Measuring the genetic contribution in developmental disorders

Strong evidence exists to point towards sizable genetic contributors to the genesis of congenital malformations in humans (Stevenson, 1993a). The two principal forms of clinical evidence which are traditionally used in this regard are the degree of familial aggregation that a trait exhibits, and twin concordance data. Differences in the prevalence of a disorder between sexes such as the observed male preponderance in pyloric stenosis (Carter and Evans, 1969) is also viewed as suggestive evidence for a genetic contribution. In the instance of congenital abnormalities, these measures have distinct limitations as tools to measure the herita-bility of these conditions.

Family studies carry the caveat that sibs share the same maternal environment over precisely the period during which the etiological determinants are exerting their effect i.e. during embryogenesis. Additionally, family members share environmental and socioeconomic status that contribute confounding effects in a transgenerational manner. This reduces the ability to distinguish between genetic and intrauterine environmental factors as causative influences. Twin concordance studies ascertain the difference in concordance of a trait between dizygotic and monozygotic twin pairs and this is interpreted as a measure of the genetic contribution towards aetiology. Such studies are limited by the observation that monozygotic twinning per se is associated with an increase in the prevalence of congenital anomalies (Schinzel et al., 1979; Hall, 1996).

Epidemiological methods that can be used to deduce etiological factors underlying developmental disorders are therefore secondary and limited. Prevalence studies designed to detect changes over time, between geographical regions and over seasons of the year, act as possible indicators of environmental influences. Examples are studies indicating geographical gradients and seasonality (Fraser and Gwyn, 1998) as influences on the prevalence of facial clefting, and parallel alterations

Table 13.4. Sibling recurrence risk for short and long segment Hirschsprung disease

Type of involvement in proband Male proband % affected Female proband % affected

Table 13.4. Sibling recurrence risk for short and long segment Hirschsprung disease

Type of involvement in proband Male proband % affected Female proband % affected





Short segment





Long segment










Modified from Garver et al. (1985).

Modified from Garver et al. (1985).

in the incidence of pyloric stenosis and maternal smoking over time (Sorensen et al., 2002).

Proxy measures of genetic influences, such as variation in the incidence of conditions between different ethnic populations, could be explained on the grounds of socioeconomic or confounding cultural influences and therefore their use must be interpreted with caution.

Evidence for a genetic contribution towards developmental disorders with complex etiology has also been obtained through laboratory studies examining animal and human subjects. Studies of monogenic malformation traits in mice have repeatedly shown that expressivity and penetrance varies with genetic background (Sibilia and Wagner, 1995; Threadgill et al., 1995; Qu et al., 1998). Dissection of the genetic background using congenic analysis and other approaches holds the promise that these lesser determinants of pheno-typic expression may be identified and their individual contribution towards the heritability of these traits quantified (Southard-Smith et al., 1999; Nadeau, 2003).

Examples of multiple loci interacting in the human to produce developmental disorders have been more difficult to identify. Certainly the variability recognized in Mendelian conditions could conceivably represent influences from environmental, stochastic and/or epistatic genetic effects. Variable expressivity of dominantly inherited developmental conditions, such as holopros-encephaly a disorder characterized by failure of midline cleavage of the forebrain (Roessler and Muenke, 2003), illustrate this point. This condition is also an example of disorders with high herit-ability and a limited number of contributing genes; the so-called oligogenic diseases (Ming and Muenke, 2002). Instances of their simplest forms -digenic diseases caused by the interaction of two loci - have been forthcoming in recent years (Katsanis et al., 2001; Ming and Muenke, 2002; Slavotinek and Biesecker, 2003). The human developmental disorder with perhaps the most defined set of oligogenic contributors to date is a condition known as Hirschsprung disease where innervation of the lower intestinal tract is incomplete.

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