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Wednesday 1 October 2003

Definition: Autism is a neurodevelopmental syndrome defined by deficits in social reciprocity and communication and by unusual repetitive behaviors. Although there is an underlying genetic predisposition, the etiology of autism is currently unknown. A recent increase in prevalence suggests that genetically determined vulnerability to environmental exposure might contribute to the causation of autism.

Autism is a common and genetically heterogeneous disorder, with an estimated heritability of >90%.

Its specific underlying causes are largely unknown. Here, I propose that low levels of autistic vulnerability, reflected in social-cognitive processing differences, do not necessarily manifest in a behavioural phenotype but are usually compensated for during development.

They are more likely to lead to a recognizable syndrome among individuals of low intelligence, who are male or have independent neurodevelopmental vulnerability owing to a wide range of gene mutations, chromosomal anomalies or environmental insults.

Consequently, the apparent association between mental retardation and autistic syndromes is not because they usually have common causes, but rather because the presence of both features greatly increases the probability of clinical ascertainment.

Susceptibility loci

- 1q21-22
- 3q25-27 (12192642)
- 7q21-q36 (Target gene: reelin) (16311013)
- 15q11-q13 (12567325)
- 17q11 (in males) (15467983)
- 17q21 (15806440, 15877280)
- GABA receptor subunit genes

Gene variants

- GLO1 variants
- MTF1 (rs3790625, P = .02) (15446388)
- SLC11A3 (rs2304704, P = .07) (15446388)

Exome sequencing studies of autism spectrum disorders (ASDs) have identified many de novo mutations but few recurrently disrupted genes. (DOI: 10.1126/science.1227764)

27 de novo events in 16 genes have been discovered in 2012, 59% of which are predicted to truncate proteins or disrupt splicing.

Recurrent disruptive mutations in six genes—CHD8, DYRK1A, GRIN2B, TBR1, PTEN, and TBL1XR1—may contribute to 1% of sporadic ASDs.

These data support associations between specific genes and reciprocal subphenotypes (CHD8-macrocephaly and DYRK1A-microcephaly) and replicate the importance of a β-catenin–chromatin-remodeling network to ASD etiology. (DOI: 10.1126/science.1227764)


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- Jacquemont ML, Sanlaville D, Redon R, Raoul O, Cormier-Daire V, Lyonnet S, Amiel J, Le Merrer M, Heron D, de Blois MC, Prieur M, Vekemans M, Carter NP, Munnich A, Colleaux L, Philippe A. Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders. J Med Genet. 2006 Nov;43(11):843-9. PMID: 16840569

- Association of Reelin gene polymorphisms with autism. Serajee FJ, Zhong H, Mahbubul Huq AH. Genomics. 2006 Jan;87(1):75-83. PMID: 16311013

- Polymorphisms in xenobiotic metabolism genes and autism. Serajee FJ, Nabi R, Zhong H, Huq M. J Child Neurol. 2004 Jun;19(6):413-7. PMID: 15446388