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 genome‐wide 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 study is called, "Fetal cleft lip and palate detection by three-dimensional ultrasonography" by W. Lee MD, J. S. Kirk, K. W. Shaheen, R. Romero, A. N. Hodges, C. H. Comstock - Ultrasound in Obstetrics & Gynecology Volume 16, Issue 4, pages 314–320, 1 September 2000.  Here is an excerpt: "Abstract - Objectives
To demonstrate a standardized approach for the evaluation of cleft lip and palate by three-dimensional (3D) ultrasonography. Design - This was a retrospective study of seven fetuses with confirmed facial cleft anomalies. Post-natal findings were compared to a blinded review of 3D volume data from abnormal fetuses with seven other normal fetuses that were matched for gestational age. Upper lip integrity was examined by 3D multiplanar imaging. Sequential axial views were used to evaluate the maxillary tooth-bearing alveolar ridge contour and anterior tooth socket alignment. Alveolar ridge disruption suggested cleft palate. Premaxillary protrusion, either by multiplanar imaging or surface rendering, indicated bilateral cleft lip and palate. Results - Post-natal findings confirmed bilateral cleft lip and palate (four cases), unilateral cleft lip and palate (one case), and unilateral cleft lip (two cases). Multiplanar review identified all three fetuses with unilateral cleft lip, three of four fetuses with bilateral cleft lip, one fetus with unilateral cleft palate, and three of four fetuses with bilateral cleft palate. Surface rendering correctly identified all cleft lips, with the exception of one fetus, who was thought to have a unilateral cleft lip and palate, despite the actual presence of a bilateral lesion. One cleft palate defect was directly visualized by 3D surface rendering. No false-positives occurred.

Another interesting study is called, "Classification and birth prevalence of orofacial clefts" by Marie M. Tolarová, Jaroslav Cervenka - American Journal of Medical Genetics
Volume 75, Issue 2, pages 126–137, 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 CL±P 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 CL±P 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.