Cytogenetic location: 17q11 Genomic coordinates (GRCh38): 17:25,100,001-33,500,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q11 | {Autism susceptibility 6} | 609378 | 2 |
Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypic, and ritualized patterns of interests and behavior (Bailey et al., 1996; Risch et al., 1999). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (see ASPG1; 608638) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (Jones et al., 2008). Genetic studies in autism often include family members with these less stringent diagnoses (Schellenberg et al., 2006).
For a discussion of genetic heterogeneity of autism, see 209850.
By genomewide linkage analysis of 152 autistic sib pairs, the International Molecular Genetic Study of Autism Consortium (2001) (IMGSAC) identified an autism locus on chromosome 17q11 (multipoint lod score of 2.34 at HTTINT2 within the SLC6A4 gene; 182138). There was evidence for increased paternal sharing at marker D17S798.
By analysis of affected sib pairs from 345 families from the AGRE (Autism Genetic Resource Exchange) with a broad phenotype including autism or an autism spectrum disorder, Yonan et al. (2003) obtained suggestive evidence for linkage on chromosomes 17, 5, 11, 4, and 8 (listed in order of decreasing MLS). The most significant findings were an MLS of 2.83 on 17q11 at marker D17S1800, near the SLC6A4 gene and an MLS of 2.54 on 5p.
The autism spectrum disorder shows a striking sex bias, with a male:female ratio of idiopathic autism estimated at 4-10:1, and with an increase in this ratio as the intelligence of the affected individuals increases (Folstein and Rosen-Sheidley, 2001). Stone et al. (2004) analyzed a subset of the AGRE families reported by Yonan et al. (2003) for sex bias of affected children. The results showed a major male-specific linkage peak (lod score of 4.3) at 17q11 flanked by markers D17S1294 and D17S798, suggesting that sexual dichotomy is an important factor in the genetics of autism. Stone et al. (2004) noted that male and female brains develop, are structured, and function differently. Furthermore, a large body of research shows not only that males and females process input in different ways, but also that this sexual dichotomy extends to the macroscopic structures of the brain.
Bartlett et al. (2005) applied the posterior probability of linkage method to the collection of families with autism studied by Yonan et al. (2003) and analyzed 6 clinically defined phenotypic subsets (e.g., autism, Asperger syndrome (608638), pervasive developmental delay, phrase-speech delay). The findings provided further characterization of a possible parent-of-origin effect (imprinting) at the 17q11 locus.
By specific analysis of markers on chromosome 17 in 340 families in which 1 child had autism and at least 1 other sib had either autism or autism spectrum disorder, Sutcliffe et al. (2005) found significant linkage to marker D17S1800 on 17q11.2. A peak recessive lod score of 5.44 was obtained for all 340 families; a peak recessive lod score of 7.86 was obtained when 189 families containing only affected males were analyzed. Corresponding nonparametric lod scores were 4.88 and 5.18 for all families and families with affected males only, respectively.
Stone et al. (2007) performed dense SNP analysis of the 13.7-Mb region flanking the centromere on chromosome 17 in 219 affected child-parent trios obtained from the AGRE. No single SNP or haplotype association was sufficient to account for the initial linkage signal previously reported by Stone et al., 2004, leading Stone et al. (2007) to suggest that there may be multiple common or rare susceptibility alleles that contribute to the disorder.
Association with the SLC6A4 Gene on 17q11
Noting that elevations in serotonin had been found in patients with autism (Abramson et al., 1989; Piven et al., 1991), Klauck et al. (1997) used the transmission/disequilibrium test (TDT) to analyze a common polymorphism (5-HTTLPR; long/short promoter polymorphism) in the upstream regulatory region of the serotonin transporter gene (SLC6A4; 182138.0001) and a VNTR in intron 2 of the same gene in a total of 117 autistic trios. They found a higher frequency and preferential transmission of the 5-HTTLPR long allele in the patients with autism. In contrast, Cook et al. (1997) found preferential transmission of the short 5-HTTLPR allele in autism, but no association between autism and the VNTR in intron 2.
Kim et al. (2002) studied 115 trios consisting of a proband with autism and both parents. Ninety-eight probands were male and 17 were female, and the sample included 94 Caucasians, 7 African Americans, 8 Asian Americans, and 6 Hispanics. Seven SNP and 4 SSR markers in and around the SLC6A4 gene showed nominally significant evidence of transmission disequilibrium. In 81 trios, there was replication of a previous finding of transmission equilibrium between a haplotype consisting of the 5-HTTLPR polymorphism and a VNTR in intron 2, but there was no preferential transmission of 5-HTTLPR as an independent marker. No mutations were detected in the SLC6A4 gene.
Maestrini et al. (1999) found no association or linkage to the 5-HTT gene in 94 families comprising 174 individuals with autism. Zhong et al. (1999) and Persico et al. (2000) found no linkage or association between the 5-HTTLR gene alleles and autism.
In 84 Irish families with autism, Conroy et al. (2004) found preferential transmission of the short 5-HTT promoter allele (p = 0.0334). A number of haplotypes, especially those involving and surrounding a T-to-C transition in promoter IB, designated SNP10, showed evidence of association. Odds ratios (ORs) ranged from 1.2 to 2.4. A haplotype defined by SNP10, a 12-repeat allele in the VNTR in intron 2, and a G-to-A transition in intron 2 (designated SNP18) was the most significant haplotype associated with transmission to affected probands (OR, 1.8; chi square, 7.3023; p = 0.0069).
Sutcliffe et al. (2005) screened 384 families in which at least 1 child had autism and a second sib had autism or autism spectrum disorder for rare genetic variants in the SLC6A4 gene. In some families, polymorphic variants appeared to be increased compared to controls. In 3 unrelated families, Sutcliffe et al. (2005) identified 3 different rare SLC6A4 variants that segregated with the disorder, further suggesting that SLC6A4 represents a susceptibility locus for autism spectrum disorders. These variants in aggregate appeared to be associated with increased rigid-compulsive behaviors when viewed as a subphenotype of autism.
Among 352 families with autism, Ramoz et al. (2006) found no association with the 5-HTTLPR allele or with 9 different SNPs in the SLC6A4 gene, including 5 SNPs that were previously shown to be associated with the disorder (Kim et al., 2002).
Weiss et al. (2006) presented evidence suggesting that genotypes in the ITGB3 (173470) and SLC6A4 genes may interact to affect autism susceptibility.
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