autism

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)

Reviews

 Skuse DH. Rethinking the nature of genetic vulnerability to autistic spectrum disorders. Trends Genet. 2007 Aug;23(8):387-95. PMID: 17630015

 Thornalley PJ. Unease on the role of glyoxalase 1 in high-anxiety-related behaviour. Trends Mol Med. 2006 May;12(5):195-9. PMID: 16616641

 Folstein SE, Rosen-Sheidley B. Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet. 2001 Dec;2(12):943-55. PMID: 11733747

 Lamb JA, Moore J, Bailey A, Monaco AP. Autism: recent molecular genetic advances. Hum Mol Genet. 2000 Apr 12;9(6):861-8. PMID: 10767308

References

 Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, Shago M, Moessner R, Pinto D, Ren Y, Thiruvahindrapduram B, Fiebig A, Schreiber S, Friedman J, Ketelaars CE, Vos YJ, Ficicioglu C, Kirkpatrick S, Nicolson R, Sloman L, Summers A, Gibbons CA, Teebi A, Chitayat D, Weksberg R, Thompson A, Vardy C, Crosbie V, Luscombe S, Baatjes R, Zwaigenbaum L, Roberts W, Fernandez B, Szatmari P, Scherer SW. Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008 Feb;82(2):477-88. PMID: 18252227

 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