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  • Review Article
  • Published:

Genetics of austim: complex aetiology for a heterogeneous disorder

Key Points

  • Initial evidence for a genetic aetiology in autism came from twin studies, which showed significantly higher concordance rates among monozygotic twins than among dizygotic twins.

  • Approximately 5% of individuals with autism have an underlying chromosomal anomaly, the most frequent of which involve duplications of the Prader–Willi/Angelman syndrome region of chromosome 15.

  • Approximately 10% of individuals with autism have an identifiable Mendelian condition or other syndrome, most commonly fragile X syndrome or tuberous sclerosis.

  • Several genome screens have yielded suggestive linkage, but results have not been consistent across studies. The regions where there seems to be the most overlap are on chromosomes 7q, 2q and 16p.

  • Candidate genes have been chosen on the basis of their position near linkage signals or chromosomal breakpoints and/or on knowledge about their function. Candidate genes studied so far include the serotonin transporter gene, DBH, GABRB3, UBE3A, RAY1/ST7, WNT2, RELN, SPCH1/FOXP2 and GRIK2.

  • The genetic basis of idiopathic autism seems to be complex, with no single inheritance pattern identified. Several loci are likely to be involved, and although environmental factors have not been shown to have a major effect, they might act as second 'hits' in genetically susceptible individuals.

  • Future research should exploit both the clinical variation and the varying segregation patterns that occur in families. Studies of brain material and relevant animal models might also prove useful in the search for autism susceptibility genes.

Abstract

Since autism was first recognized as a disorder in 1943, speculation about its aetiology has ranged from biological to psychological and back again. After twin studies during the 1970s and 1980s yielded unequivocal evidence for a genetic component, aetiological research in autism began to focus primarily on uncovering the genetic mechanisms involved. The identification of chromosomal abnormalities and Mendelian syndromes among individuals with autism, in conjunction with data from genome screens and candidate-gene studies, has helped to refine the view of the complex genetics that underlies autism spectrum conditions.

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Figure 1: Genome screens for loci that predispose to autism spectrum disorders.
Figure 2: Regions of chromosome 15 that are implicated in autism.
Figure 3: Regions of chromosome 7 that are implicated in autism.

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Correspondence to Beth Rosen-Sheidley.

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DATABASES

LocusLink 

DBH

Dvl

FOXP2

GABRB3

GRIK2

MECP2

myelin basic protein

neurofilament proteins

oxytocin

RELN

ST7

TSC1

UBE3A

vasopressin

WNT2 

OMIM 

Alzheimer disease

Angelman syndrome

autism

fragile X syndrome

lissencephaly

neurofibromatosis

phenylketonuria

Prader–Willi syndrome

Rett syndrome

tuberous sclerosis

Turner syndrome

FURTHER INFORMATION

Autism Genetic Research Exchange (AGRE)

Autism research in genetics and neuroimaging

Autism Society of America

Encyclopedia of Life Sciences: Autism

M.I.N.D. Institute

National Alliance for Autism Research

National Society of Genetic Counselors, Inc.

The Center for Human Genetics

The National Autistic Society (NAS)

Glossary

EUGENE BLEULER

A Swiss psychiatrist whose diagnostic criteria for schizophrenia were widely used throughout the 1950s.

BRACHYCEPHALY

A shortened diameter of the skull from front to back, leading to a relatively wide side-to-side diameter.

PURKINJE CELLS

Purkinje cells are the output neurons of the cerebellum. They integrate complex inputs in the cerebellum and project to the deep motor nuclei of the brain.

HERITABILITY

Stastical description of the proportion of phenotypic variance due to genetic variance.

RECURRENCE RISK

The likelihood that a given condition diagnosed in one or more family members will recur in other family members or in subsequent generations.

MAJOR HISTOCOMPATIBILITY COMPLEX

(MHC). A complex locus on chromosome 6p, which comprises numerous genes, including the human leukocyte antigen genes, which are involved in the immune response.

MARKER CHROMOSOME

(also known as an extra structurally abnormal chromosome (ESAC) or 'supernumerary' chromosome). These are typically seen in addition to the normal chromosome complement. Fluorescence in situ hybridization can be useful to determine the chromosome from which a marker chromosome originates.

PERVASIVE DEVELOPMENTAL DISORDER

(PDD). A group of disorders that are characterized by deficits in communication and social interaction, as well as repetitive or stereotyped behaviours and interests. The five PDD diagnoses in the current DSMIV classification system are autistic disorder, Asperger disorder, pervasive developmental disorder not otherwise specified (PDD/NOS), Rett disorder and childhood disintegrative disorder.

TUBERS

Focal lesions in the brain seen commonly in individuals with tuberous sclerosis (TSC). There is some correlation between the number of tubers and the extent of seizures and mental retardation in patients with TSC.

WOOD'S LAMP

Ultraviolet light used to examine the skin for evidence of abnormal pigmentation, such as those often seen in tuberous sclerosis and certain dermatological inflammations.

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Folstein, S., Rosen-Sheidley, B. Genetics of austim: complex aetiology for a heterogeneous disorder. Nat Rev Genet 2, 943–955 (2001). https://doi.org/10.1038/35103559

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