Genetics of Syndromic and Nonsyndromic Cleft Lip and Palate

Abstract

Cleft of the lip with or without cleft palate (CL/P) represents one of the commonest congenital malformations in Western countries. Based on their association with specific malformative patterns or their presence as isolated defects, CL/P can be classified as syndromic and nonsyndromic, respectively. Both forms of CL/P are characterized by a strong genetic component. Syndromic forms are in many cases due to chromosomal aberrations or monogenic diseases. Among these, the Van der Woude syndrome, caused by mutation of the IRF6 gene, represents the commonest form of syndromic CL/P, accounting for about 2% of all cases. On the other hand, nonsyndromic CL/P is a multifactorial disease derived by the interaction between genetic and environmental factors. In recent years, great efforts have been made to identify the genes involved in the susceptibility to nonsyndromic CL/P and to disclose their relationship with specific environmental risk factors, to get information about the pathogenic mechanism leading to the malformation. In this article, we will review the most recent findings about the genes involved in the pathogenesis of syndromic and nonsyndromic CL/P, to provide information about the opportunity in the future to use specific genetic testing for the identification of at-risk mothers and the prevention of the disease based on a personalized approach.

Fishing for Fetal Alcohol Spectrum Disorders: Zebrafish as a Model for Ethanol Teratogenesis

“…In addition, maternal alcohol consumption is a risk factor for orofacial clefting. 12 Numerous structural defects of the brain are found in children with FASD. This includes changes to the brain shape and size, with individuals with FAS showing a reduction in total size.…”

A Novel Heterozygous Mutation (F252Y) in Exon 7 of the IRF6 Gene is Associated with Oral Squamous Cell Carcinomas

“…The exon 7 of IRF6 gene encodes for major region of the C-terminal IAD region and hence mutations within this region may be expected cause functional impairment. Indeed, a single point mutation that causes conversion of GTC to ATC creating valine to isoleucine substitution at position 274 in IRF6 protein has been found to be significantly associated with cleft in several populations (Mangold et al, 2011;Salahshourifar et al, 2011;Stuppia et al, 2011). The identification of loss of IRF6 expression due to promoter hypermethylation of IRF6 in cutaneous squamous cell carcinomas and function impairing mutations in exon 7 of IRF6 in CL/CP/CLP prompted us to investigate, whether such mutations occurred in well differentiated OSCC lesions.…”

Prenatal Counseling on Prenatal Diagnosis of Cleft Lip and/or Cleft Palate at Tokyo Dental College Ichikawa General Hospital

“…According to Multifactor Threshold theory, facial cleft, including CL/P, is not only due to genetic factors, but also a complex interaction with environmental factors 4,14) . Therefore, it is important to make this clear to avoid the parents mistakenly believing that some genetic mutation of their own is responsible for the baby's condition.…”