Vol 3 n° 1 - Genetic Approach to Neuropsychiatric Disorders
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The search for the mutant genes for monogenic disorders

has  been  a  spectacular  success.  This  was  accomplished

 because of the mapping and sequencing of the human genome, the determination of the sequence variability, the collection of well-characterized families with mendelian disorders, the development of statistical methods for link- age analysis, and laboratory methods for mutation search. The challenge of the genetic medicine is now to decipher the nucleotide sequence variants that predispose to com- mon complex, polygenic phenotypes. The methodology for this challenge is in development and constant evolution. It is anticipated that, in the next 10 to 20 years, susceptibility alleles for these common disorders will be identified. he principal aim of the field of genetic medi- cine is to discover the links between nucleotide sequence variation in the human genome and the various human phenotypes. The methodologies of linkage analysis and mutation detection, along with progress in the mapping and sequencing of the human genome and that of model organisms, resulted in a plethora of exciting discoveries concerning mutant alleles of genes and their related phe- notypes. In this review, I will briefly summarize some general principles regarding the search for genes (more specifically, mutant alleles of these genes) that either cause the various human genetic disorders or confer predisposition to common, complex phenotypes. Monogenic disorders There are a large number of phenotypes (each of which is rare in the population) due to abnormal mutant alle- les of single genes. These disorders are usually called monogenic since there is one gene of paramount impor- tance related to the development of the phenotype; con- sequently, these phenotypes show a mendelian mode of inheritance. For a particular disorder, the mapping of the  responsible  gene  could  easily  be  determined  by studying  the  transmission  of  polymorphic  markers within  a  family.  Positional  candidate  gene–cloning strategies  could  then  be  employed  to  identify  the responsible gene by virtue of mutations (nucleotide sequence variants) present in a patient’s DNA and not in controls. The genetic methodology identified a route to understanding the molecular basis of disease, which otherwise seemed intractable. On May 25, 2001, the knowledge-based database OMIM (Online Mendelian Inheritance  in  Man)1,2  contained  1168  mutant  genes linked to human monogenic disorders. Several notable examples of neurological disorders are shown in Table I, which lists disease genes, their corresponding pheno- types, and the years of the linkage mapping and their positional cloning. The first mutant gene–disease link discovered by positional cloning strategies was that of chronic granulomatous disease in 1986. The search for allelic variants that cause monogenic disorders or predispose to common, complex polygenic phenotypes Stylianos E. Antonarakis, MD, DSc

Keywords: monogenic disorder; complex polygenic phenotype; pathogenic allele; linkage analysis; linkage disequilibrium

Author affiliations: Division of Medical Genetics, University of Geneva Medical School and University Hospitals of Geneva, Switzerland

Address for correspondence:  Division of Medical Genetics, University of Geneva Medical School and University Hospitals of Geneva, 1 rue Michel-Servet, 1211 Geneva, Switzerland (e-mail: Stylianos.Antonarakis@medecine.unige.ch)

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