Genetics and ASD
ASD has a relatively low prevalence of approximately two per 1000, yet the recurrence risk to siblings is 4 to 5%. Concordance in monozygotic twin pairs has ranged from 60 to 90%, while dizygotic twin pairs in these studies have generally found a con-cordance similar to that found in siblings of affected children. Even these concordance numbers are likely underestimates of the genetic contribution, since many pairs discordant for autistic disorder were concordant for another ASD. When considered as a spectrum disorder, twin studies suggest that at least 92% of monozygotic twin pairs are concordant for at least milder but sim-ilar deficits in the social and communication realms (compared with a 10% rate in these studies for dizygotic twin pairs)
ASD is currently thought to be a complex genetic disor-der. The varying strength of the contributions of different loci is likely also to be responsible for the genetic heterogeneity that characterizes ASD. In ASD, findings so far suggest a disease process with greater than 10, and perhaps as many as 100 loci.
Chromosomal abnormalities have provided some clues as to where some of these susceptibility genes may be (Table 27.2). The most common chromosomal abnormality associated with ASD has been in a region of chromosome 15 (15q11–13). These abnormalities usually involve either an interstitial duplication or a supernumerary pseudodicentric chromosome (an extra chromosome with two centromeres; “pseudo” refers to the fact that only one centromere can be active).
Linkage studies have shown evidence of linkage in sev-eral polymorphisms in the area of chromosome 15 noted above, including the gamma-aminobutyric acid receptor subunit gene (GABRB3) and transmission disequilibrium for markers in GABRB3 has also been found. Most recently, evidence of trans-mission disequilibrium was found to peak at another region of the serotonin transporter gene, supporting evidence of involvement of the gene, but not specifically the 5HTTLPRvariant (Kim et al., 2002).
There has been significant progress in terms of identify-ing the genetic basis of Rett’s syndrome. Mutations in the gene (MECP2) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) have been identified as the cause of more than 80% of classic cases of Rett’s syndrome.