Gene Targeting Technology And Craniofacial Development

One interesting study is called, Genetics of cleft lip and palate: syndromic genes contribute to the incidence of non-syndromic clefts - Hum. Mol. Genet. (2004) 13 (suppl 1): R73-R81. Here is an excerpt: Abstract - Clefts of the lip and/or palate (CL/P) are among the most common birth defects worldwide. The majority are non-syndromic where CL/P occurs in isolation of other phenotypes. Where one or more additional features are involved, clefts are refered to as syndromic. Collectively CL/P has a major clinical impact requiring surgical, dental, orthodontic, speech, hearing and psychological treatments or therapies throughout childhood. The etiology of CL/P is complex and thought to involve both major and minor genetic influences with variable interactions from environmental factors. Using a combination of gene targeting technology and traditional developmental techniques in both mouse and chick, significant progress has been made in the identification of numerous genes and gene pathways critical for craniofacial development. Despite this, it has been a particular source of frustration that mutation screening of specific candidates, association studies and even genomewide scans have largely failed to reveal the molecular basis of human clefting. Nevertheless, some important findings have recently come from studies involving syndromic forms of the disorder. These include several genes which have now been shown to contribute

Another interesting article is called, Association of genetic variation of the transforming growth factor-alpha gene with cleft lip and palate. By H H Ardinger, K H Buetow, G I Bell, J Bardach, D R VanDemark, and J C Murray - Department of Pediatrics, University of Iowa, Iowa City 52242. Am J Hum Genet. 1989 September; 45(3): 348353. Here is an excerpt: Complex segregation analysis of pedigrees having nonsyndromic cleft lip with or without cleft palate (CL/P) (Chung et al. 1986; Marazita et al. 1986) has shown that a major-locus model best explains the observed recurrence of CL/P in Caucasian families. To identify this major gene, we compared the frequencies of 12 RFLPs at five loci-epidermal growth factor, transforming growth factor-alpha, epidermal growth factor receptor, glucocorticoid receptor, and estrogen receptor-in both a group of 80 subjects with nonsyndromic CL/P and 102 controls. These candidate genes were selected because studies in rodents had suggested their possible involvement in palatogenesis. A significant association was observed between two RFLPs at the transforming-growth-factor-alpha (TGFA) locus and the occurrence of clefting (P = .0047 and P = .0052). This suggests that either the TGFA gene itself or DNA sequences in an adjacent region contribute to the development of a portion of cases of CL/P in humans and provides an opportunity to begin to examine the molecular events underlying lip and palate formation.

Another interesting study is called, Classification and birth prevalence of orofacial clefts by Marie M. Tolarov, Jaroslav Cervenka - American Journal of Medical Genetics Volume 75, Issue 2, pages 126137, 13 January 1998. Here is an excerpt: Abstract - To determine the proportion and birth prevalence of typical orofacial clefts (cleft lip (CL), cleft palate (CP), cleft lip and palate (CLP)) and atypical clefts (median, transversal, or oblique facial clefts) and the conditions in which they occur, we analyzed a population-based sample of 4,433 cases ascertained from 2,509,881 California births. We classified cases into: isolated cleft anomalies, sequences of the primary defect, chromosomal aberrations, monogenic syndromes, results of known teratogens, associations, multiple congenital anomaly (MCA) of unknown etiology, or conjoined twins. The birth prevalence of isolated CLP was 0.77 per 1,000 births (CL 0.29/1,000, CLP 0.48/1,000) and of isolated CP, 0.31 per 1,000 births. Non-Hispanic Whites had the greatest prevalence of isolated clefts, Asians slightly lower prevalences, and Blacks the lowest. Asians had the lowest prevalence of Robin sequence and non-Hispanic Whites the highest, twice that of Hispanics. Hispanics, followed by Asians, had the highest prevalence of CLP with MCA; non-Hispanic Whites had the lowest. Asians had the lowest prevalence of CP; in Whites and Hispanics it was almost twice as high. Blacks had the highest CL:CLP ratio, followed by non-Hispanic Whites and Asians; Hispanics had the lowest. Isolated anomalies constituted 61.67% of clefts. In the total sample there were 3.9% sequences, 8.79% chromosomal aberrations, 6.02% monogenic syndromes, 0.2% known teratogens, 0.79% associations, 18.55% MCA of unknown etiology, and 0.1% in conjoined twins. This study supports evaluation of each child on a case level, and provides a framework for genetic counseling and other studies focused on causes and prevention of these serious anomalies.

We all owe a debt of gratitude to these researchers for their fine work and dedication. For more information, please read the studies in their entirety.