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Prioritization of neurodevelopmental disease genes by discovery of new mutations

Abstract

Advances in genome sequencing technologies have begun to revolutionize neurogenetics, allowing the full spectrum of genetic variation to be better understood in relation to disease. Exome sequencing of hundreds to thousands of samples from patients with autism spectrum disorder, intellectual disability, epilepsy and schizophrenia provides strong evidence of the importance of de novo and gene-disruptive events. There are now several hundred new candidate genes and targeted resequencing technologies that allow screening of dozens of genes in tens of thousands of individuals with high specificity and sensitivity. The decision of which genes to pursue depends on many factors, including recurrence, previous evidence of overlap with pathogenic copy number variants, the position of the mutation in the protein, the mutational burden among healthy individuals and membership of the candidate gene in disease-implicated protein networks. We discuss these emerging criteria for gene prioritization and the potential impact on the field of neuroscience.

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Figure 1: Genes with recurrent de novo mutations in four neurodevelopmental disorders.
Figure 2: CNV and exome intersections define candidate genes.
Figure 3: Phenotypic similarity of two patients with identical PACS1 de novo mutations and two patients with similar ADNP mutations.
Figure 4: Examples of coincidental de novo mutations in cancer and neurodevelopmental disorders.

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Acknowledgements

We are grateful to T. Brown and C. Gilissen for assistance during manuscript preparation, F. Kooy for early preprint access and H.G. Brunner for sharing patient photographs used in Figure 3. A.H. is supported by a ZonMW grant (916–12–095); E.E.E. is supported by a US National Institute of Mental Health grant (1R01MH101221–01) and is an investigator of the Howard Hughes Medical Institute.

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Correspondence to Alexander Hoischen or Evan E Eichler.

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E.E.E. is on the scientific advisory board of DNAnexus, Inc. and was a scientific advisory board member of Pacific Biosciences, Inc. (2009–2013) and SynapDx Corp. (2011–2013).

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Glossary

Exome

The exome is the part of a genome that encodes proteins, approximately 1% of the human genome.

Trio family study

A trio family study is an analysis of probands and both of their parents. Sequencing-based trio studies often focus on de novo mutations that are present in the proband's genome, but are not detected in the genomes of his or her parents.

Proband

A proband is an individual being studied or reported on. The term is often used to refer to an individual affected with a disease or disorder, as distinct from their unaffected relatives.

de novo mutation (DNM)

A de novo mutation (DNM) is a mutation that is part of an individual's genome that is not detected in the genome of either parent (although it may have arisen from a mutation in the parental germline). With the exception of de novo mutations in monozygotic twins, or those shared by siblings as a result of germline mosaicism, most new mutations are not shared by relatives and do not contribute to heritability estimates.

Rare variant

Rare variant describes variants that are private to individuals and families. In some usage, the term rare variant is used more expansively to include all variants that are not common.

Copy number variation (CNV)

A copy number variation (CNV) is a type of submicroscopic genetic variation involving the deletion or duplication of a genomic region. Although CNVs can involve genomic segments as small as a kilobase or as large as several megabases, most CNVs detected are relatively large (100 kilobases or larger) because of the resolution of genotyping arrays; in the future, sequencing-based studies may analyze many smaller CNVs.

Mendelian disease

A Mendelian disease describes a single gene disorder that is caused by the presence of one (dominant) or two (recessive) alleles.

Next generation sequencing (NGS)

Next generation sequencing (NGS) refers to a set of technologies that sequence DNA in massively parallel ways; for example, by optically detecting the incorporation of specific bases into millions of different DNA molecules, spatially segregated on an imageable glass surface, at the same time.

Candidate gene

A candidate gene is a pre-specified gene of potential interest. Candidate gene studies are often distinguished from unbiased genome-wide studies that analyze variation in all or most genes simultaneously.

Locus

A locus is a place on a chromosome. A locus may contain one gene, multiple genes or no genes at all.

Resequencing

Resequencing is the activity of sequencing a gene or genomic segment that has already been sequenced in other members of that species; for example, to identify genetic variations within the species.

Case-control study

A case-control study is a study design that compares the distribution of a genetic or other variable between individuals affected with a disease (cases) and unaffected individuals (controls).

Single-nucleotide variant (SNV)

A single-nucleotide variant (SNV) is a DNA sequence variation occurring when a single nucleotide differs between members of a species. The term SNV is often used to describe sequence variants that are not common, or whose allele frequency is not known.

Genetic background

Genetic background refers to the genotype of all genes that may modify the expression or presentation of a phenotype related to a gene of interest.

Complex disease

A complex disease describes a disorder caused by many contributing factors, both genetic and non-genetic, and does not display a simple pattern of inheritance.

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Hoischen, A., Krumm, N. & Eichler, E. Prioritization of neurodevelopmental disease genes by discovery of new mutations. Nat Neurosci 17, 764–772 (2014). https://doi.org/10.1038/nn.3703

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