB, anteroposterior mandibular position to anterior cranial plane; SN to GoGn (angle 1), inclination of the frontal cranial base SN to mandible plate GoGn; SN to FH (angle 2), inclination of the frontal cranial base SN to Frankfort horizontal (FH) plane.

Figure 3.

Non-parametric linkage results of chromosome 1 for four families with an autosomal-dominant Class III trait. Y axis indicates LOD score; X-axis indicates map position in centi-Morgan (cM); microsatellite markers are indicated above the peak tracing.