Project Summary
The term “Cleft lip with or without cleft palate (CL/P)” encompasses a variety of clinical presentations that
collectively represent one of the most common human birth defects. For each patient, the impact can also be
significant. The severity of a patient’s clinical presentation is the major determinant of the duration and
frequency of significant surgical intervention and long-term clinical care. Considerable progress has been
made over the last few decades to determine the genes responsible for syndromic forms of CL/P. However,
the low penetrance and variability in presentation pose challenges when counseling families about recurrence
risks, as it is currently impossible to predict whether a child will be born with CL/P or how severe the
presentation might be regardless of whether a genetic predisposition is known. This new proposal builds on
important new observations and exciting preliminary data on established mouse models of CL/P to begin to
dissect the factors that influence the cleft penetrance and severity in embryos that are genetically predisposed
to CL/P. Specifically, this project will address the role of maternal diet (specifically vitamin A) as a modifier of
genetic susceptibility, severity of presentation and in utero correction prior to birth, as well as investigate the
basis for the left bias in unilateral cleft presentations. Although vitamin A and its derivatives have long been
implicated as a risk factor in CL/P, this project will exploit a novel mouse mutant background that overcomes
the limitations of prior animal model studies such as the need for excessive, non-physiologic levels of vitamin A
and unnatural routes of administration. Furthermore, we test the impact on two distinct underlying genetic
susceptibilities. The successful demonstration of modifying roles for these factors could ultimately have a
significant impact on patient counselling and potentially open up the possibility of developing simple and
effective interventional and preventative maternal dietary interventions such as personalized dietary
supplementation for mothers carrying CL/P risk alleles, or crop biofortification approaches for whole
populations where dietary deficiencies and genetic risk factors are known. Such approaches could have a
profound impact on the incidence of NS-CL/P, much like the successes seen for maternal folic acid
supplementation for reducing the risk of neural tube defects.
