The genetics of neurodevelopmental disease

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The term neurodevelopmental disorder encompasses a wide range of diseases, including recognizably distinct syndromes known to be caused by very rare mutations in specific genes or chromosomal loci, and also much more common disorders such as schizophrenia, autism spectrum disorders, and idiopathic epilepsy and mental retardation.

After decades of frustration, the past couple of years have suddenly seen tremendous progress in unravelling the genetics of these common disorders. These findings have led to a paradigm shift in our conception of the genetic architecture of common neurodevelopmental disease, highlighting the importance of individual, rare mutations and overlapping genetic aetiology of various disorders. They have also converged on specific neurodevelopmental pathways, providing insights into pathogenic mechanisms.

Introduction

A lot can go wrong in the development of a human brain. The staggeringly complex circuitry that constitutes the substrate of the mind requires an equally complex network of genes to orchestrate its self-assembly. Mutations affecting any of a wide range of cellular processes can lead to altered neurodevelopment and result in neurological or psychiatric disease. In some cases, the effects are quite specific, as in the link between mutations in genes controlling asymmetric cell division and microcephaly [1], in genes affecting the guidance of specific axonal tracts which lead to very distinctive neurological syndromes [2] or in genes controlling cell migration which underlie various cortical malformations [3].

Many neurodevelopmental mutations, however, result in a diffuse and variable presentation of psychiatric or neurological symptoms, which by themselves are not sufficiently specific to recognise a distinct aetiology. Individual disorders are often diagnosed instead on the basis of additional characteristic phenotypes, such as typical facial morphology (e.g. Down syndrome or Williams syndrome), somatic markers (e.g. neurofibromatosis and tuberous sclerosis) or diagnostic magnetic resonance imaging findings (e.g. for cortical malformations). More and more commonly, however, karyotypic or molecular genetic tests, such as those for Fragile X or Rett syndrome, are being used to directly determine the underlying cause and diagnose patients with a specific genetic syndrome. Depending on one's definition of neurodevelopmental, there are hundreds to thousands of such Mendelian syndromes, each very rare.

The term neurodevelopmental disorder is also used to refer to disorders that are really quite common in the population, however, including schizophrenia (SZ, ∼1%), autism spectrum disorders (ASD, nearly 1%), epilepsy (∼0.85%) and mental retardation (or intellectual disability, ∼2%). After decades of frustration, the past couple of years have suddenly seen tremendous progress in unravelling the genetics of these disorders. This review will focus on these recent findings and their implications for the genetic architecture and pathogenic mechanisms of common neurodevelopmental disorders.

Section snippets

The genetic architecture of common neurodevelopmental disorders

Although research into epilepsy and mental retardation has mainly proceeded on the model of genetic heterogeneity and has been very successful in defining rare genetic syndromes, research into psychiatric disorders largely took a different route. Despite seminal findings of very rare mutations predisposing individually to SZ (e.g. DISC1 [4]) or ASD (e.g. NLGNs [5]), these fields largely turned to a common disease/common variant (CD/CV) model where disease is thought to be caused by the

Overlapping genetic aetiology

One of the surprises from this research has been the finding that many of the more common, recurrent CNVs and a number of single-gene mutations predispose not to one specific ‘disorder’ or diagnostic category, but to many [35, 36•, 37••, 38]. This suggests a fundamental aetiological overlap between what have largely been defined clinically as distinct disorders. This conclusion is in agreement with the recognized fluidity of diagnoses in individual patients over time and is also supported by

From genotype to phenotype

The sources of phenotypic variability include both additional genetic and non-genetic factors. Non-genetic factors must play important roles in the ultimate expression of many phenotypes, as demonstrated by the fact that concordance rates for monozygotic twins for any of these disorders are substantially below one hundred percent. Phenotypic expression may be strongly affected by various environmental factors, second ‘hits’, such as head injuries or febrile seizures in the development of

Convergence on neurodevelopmental pathways

Perhaps the most striking finding from recent genetic studies has been the convergence on genes involved in neurodevelopment [17••, 23•, 27•, 33, 37••, 49••, 50, 51], particularly in aspects of synaptogenesis. A partial list of such ‘synaptic’ genes with mutations found in disease cases is given in Table 1. These include a greater-than-expected number of mutations affecting multiple members of particular gene families (e.g. CNTN, CNTNAP, DLG, NLGN, SHANK, and SLITRK), or genes whose protein

The future is now

The arrival of affordable whole-genome sequencing now promises to reveal the full spectrum of mutations associated with these diseases and to further delineate the relevant molecular pathways. As well as a ‘forward genetic’ approach based on sequencing cases, it will be equally important to do ‘reverse genetics’ to define the range of possible phenotypes that can arise when gene X is mutated. This will be most readily achieved in family studies where all mutation-carriers can be identified and

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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