Etiologies of Intellectual Disability. Intellectual disability arises from a variety of causes, including congenital, prenatal, perinatal, toxic, infectious, psychosocial, chromosomal, and hereditary factors (Xxxxx et al. 1997). The most common etiologies are chromosomal abnormalities, such as aneuploidies and segmental aneusomies. Chief among these is trisomy 21, which causes 9.2% of all ID. Other noteworthy causes include the DiGeorge and Xxxxxxxx-Beuren microdeletion syndromes, which represent 2.4% and 1.3% of ID, respectively (Xxxxx et al. 2006). It is hypothesized that haploinsufficiency or genetic overdosage of a specific gene or genes leads to the ID seen in many aneuploidies and segmental aneusomies (Rachidi and Xxxxx 2008). However, while genomic critical regions have been defined in Down, DiGeorge, and Xxxxxxxx-Beuren syndromes, no single genes have yet been identified as the sole cause of ID in these chromosomal abnormalities (Xxxxxxx et al. 1989; Ferrero et al. 2009; Xxxxxxx et al. 2009). The second most frequent causes of intellectual disability are single gene mutations (Xxxxx et al. 2006). In fact, over 100 genes have been associated with ID (Basel-Vanagaite 2007; Gecz et al. 2009). Mutations in some of these genes lead to a collection of recurrent, recognizable signs and symptoms which define a clinical syndrome. The most common of these is fragile X syndrome, which is caused by trinucleotide repeat expansion in the FMR1 gene (Verkerk et al. 1991). Other significant monogenic ID syndromes include Xxxxx-Xxxxx-Xxxxx syndrome, Rett syndrome, and Xxxxxx-Xxxxx syndrome, caused, respectively, by mutations in DHCR7, MECP2, and RPS6KA3 (Xxxxxxx and Xxxxx 2002; Xxxxxx 2008; Xxxxxxxxx et al. 2009). More common than syndromic ID, however, is nonsyndromic ID, in which there is no specific clinical phenotype beyond the intellectual disability. While this nonsyndromic preponderance may be an artifact of incomplete phenotyping and small sample sizes of discrete disorders, the observed clinical homogeneity has made genetic linkage studies quite challenging (Ropers 2008). Although much progress has been made in elucidating the varied causes of ID, 50% to 80% of intellectual disability remains of unknown origin (Xxxxx et al. 2006). The lack of a diagnosis can be quite troubling, particularly to the parents of someone affected with ID. Feelings of guilt or culpability and a lack of acceptance of the condition’s permanence and significance are commonly reported by the parents of children with undia...
