Cytogenetic location: 1q41-q42 Genomic coordinates (GRCh38): 1:214,400,001-236,400,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q41-q42 | {Autism susceptibility 11} | 610836 | 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.
In a study of 62 families with autism selected for severe obsessive-compulsive behaviors, Buxbaum et al. (2004) found linkage to chromosome 1q42 (multipoint lod score of 3.06 and 2-point nonparametric lod score of 3.21 at D1S1656). The candidate 35-Mb susceptibility locus was between D1S346 and D1S547 on chromosome 1q41-q42.2 (Maussion et al., 2008). In these families, at least 2 individuals had autism or an autism spectrum disorder.
Maussion et al. (2008) refined the AUTS11 locus to a 7.3-Mb region on 1q41-q42. Genotyping of 276 families with autism across this region found an association between autism and several SNPs in the MARK1 gene (606511) on chromosome 1q41. A haplotype including the C allele of rs12740310, the G allele of rs3737296, and the A allele of rs12410279 was overtransmitted (corrected p value of 0.0016) to autistic individuals (relative risk of 1.8 in homozygous carriers). In vitro functional expression studies showed that rs12410279 modulates the level of transcription of MARK1, a kinase involved in microtubule regulation. Postmortem brain tissue from 9 autistic patients showed overexpression of MARK1 in the prefrontal cortex compared to brain tissue from controls, and cellular studies showed that overexpression of MARK1 resulted in shorter dendrite length and decreased transport speed. Maussion et al. (2008) suggested that MARK1 overexpression in individuals with autism may underlie subtle changes in synaptic plasticity linked to dendritic trafficking.
Heterogeneity
Bartlett et al. (2005) applied the posterior probability of linkage (PPL) method to a collection of families with autism. The results indicated a 'substantial' probability of linkage to chromosome 1q23-q24.
Bailey, A., Phillips, W., Rutter, M. Autism: towards an integration of clinical, genetic, neuropsychological, and neurobiological perspectives. J. Child Psychol. Psychiat. 37: 89-126, 1996. [PubMed: 8655659] [Full Text: https://doi.org/10.1111/j.1469-7610.1996.tb01381.x]
Bartlett, C. W., Goedken, R., Vieland, V. J. Effects of updating linkage evidence across subsets of data: reanalysis of the Autism Genetic Resource Exchange data set. Am. J. Hum. Genet. 76: 688-695, 2005. [PubMed: 15729670] [Full Text: https://doi.org/10.1086/429345]
Buxbaum, J. D., Silverman, J., Keddache, M., Smith, C. J., Hollander, E., Ramoz, N., Reichert, J. G. Linkage analysis for autism in a subset families with obsessive-compulsive behaviors: evidence for an autism susceptibility gene on chromosome 1 and further support for susceptibility genes on chromosomes 6 and 19. Molec. Psychiat. 9: 144-150, 2004. [PubMed: 14699429] [Full Text: https://doi.org/10.1038/sj.mp.4001465]
Jones, J. R., Skinner, C., Friez, M. J., Schwartz, C. E., Stevenson, R. E. Hypothesis: dysregulation of methylation of brain-expressed genes on the X chromosome and autism spectrum disorders. Am. J. Med. Genet. 146A: 2213-2220, 2008. [PubMed: 18698615] [Full Text: https://doi.org/10.1002/ajmg.a.32396]
Maussion, G., Carayol, J., Lepagnol-Bestel, A.-M., Tores, F., Loe-Mie, Y., Milbreta, U., Rousseau, F., Fontaine, K., Renaud, J., Moalic, J.-M., Philippi, A., Chedotal, A., Gorwood, P., Ramoz, N., Hager, J., Simonneau, M. Convergent evidence identifying MAP/microtubule affinity-regulating kinase 1 (MARK1) as a susceptibility gene for autism. Hum. Molec. Genet. 17: 2541-2551, 2008. [PubMed: 18492799] [Full Text: https://doi.org/10.1093/hmg/ddn154]
Risch, N., Spiker, D., Lotspeich, L., Nouri, N., Hinds, D., Hallmayer, J., Kalaydjieva, L., McCague, P., Dimiceli, S., Pitts, T., Nguyen, L., Yang, J., and 19 others. A genomic screen of autism: evidence for a multilocus etiology. Am. J. Hum. Genet. 65: 493-507, 1999. [PubMed: 10417292] [Full Text: https://doi.org/10.1086/302497]
Schellenberg, G. D., Dawson, G., Sung, Y. J., Estes, A., Munson, J., Rosenthal, E., Rothstein, J., Flodman, P., Smith, M., Coon, H., Leong, L., Yu, C.-E., Stodgell, C., Rodier, P. M., Spence, M. A., Minshew, N., McMahon, W. M., Wijsman, E. M. Evidence for multiple loci from a genome scan of autism kindreds. Molec. Psychiat. 11: 1049-1060, 2006. [PubMed: 16880825] [Full Text: https://doi.org/10.1038/sj.mp.4001874]