There is growing appreciation of the influence of genetic constitution on predisposition to disease, even that not usually considered ‘genetic’. Approximately 40% of the estimated 30000 human genes are expressed in the nervous system, the majority of these exclusively (Hurko, 1997; International Human Genome Sequencing Consortium, 2001; Sutcliffe, 1988; Venter et al., 2001). Neurological and psychiatric health might thus be especially susceptible to genetic influence. Furthermore, the nervous system can be uniquely vulnerable to mutations in genes expressed ubiquitously, as with huntingtin (Trottier et al., 1995), and to primary metabolic derangements in non-neural tissue, as with hepatic porphyrias (Strand et al., 1970) or diabetes mellitus. A disproportionate number of single gene disorders manifest as neurological or psychiatric dysfunction (Hurko, 2001).

Many of the successes of human molecular genetics have come from study of neurological disease. Neurological patients suffering from monogenic disorders have thus far only benefited from improved diagnosis. Identification of pathogenic genes has provided powerful reagents, transgenic animals, lessons from homologues in lower organisms and other insights into pathophysiology. These will hasten the development of effective therapies. However, most of these benefits, both realized and anticipated, have been confined to monogenic disorders. Such single gene, or Mendelian, disorders are rare.

Complexity in single gene disorders

Furthermore, even in monogenic disorders the relationship to clinical phenotype is not always straightforward (Estivill 1996). A given phenotype can result from mutation of any of a number of genes. Genetic heterogeneity exists in early-onset Alzheimer's disease (Dartigues & Letenneur, Furthermore, even in monogenic disorders the relationship to clinical phenotype is not always straightforward (Estivill 1996). A given phenotype can result from mutation of any of a number of genes. Genetic heterogeneity exists in early-onset Alzheimer's disease (Dartigues & Letenneur, 2000), autosomal dominant spinocerebellar atrophies (Durr & Brice, 2000), limb-girdle muscular dystrophies (Beckmann, 1999; Bushby, 1999; Kissel & Mendell, 1999) and X-linked mental retardation (Toniolo & D'Adamo, 2000), among others.

Allelic heterogeneity

Different mutations within a single gene also contribute complexity. Frame-shift mutations abolish activity of dystrophin, causing Duchenne muscular dystrophy (DMD); mutations that do not shift reading frame compromise function only partially, resulting in milder Becker dystrophy or just subclinical elevation of serum creatine kinase (England et al., 1990; Matsuo et al., 1990).