Genetic defects responsible for tooth agenesis are only now beginning to be uncovered. MSX1 and PAX9 have been associated with tooth agenesis in mice and humans, but interestingly for humans, these genes are associated with specific missing teeth. Mouse models also show that specific genes contribute to the development of specific types of teeth. A precise description of the phenotype specifying which teeth are missing has become fundamental. Mendelian segregation can be identified in families with tooth agenesis, but heterogenous or multiple genes may be responsible for the development of specific types of teeth agenesis in humans. Data from animal models are still very complex, and the human embryology is still poorly understood. Oral clefts and syndromic forms of tooth agenesis may be the best models for isolated tooth agenesis. In the future, a precise description of the missing teeth in syndromes involving tooth agenesis may be useful.

Most of the studies on genetic variation contributing to TMD are approaching the disease mainly from an immune-inflammatory perspective. Recent investigations of the genetic variables which may predict identifiable levels of pain perception may uncover new approaches to our traditional treatment modalities for the chronic pain patient.

It has been proposed that susceptibility to clefting in South America is related to Amerindian ancestry, where clefting is present at a higher frequency than in the other admixed populations (Caucasian and African) that make up the diverse racial mix of current South Americans. To clarify the genetic origins and establish a method for genetic mapping, mitochondrial DNA variation and Y-chromosome markers were studied in a South American population affected with clefting. Two-hundred and seventeen subjects and matched controls were selected through the Latin-American Collaborative Study of Congenital Malformations (ECLAMC). The case group showed a higher frequency of Native American haplogroups and a lower frequency of African haplogroups (p < 0.00001). In addition, the case group showed a much higher frequency of the specific native American haplogroup D than the control group (p < 0.00001). For the Y-chromosome markers, the case group showed a lower frequency of the African-specific marker, YAP (p = 0.002), and a higher frequency of the Native American-specific marker, DYS199 (p < 0.00001). Even though differences were found in the frequencies of the markers studied, the contribution of each founder population was similar for both groups. Results suggest a strong Native American maternal contribution and a strong Caucasian (Spanish and Portuguese) paternal contribution to the population studied. The implications of this finding include the possibility of using admixture mapping approaches to this population.

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Phenotypic heterogeneity is a hallmark of complex traits, and genetic studies of such traits may focus on them as a single diagnostic entity or by analyzing specific components. For example, in orofacial clefting (OFC), three subtypes -cleft lip (CL), cleft lip and palate (CLP), and cleft palate (CP) have been studied separately and in combination. To further dissect the genetic architecture of OFCs and how a given associated locus may be contributing to distinct subtypes of a trait we developed a framework for quantifying and interpreting evidence of subtype-specific or shared genetic effects in complex traits. We applied this technique to create a "cleft map" of the association of 30 genetic loci with three OFC subtypes. In addition to new associations, we found loci with subtype-specific effects (e.g., GRHL3 (CP), WNT5A (CLP)), as well as loci associated with two or all three subtypes. We crossreferenced these results with mouse craniofacial gene expression datasets, which identified additional promising candidate genes. However, we found no strong correlation between OFC subtypes and expression patterns. In aggregate, the cleft map revealed that neither subtype-specific nor shared genetic effects operate in isolation in OFC architecture. Our approach can be easily applied to any complex trait with distinct phenotypic subgroups.