Orofacial cleft defects: inference from nature and nurture

Cleft lip with or without cleft palate (CL/P), and cleft palate (CP) are most common congenital malformation conditions. Prognosis mainly rests on the possibility of associated symptoms, since more than a hundred recognised Mendelian disorders involve this orofacial defect (thereby defining syndromic CL/P, or CP). Multiplex non-syndromic CL/P, or CP families indicate that genetic factors are likely involved in causation. Inheritance is generally regarded as multigenic, allelic variation at different loci (TGF alpha, TGF beta 3, RARA) determining a fraction of the genetic risk, as demonstrated by association or transmission/disequilibrium non-parametric tests. Some pedigrees are however clearly monogenic, consistent with either autosomal dominant or recessive inheritance. X-linked recessive CP (with or without ankyloglossia) is an additional possibility. Significant linkage to 6p23 (EDN1) or 19q13 (BCL3) could be achieved using parametric models with reduced penetrance. Environmental exposures were also demonstrated to interfere with lip and/or palatal formation when present during the first trimester of pregnancy. Whereas ethanol, retinoids or folate antagonists are clearly teratogenic, indictment of more common exposures such as caffeine is merely tentative. The development of animal models allowed to confirm the genetic bases of CL/P, or CP, exemplify the role of teratogens, and study the interaction of nature and nurture.