| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
ELECTRONIC ARTICLE |
The Genetics of Autism
* Class of 2004, Albert Einstein College of Medicine, Bronx, New York
Saul R. Korey Department of Neurology, Department of Pediatrics, and Rose F. Kennedy Center for Research in Mental Retardation and Human Development, Albert Einstein College of Medicine, Bronx, New York
Autism is a complex, behaviorally defined, static disorder of the immature brain that is of great concern to the practicing pediatrician because of an astonishing 556% reported increase in pediatric prevalence between 1991 and 1997, to a prevalence higher than that of spina bifida, cancer, or Down syndrome. This jump is probably attributable to heightened awareness and changing diagnostic criteria rather than to new environmental influences. Autism is not a disease but a syndrome with multiple nongenetic and genetic causes. By autism (the autistic spectrum disorders [ASDs]), we mean the wide spectrum of developmental disorders characterized by impairments in 3 behavioral domains: 1) social interaction; 2) language, communication, and imaginative play; and 3) range of interests and activities. Autism corresponds in this article to pervasive developmental disorder (PDD) of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and International Classification of Diseases, Tenth Revision. Except for Rett syndrome—attributable in most affected individuals to mutations of the methyl-CpG-binding protein 2 (MeCP2) gene—the other PDD subtypes (autistic disorder, Asperger disorder, disintegrative disorder, and PDD Not Otherwise Specified [PDD-NOS]) are not linked to any particular genetic or nongenetic cause. Review of 2 major textbooks on autism and of papers published between 1961 and 2003 yields convincing evidence for multiple interacting genetic factors as the main causative determinants of autism. Epidemiologic studies indicate that environmental factors such as toxic exposures, teratogens, perinatal insults, and prenatal infections such as rubella and cytomegalovirus account for few cases. These studies fail to confirm that immunizations with the measles-mumps-rubella vaccine are responsible for the surge in autism. Epilepsy, the medical condition most highly associated with autism, has equally complex genetic/nongenetic (but mostly unknown) causes. Autism is frequent in tuberous sclerosis complex and fragile X syndrome, but these 2 disorders account for but a small minority of cases. Currently, diagnosable medical conditions, cytogenetic abnormalities, and single-gene defects (eg, tuberous sclerosis complex, fragile X syndrome, and other rare diseases) together account for <10% of cases. There is convincing evidence that "idiopathic" autism is a heritable disorder. Epidemiologic studies report an ASD prevalence of 
3 to 6/1000, with a male to female ratio of 3:1. This skewed ratio remains unexplained: despite the contribution of a few well characterized X-linked disorders, male-to-male transmission in a number of families rules out X-linkage as the prevailing mode of inheritance. The recurrence rate in siblings of affected children is 2% to 8%, much higher than the prevalence rate in the general population but much lower than in single-gene diseases. Twin studies reported 60% concordance for classic autism in monozygotic (MZ) twins versus 0 in dizygotic (DZ) twins, the higher MZ concordance attesting to genetic inheritance as the predominant causative agent. Reevaluation for a broader autistic phenotype that included communication and social disorders increased concordance remarkably from 60% to 92% in MZ twins and from 0% to 10% in DZ pairs. This suggests that interactions between multiple genes cause "idiopathic" autism but that epigenetic factors and exposure to environmental modifiers may contribute to variable expression of autism-related traits. The identity and number of genes involved remain unknown. The wide phenotypic variability of the ASDs likely reflects the interaction of multiple genes within an individual's genome and the existence of distinct genes and gene combinations among those affected. There are 3 main approaches to identifying genetic loci, chromosomal regions likely to contain relevant genes: 1) whole genome screens, searching for linkage of autism to shared genetic markers in populations of multiplex families (families with >1 affected family member); 2) cytogenetic studies that may guide molecular studies by pointing to relevant inherited or de novo chromosomal abnormalities in affected individuals and their families; and 3) evaluation of candidate genes known to affect brain development in these significantly linked regions or, alternatively, linkage of candidate genes selected a priori because of their presumptive contribution to the pathogenesis of autism. Data from whole-genome screens in multiplex families suggest interactions of at least 10 genes in the causation of autism. Thus far, a putative speech and language region at 7q31-q33 seems most strongly linked to autism, with linkages to multiple other loci under investigation. Cytogenetic abnormalities at the 15q11-q13 locus are fairly frequent in people with autism, and a "chromosome 15 phenotype" was described in individuals with chromosome 15 duplications. Among other candidate genes are the FOXP2, RAY1/ST7, IMMP2L, and RELN genes at 7q22-q33 and the GABAA receptor subunit and UBE3A genes on chromosome 15q11-q13. Variant alleles of the serotonin transporter gene (5-HTT) on 17q11-q12 are more frequent in individuals with autism than in nonautistic populations. In addition, animal models and linkage data from genome screens implicate the oxytocin receptor at 3p25-p26. Most pediatricians will have 1 or more children with this disorder in their practices. They must diagnose ASD expeditiously because early intervention increases its effectiveness. Children with dysmorphic features, congenital anomalies, mental retardation, or family members with developmental disorders are those most likely to benefit from extensive medical testing and genetic consultation. The yield of testing is much less in high-functioning children with a normal appearance and IQ and moderate social and language impairments. Genetic counseling justifies testing, but until autism genes are identified and their functions are understood, prenatal diagnosis will exist only for the rare cases ascribable to single-gene defects or overt chromosomal abnormalities. Parents who wish to have more children must be told of their increased statistical risk. It is crucial for pediatricians to try to involve families with multiple affected members in formal research projects, as family studies are key to unraveling the causes and pathogenesis of autism. Parents need to understand that they and their affected children are the only available sources for identifying and studying the elusive genes responsible for autism. Future clinically useful insights and potential medications depend on identifying these genes and elucidating the influences of their products on brain development and physiology.
Key Words: autism • genetic • chromosome • review
Abbreviations: ASD, autistic spectrum disorder • PDD, pervasive developmental disorder • MMR, measles-mumps-rubella • DSM-IV, Diagnostic and Statistical Manual of Mental Disorders Fourth Edition • ICD-10, International Classification of Diseases Tenth Revision • TSC, tuberous sclerosis complex • FXS, fragile X syndrome • AS, Angelman syndrome • PWS, Prader-Willi syndrome • MZ, monozygotic • DZ, dizygotic • LD, linkage disequilibrium • GABA, 
-amino butyric acid • IMGSAC, International Molecular Genetic Study of Autism Consortium • MLS, multipoint logarithm of the odds score • DBH, dopamine ß hydroxylase • Hox, homeobox • OT, oxytocin
Received for publication Aug 27, 2002; Accepted Dec 1, 2003.
CiteULike 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
This article has been cited by other articles:
|
|
 |
|
  A. O'Hare Autism spectrum disorder: diagnosis and management Arch. Dis. Child. Ed. Pract., December 1, 2009; 94(6): 161 - 168. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. E. Rosenberg, J. K. Law, G. Yenokyan, J. McGready, W. E. Kaufmann, and P. A. Law Characteristics and Concordance of Autism Spectrum Disorders Among 277 Twin Pairs Arch Pediatr Adolesc Med, October 1, 2009; 163(10): 907 - 914. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. H Kilburn, J. D Thrasher, and N. B Immers Do terbutaline- and mold-associated impairments of the brain and lung relate to autism? Toxicology and Industrial Health, October 1, 2009; 25(9-10): 703 - 710. [Abstract] [PDF]
|
|
|
|
 |
|
 Y Qiao, N Riendeau, M Koochek, X Liu, C. Harvard, M J Hildebrand, J J A Holden, E Rajcan-Separovic, and M E S Lewis Phenomic determinants of genomic variation in autism spectrum disorders J. Med. Genet., October 1, 2009; 46(10): 680 - 688. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. G. Johnson, S. Buyske, A. E. Mars, M. Sreenath, E. S. Stenroos, T. A. Williams, R. Stein, and G. H. Lambert HLA-DR4 as a Risk Allele for Autism Acting in Mothers of Probands Possibly During Pregnancy Arch Pediatr Adolesc Med, June 1, 2009; 163(6): 542 - 546. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Sano, V. G. Ornthanalai, K. Yamada, C. Homma, H. Suzuki, T. Suzuki, N. P. Murphy, and S. Itohara X11-Like Protein Deficiency Is Associated with Impaired Conflict Resolution in Mice J. Neurosci., May 6, 2009; 29(18): 5884 - 5896. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. B Kelly and A Salt QUESTION 2 Arch. Dis. Child., April 1, 2009; 94(4): 323 - 324. [Full Text] [PDF]
|
|
|
|
 |
|
 D. T. Page, O. J. Kuti, C. Prestia, and M. Sur Haploinsufficiency for Pten and Serotonin transporter cooperatively influences brain size and social behavior PNAS, February 10, 2009; 106(6): 1989 - 1994. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C Lintas and A M Persico Autistic phenotypes and genetic testing: state-of-the-art for the clinical geneticist J. Med. Genet., January 1, 2009; 46(1): 1 - 8. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Miller, E. Spiteri, M. C. Condro, R. T. Dosumu-Johnson, D. H. Geschwind, and S. A. White Birdsong Decreases Protein Levels of FoxP2, a Molecule Required for Human Speech J Neurophysiol, October 1, 2008; 100(4): 2015 - 2025. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Allan, X. Liang, Y. Luo, C. Pak, X. Li, K. E. Szulwach, D. Chen, P. Jin, and X. Zhao The loss of methyl-CpG binding protein 1 leads to autism-like behavioral deficits Hum. Mol. Genet., July 1, 2008; 17(13): 2047 - 2057. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. T. Schultz, H. S. Klonoff-Cohen, D. L. Wingard, N. A. Akshoomoff, C. A. Macera, and Ming Ji Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: The results of a parent survey Autism, May 1, 2008; 12(3): 293 - 307. [Abstract] [PDF]
|
|
|
|
 |
|
 D. J. Amor and C. Cameron PGD gender selection for non-Mendelian disorders with unequal sex incidence Hum. Reprod., April 1, 2008; 23(4): 729 - 734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Nishimura, C. L. Martin, A. Vazquez-Lopez, S. J. Spence, A. I. Alvarez-Retuerto, M. Sigman, C. Steindler, S. Pellegrini, N. C. Schanen, S. T. Warren, et al. Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways Hum. Mol. Genet., July 15, 2007; 16(14): 1682 - 1698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. A. Williams, A. E. Mars, S. G. Buyske, E. S. Stenroos, R. Wang, M. F. Factura-Santiago, G. H. Lambert, and W. G. Johnson Risk of Autistic Disorder in Affected Offspring of Mothers With a Glutathione S-Transferase P1 Haplotype Arch Pediatr Adolesc Med, April 1, 2007; 161(4): 356 - 361. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Sadakata, W. Kakegawa, A. Mizoguchi, M. Washida, R. Katoh-Semba, F. Shutoh, T. Okamoto, H. Nakashima, K. Kimura, M. Tanaka, et al. Impaired Cerebellar Development and Function in Mice Lacking CAPS2, a Protein Involved in Neurotrophin Release J. Neurosci., March 7, 2007; 27(10): 2472 - 2482. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Weiss, S. Purcell, S. Waggoner, K. Lawrence, D. Spektor, M. J. Daly, P. Sklar, and D. Skuse Identification of EFHC2 as a quantitative trait locus for fear recognition in Turner syndrome Hum. Mol. Genet., January 1, 2007; 16(1): 107 - 113. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. J. Marco and D. H. Skuse Autism-lessons from the X chromosome Soc Cogn Affect Neurosci, December 1, 2006; 1(3): 183 - 193. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. M. Nacewicz, K. M. Dalton, T. Johnstone, M. T. Long, E. M. McAuliff, T. R. Oakes, A. L. Alexander, and R. J. Davidson Amygdala Volume and Nonverbal Social Impairment in Adolescent and Adult Males With Autism Arch Gen Psychiatry, December 1, 2006; 63(12): 1417 - 1428. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. B. Campbell, J. S. Sutcliffe, P. J. Ebert, R. Militerni, C. Bravaccio, S. Trillo, M. Elia, C. Schneider, R. Melmed, R. Sacco, et al. From the Cover: A genetic variant that disrupts MET transcription is associated with autism PNAS, November 7, 2006; 103(45): 16834 - 16839. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. H. Friedlander, J. A. Yagiela, V. I. Paterno, and M. E. Mahler The neuropathology, medical management and dental implications of autism. J Am Dent Assoc, November 1, 2006; 137(11): 1517 - 1527. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. J. Barbaresi, S. K. Katusic, and R. G. Voigt Autism: A Review of the State of the Science for Pediatric Primary Health Care Clinicians. Arch Pediatr Adolesc Med, November 1, 2006; 160(11): 1167 - 1175. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Splawski, D. S. Yoo, S. C. Stotz, A. Cherry, D. E. Clapham, and M. T. Keating CACNA1H Mutations in Autism Spectrum Disorders J. Biol. Chem., August 4, 2006; 281(31): 22085 - 22091. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. H.C. Wong, I. I. Gottesman, and A. Petronis Phenotypic differences in genetically identical organisms: the epigenetic perspective Hum. Mol. Genet., April 15, 2005; 14(suppl_1): R11 - R18. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. Belmonte, G. Allen, A. Beckel-Mitchener, L. M. Boulanger, R. A. Carper, and S. J. Webb Autism and Abnormal Development of Brain Connectivity J. Neurosci., October 20, 2004; 24(42): 9228 - 9231. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Korioth Vaccines and thimerosal not associated with autism, says IOM report AAP News, July 1, 2004; 25(1): 37 - 37. [Full Text] [PDF]
|
|
eLetters:
Read all eLetters
- Genetic Complexity, Evolution, and Autism
- Manuel F Casanova, et al.
- Pediatrics Online, 16 Jun 2004 [Full text]
- Re: Genetic Complexity, Evolution, and Autism
- R.Walter Lovell
- Pediatrics Online, 21 Jan 2005 [Full text]
