MSX1 in relation to clefting. hypodontia and hydrocephaly in humans

Abstract

Orofacial clefting and hypodontia are both common congenital disorders with a complex etiology in which genetic and environmental factors might play a role. In the Netherlands, approximately 300 children are born annually with a cleft lip and/or palate. The occurrence of hypodontia is approximately 5,5 % in the general population. The general aim of this thesis is to expand the knowledge on the genetic basis of clefting and hypodontia and in this way to improve diagnostics and genetic counseling of patients and their family members. We performed a systematic review of associated structural and chromosomal defects in oral clefts. This systematic review was conducted to get insight in the prenatal and postnatal prevalence of associated anomalies and chromosomal defects related to cleft category. This provided a basis for pre- and postnatal counseling and prenatal invasive diagnostics in oral clefts. We found evidence that different cleft categories are variously associated with additional congenital anomalies and underlying chromosomal defects. Data from prenatal and postnatal studies showed that the prevalence of associated anomalies was lowest in cleft lip which has the most favourable prognosis. For cleft lip in combination with cleft palate, higher frequencies were found both pre-and postnatally. Cleft palate was the category that was most frequently associated with accompanying defects postnatally. Chromosomal abnormalities were most frequently seen in association with additional anomalies. The increased rate of hypodontia in orofacial clefting suggests a related etiology. To date, a growing number of genes is identified that are involved in the etiology of both clefting and hypodontia. In 2000, we identified MSX1 as a causative gene for monogenetic orofacial clefting in combination with hypodontia in a Dutch family. We then continued to focus on the role of MSX1 in the etiology of both disorders in the Dutch population. It was demonstrated that MSX1 contributes in the etiology of non-syndromic clefting and isolated hypodontia albeit small. We found that periconceptional smoking by both parents may interact with a specific allelic variant of MSX1 to significantly increase the orofacial cleft risk in their offspring. In Msx1 mice mutants the occurrence of a severe hydrocephalus with a collapse of the cerebral aqueduct besides the craniofacial defect and tooth agenesis, motivated us to study also the role of MSX1 in the etiology of hydrocephaly in humans. Although we could not confirm a major role for MSX1 in the etiology of hydrocephaly due to aqueduct stenoses in humans, this hypothesis deserves further study. Interestingly, in the search for other candidate hypodontia genes besides MSX1, we identified WNT10A as a major gene in the etiology of hypodontia. By including WNT10A in the DNA diagnostics of isolated tooth agenesis, the cause of tooth agenesis can be identified in significantly more patients. The yield of molecular testing in this condition was increased from 15% to 71%.