Molecular genetic testing for X-linked mental retardation disorders

This chapter discusses the four X-linked mental retardation disorders. Neurogenetic disorders display a variety of clinical phenotypes that are associated with mutations in specific genes. These genes often exhibit characteristic mutation profiles that illustrate different mutational mechanisms underlying human disease. These maternally inherited disorders include: fragile X syndrome (FXS) or FMR1-associated disorders, Rett syndrome or MECP2-associated disorders, CDKL5-associated disorders, and ARX-related disorders. Fragile X syndrome (FXS) is the most common inherited mental retardation disorder, occurring in about 1 in 3,500 males and approximately 1 in 7,000 females. Affected males are characterized by mild to moderate mental retardation, developmental delay, and behavioral problems. Physical features of FXS include a characteristic long face, prominent forehead, large ears, prominent jaw, and enlarged testicles or macro-orchidism. Affected females usually have mild mental retardation and a more variable phenotype, which renders them more difficult to diagnose clinically. The molecular basis of FXS is mutation of the FMR1gene. The FMR1mutation profile consists of unstable expansions of a CGG triplet repeat, which accounts for over 98% of mutations. Other mutations are rare and include point mutations in the RNA binding site, and intragenic or whole gene deletions involving FMR1. The major mutation affects a polymorphic CGG triplet repeat located at the 5' untranslated region (UTR) of FMR1.