Cleft Lip and Cleft Palate

Cleft Lip and Cleft Palate

C l e f t L i p a n d C l e f t P a l a t e 385 which contains both the group studied and one or more outgroups. See also: Clade; Phylogeny; Taxonomy,...

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C l e f t L i p a n d C l e f t P a l a t e 385 which contains both the group studied and one or more outgroups. See also: Clade; Phylogeny; Taxonomy, Evolutionary; Trees

Class Switching Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.1786

Class switching is a change in the expression of the constant region of an immunoglobulin heavy chain during lymphocyte differentiation, resulting in the production of a different antibody type. See also: Antibody; Immunoglobulin Gene Superfamily

Cleavage See: Nuclease, Restriction Endonuclease

Cleft Lip and Cleft Palate M Melnick Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0228

The human lip and palate form as a result of the cell proliferation (growth), apposition, and fusion of embryonic facial processes between the fifth and twelfth weeks of gestation. This requires that the processes appear in the correct place, achieve the correct shape and size, and have no obstruction to fusion. Given the complex nature of this oral development, one can readily imagine a long list of potential mishaps. Indeed, oral clefts are a major public health problem worldwide. Cleft lip with or without cleft palate (CL  P) has an incidence at birth of about 1 in 500±1000 that varies by population; persons of Asian descent are often at higher risk than those of Caucasian or African

descent. In all populations there are significantly more males born with CL  P than females. The incidence at birth for cleft palate alone (CP) is relatively uniform across populations at about 1 in 2000; significantly more females are born with CP than males. It has clearly been established that CL  P and CP are etiologically distinct. Persons with CL  P very rarely have relatives with CP and vice versa. What CL  P and CP do share is that despite over 50 years of intense study the etiologies of both are largely an enigma.

Inheritance of Oral Clefts In 1942 Poul Fogh-Andersen published his groundbreaking study of hundreds of CL  P and CP families from which he concluded that oral clefts are Mendelian autosomal dominant disorders with greatly reduced penetrance. Sixty years hence we are marginally more knowledgeable than Fogh-Andersen about the etiologies of CL  P and CP. From the weight of the evidence it is clear that there are important major gene effects; these tentatively appear to involve genes related to growth or fusion of facial processes. Nevertheless, the inheritance patterns of CL  P and CP are not classically Mendelian, exhibiting phenocopies, incomplete penetrance, genetic heterogeneity within and between populations, and the influence of modifier genes and diverse environmental factors. This is well-illustrated by the Fraser±Juriloff paradigm of differences in susceptibility to an environmental teratogen resulting from a genetically determined difference in normal oral development (Figure 1).

Recurrence Risk Because the etiologies of CL  P and CP are so largely undefined, the counseling of affected families relies almost entirely on empirical studies of recurrence risk. For Caucasians, it has been found that if the proband has other affected first and/or second degree relatives, the risk to subsequent siblings or offspring is about 15%. If the proband has no other affected first and/or second degree relatives, the risk is about 3±5%. Unfortunately, similar empirical risk determinations for other racial groups have not been made, but it is

Figure 1 (See over) Fraser±Juriloff model of CP susceptibility. The roof with holes in it represents the maternal barrier between teratogen (arrows) and embryo. The x-axis represents the phenotypic distribution, normal to the left of the vertical threshold and abnormal to the right; the threshold separates palate closure from palate nonclosure. (A) Palate closure is normally late (slow growth), so the phenotypic distribution for this genotype (dashed curve) is near the threshold, and the delaying effect of the teratogen causes all embryos (solid curve) of this genotype to fall beyond the threshold and be affected (hatched area). (B) In an early closing (faster growth) genotype, the same delay causes a minority of embryos to be affected. Of course, these two cases are the outer boundaries of the model, and there will be many genotypes (dashed curves) at varying distances to the left of the threshold. (Reproduced with permission from Fraser FC (1980) Animal models for craniofacial disorders. In: Melnick M, Bixler D and Shields ED (eds) Etiology of Cleft Lip and Cleft Palate, pp 1±23. New York: Alan R. Liss. Reprinted with permission of John Wiley & Sons, Inc.)

386

C l i n i c a l G e n etics

(A)

generally agreed that the above estimates are reasonable for non-Caucasians as well. See also: Dysmorphology

Clinical Genetics J M Connor Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0229

Clinical genetics (also termed medical genetics) is the science of human biological variation as it relates to health and disease. Although people have long been aware that individuals differ, that children tend to resemble their parents, and that certain diseases tend to run in families, the scientific basis for these observations was only discovered during the past 125 years. The clinical applications of this knowledge are even more recent with most progress confined to the past 35 years. The term clinical genetics is also applied to the clinical speciality which is concerned with the delivery of medical genetics services. These services include clinicians, genetic counselors, nurses, scientists, and support staff and provide genetic testing and genetic assessment and counseling. See also: Genetic Counseling; Genetic Diseases

Clock Mutants C P Kyriacou Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0230

The genetic analysis of circadian 24-hour biological rhythms is an exciting and fast-moving field. Its

(B)

popularity is partly due to the fact that everyone can relate to their own circadian sleep±wake cycle, and so this subject has an instant `street credibility' for both students of biology and lay(wo)men alike. Central to the approach hasbeen, and still is, the use ofmutagenesis to generate clock variants in the organism of choice. The identification of clock mutants was first documented in 1971 with Drosophila melanogaster, but a number of other model organisms have more recently come into prominence, particularly cyanobacteria, Neurospora, and mice. However Drosophila takes center stage historically, and the molecular mechanisms that provide circadian cycles of behavior and physiology to the fly have striking similarities to those described in other organisms, so we shall focus on the fruit fly as the model model.

The Fly Model: Circadian Phenotypes and the Period Gene Drosophila means `dew lover', and this inspired taxonomical insight describes the behavior of an adult fly as it emerges from its pupal case at dawn, when humidity is at its peak. This allows the fly a few hours to tan its cuticle and pump out its wings before the midday sun of sub-Saharan Africa (fruit flies evolved in this part of the continent) desiccates the fly. If a fly is ready to emerge in mid-afternoon, it will wait for the next morning `gate,' and so a population of mixed-age pupae will show several cycles of morning eclosion, giving a circadian 24-h rhythm which persists even in constant conditions of darkness and temperature. In 1971, a chemical mutagenesis of D. melanogaster performed by Ronald Konopka and Seymour Benzer (see Behavioral Genetics; Neurogenetics in Drosophila; Benzer, Seymour) generated three sex-linked mutants, whose rhythmic eclosion profiles were dramatically altered. In constant (or `freerunning') conditions, one mutant had a fast 19-h cycle, another