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The role of de novo mutations in the genetics of autism spectrum disorders

Nature Reviews Genetics volume 15, pages 133–141 (2014)Cite this article

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Abstract

The identification of the genetic components of autism spectrum disorders (ASDs) has advanced rapidly in recent years, particularly with the demonstration of de novo mutations as an important source of causality. We review these developments in light of genetic models for ASDs. We consider the number of genetic loci that underlie ASDs and the relative contributions from different mutational classes, and we discuss possible mechanisms by which these mutations might lead to dysfunction. We update the two-class risk genetic model for autism, especially in regard to children with high intelligence quotients.

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Figure 1: A unified two-class risk model and its consequences for the composition of a simplex collection.
Figure 2: Differential signal of de novo mutations in affected and unaffected siblings.
Figure 3: Estimates of ASD gene target sizes.
Figure 4: Non-verbal IQ in SSC studies by gender and mutational type.

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Authors and Affiliations

  1. Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, 11724, New York, USA

    Michael Ronemus, Ivan Iossifov, Dan Levy & Michael Wigler

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  1. Michael Ronemus
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  2. Ivan Iossifov
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Correspondence to Michael Wigler.

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PowerPoint slides

Glossary

Coincident mutations

Mutations in both alleles at a given locus.

Comparative genomic hybridization

(CGH). A microarray-based technique for identifying large deletions or duplications in the genome.

Concordance

The probability that multiple siblings are affected given that one of them is already known to be affected.

Copy number variants

(CNVs). Large deletions or duplications that either alter the number of copies of genes or disrupt the function of genes.

De novo mutations

New mutations that arise either in the parental germ line or somatically.

Dosage sensitivity

A defining feature of phenotypes that result from heterozygous mutation.

Gender bias

The phenomenon whereby four times as many males are affected by autism spectrum disorders compared with females, with a male:female ratio of nearly 6:1 among individuals who are diagnosed as being high functioning.

High-risk families

Families that contain a highly penetrant segregating risk allele for autism spectrum disorders.

Insertions and deletions

(Indels). Small insertions or deletions in the genome that are generally <10 bp.

Loss-of-function mutations

In the context of this article, events that result in a nonsense allele or that change the reading frame.

Low-risk families

Families that do not contain a segregating risk allele for autism spectrum disorders (ASDs) and that are only at risk of ASDs in cases of de novo mutation.

Monoallelic

Pertaining to the expression of only one allele at a given locus.

Multiplex families

Families with multiple affected children.

Neuroplasticity

The dynamic state of the brain, which enables it to respond to changes in environment and development.

Penetrant

Pertaining to the probability that an individual with a given mutation will be affected by the corresponding condition.

Recurrence

Independent mutational 'hits' within a given gene in unrelated individuals.

Sibling risk

The probability that a sibling of an affected child will also be affected.

Simplex families

Families with only one affected child; all other children (if any) of these families are unaffected.

Transmitted

Inheritance of a mutant allele from a parent, who may be phenotypically normal owing to gender bias.

Trios

Family units that consist of both parents and one child in each unit.

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Ronemus, M., Iossifov, I., Levy, D. et al. The role of de novo mutations in the genetics of autism spectrum disorders. Nat Rev Genet 15, 133–141 (2014). https://doi.org/10.1038/nrg3585

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