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REVIEW ARTICLE the Genetics of Autism REVIEW ARTICLE The Genetics of Autism Rebecca Muhle, BA*; Stephanie V. Trentacoste, BA*; and Isabelle Rapin, MD‡ ABSTRACT. Autism is a complex, behaviorally de- tribution of a few well characterized X-linked disorders, fined, static disorder of the immature brain that is of male-to-male transmission in a number of families rules great concern to the practicing pediatrician because of an out X-linkage as the prevailing mode of inheritance. The astonishing 556% reported increase in pediatric preva- recurrence rate in siblings of affected children is ϳ2% to lence between 1991 and 1997, to a prevalence higher than 8%, much higher than the prevalence rate in the general that of spina bifida, cancer, or Down syndrome. This population but much lower than in single-gene diseases. jump is probably attributable to heightened awareness Twin studies reported 60% concordance for classic au- and changing diagnostic criteria rather than to new en- tism in monozygotic (MZ) twins versus 0 in dizygotic vironmental influences. Autism is not a disease but a (DZ) twins, the higher MZ concordance attesting to ge- syndrome with multiple nongenetic and genetic causes. netic inheritance as the predominant causative agent. By autism (the autistic spectrum disorders [ASDs]), we Reevaluation for a broader autistic phenotype that in- mean the wide spectrum of developmental disorders cluded communication and social disorders increased characterized by impairments in 3 behavioral domains: 1) concordance remarkably from 60% to 92% in MZ twins social interaction; 2) language, communication, and and from 0% to 10% in DZ pairs. This suggests that imaginative play; and 3) range of interests and activities. interactions between multiple genes cause “idiopathic” Autism corresponds in this article to pervasive develop- autism but that epigenetic factors and exposure to envi- mental disorder (PDD) of the Diagnostic and Statistical ronmental modifiers may contribute to variable expres- Manual of Mental Disorders, Fourth Edition and Interna- sion of autism-related traits. The identity and number of tional Classification of Diseases, Tenth Revision. Except genes involved remain unknown. The wide phenotypic for Rett syndrome—attributable in most affected indi- variability of the ASDs likely reflects the interaction of viduals to mutations of the methyl-CpG-binding protein multiple genes within an individual’s genome and the 2(MeCP2) gene—the other PDD subtypes (autistic disor- existence of distinct genes and gene combinations among der, Asperger disorder, disintegrative disorder, and PDD those affected. There are 3 main approaches to identify- Not Otherwise Specified [PDD-NOS]) are not linked to ing genetic loci, chromosomal regions likely to contain any particular genetic or nongenetic cause. Review of 2 relevant genes: 1) whole genome screens, searching for major textbooks on autism and of papers published be- linkage of autism to shared genetic markers in popula- tween 1961 and 2003 yields convincing evidence for mul- tions of multiplex families (families with >1 affected tiple interacting genetic factors as the main causative family member); 2) cytogenetic studies that may guide determinants of autism. Epidemiologic studies indicate molecular studies by pointing to relevant inherited or de that environmental factors such as toxic exposures, ter- novo chromosomal abnormalities in affected individuals atogens, perinatal insults, and prenatal infections such as and their families; and 3) evaluation of candidate genes rubella and cytomegalovirus account for few cases. These known to affect brain development in these significantly studies fail to confirm that immunizations with the mea- linked regions or, alternatively, linkage of candidate sles-mumps-rubella vaccine are responsible for the surge genes selected a priori because of their presumptive con- in autism. Epilepsy, the medical condition most highly tribution to the pathogenesis of autism. Data from associated with autism, has equally complex genetic/non- whole-genome screens in multiplex families suggest in- genetic (but mostly unknown) causes. Autism is frequent teractions of at least 10 genes in the causation of autism. in tuberous sclerosis complex and fragile X syndrome, Thus far, a putative speech and language region at 7q31- but these 2 disorders account for but a small minority of q33 seems most strongly linked to autism, with linkages cases. Currently, diagnosable medical conditions, cytoge- to multiple other loci under investigation. Cytogenetic netic abnormalities, and single-gene defects (eg, tuber- abnormalities at the 15q11-q13 locus are fairly frequent ous sclerosis complex, fragile X syndrome, and other rare in people with autism, and a “chromosome 15 pheno- diseases) together account for <10% of cases. There is type” was described in individuals with chromosome 15 convincing evidence that “idiopathic” autism is a herita- duplications. Among other candidate genes are the ble disorder. Epidemiologic studies report an ASD prev- FOXP2, RAY1/ST7, IMMP2L, and RELN genes at 7q22- alence of ϳ3 to 6/1000, with a male to female ratio of 3:1. q33 and the GABAA receptor subunit and UBE3A genes This skewed ratio remains unexplained: despite the con- on chromosome 15q11-q13. Variant alleles of the seroto- nin transporter gene (5-HTT) on 17q11-q12 are more fre- From the *Class of 2004, Albert Einstein College of Medicine, Bronx, New quent in individuals with autism than in nonautistic York; and ‡Saul R. Korey Department of Neurology, Department of Pedi- populations. In addition, animal models and linkage atrics, and Rose F. Kennedy Center for Research in Mental Retardation and data from genome screens implicate the oxytocin receptor Human Development, Albert Einstein College of Medicine, Bronx, New at 3p25-p26. Most pediatricians will have 1 or more chil- York. dren with this disorder in their practices. They must Received for publication Aug 27, 2002; accepted Dec 1, 2003. diagnose ASD expeditiously because early intervention Ms Muhle and Ms Trentacoste contributed equally to this work. increases its effectiveness. Children with dysmorphic Address correspondence to Isabelle Rapin, MD, Albert Einstein College of Medicine, K 807, 1300 Morris Park Ave, Bronx NY 10461. E-mail: features, congenital anomalies, mental retardation, or [email protected] family members with developmental disorders are those PEDIATRICS (ISSN 0031 4005). Copyright © 2004 by the American Acad- most likely to benefit from extensive medical testing and emy of Pediatrics. genetic consultation. The yield of testing is much less in e472 PEDIATRICS Vol.Downloaded 113 No. 5 from May www.aappublications.org/news 2004 http://www.pediatrics.org/cgi/content/full/113/5/ by guest on September 24, 2021 e472 high-functioning children with a normal appearance and Asperger disorder (language development at the ex- IQ and moderate social and language impairments. Ge- pected age, no mental retardation), 3) disintegrative netic counseling justifies testing, but until autism genes disorder (behavioral, cognitive, and language regres- are identified and their functions are understood, prena- sion between ages 2 and 10 years after entirely nor- tal diagnosis will exist only for the rare cases ascribable mal early development, including language), 4) PDD to single-gene defects or overt chromosomal abnormali- not otherwise specified (individuals who have autis- ties. Parents who wish to have more children must be told of their increased statistical risk. It is crucial for tic features and do not fit any of the other subtypes), pediatricians to try to involve families with multiple and 5) Rett disorder (a genetic disorder of postnatal affected members in formal research projects, as family brain development, caused by a single-gene defect studies are key to unraveling the causes and pathogene- predominantly affecting girls). sis of autism. Parents need to understand that they and The highly variable cognitive manifestations of the their affected children are the only available sources for ASDs range from a nonverbal child with severe men- identifying and studying the elusive genes responsible tal retardation and self-injury9 to a high-functioning for autism. Future clinically useful insights and potential college student with an above-average IQ despite medications depend on identifying these genes and elu- impaired language use and inadequate social skills.10 cidating the influences of their products on brain devel- Mental retardation thus is not a defining criterion for opment and physiology. Pediatrics 2004;113:e472–e486. autism (albeit certain cognitive abilities are charac- URL: http://www.pediatrics.org/cgi/content/full/113/ teristically affected), but the mean distribution of IQs 5/e472; autism, genetic, chromosome, review. is lower than average,11 and the likelihood of retar- dation increases with more widespread brain dys- ABBREVIATIONS. ASD, autistic spectrum disorder; PDD, perva- function.12 Mental retardation is itself a behaviorally sive developmental disorder; MMR, measles-mumps-rubella; defined disorder of complex human abilities with DSM-IV, Diagnostic and Statistical Manual of Mental Disorders Fourth Edition; ICD-10, International Classification of Diseases Tenth Revi- many genetic and nongenetic causes. The more se- sion; TSC, tuberous sclerosis complex; FXS, fragile X syndrome; vere the retardation, the more likely the underlying AS, Angelman syndrome; PWS, Prader-Willi syndrome; MZ, brain dysfunction will affect the widely distributed
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