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Genetic studies in intellectual disability and related disorders

Key Points

  • Whole-exome and whole-genome sequencing approaches have provided new insights into the genetics of intellectual disability (ID) and are rapidly being introduced as first-tier diagnostic assays.

  • A genetic diagnosis can now be made in most patients with severe ID.

  • Severe ID is mostly caused by a de novo point mutation, an insertion or deletion, or a structural genomic variation.

  • More than 700 genes have been found to play a part in isolated ID and ID-associated disorders, and many more await discovery.

  • New genetic research will focus on studying the role of somatic, non-coding and complex forms of inheritance in ID.

  • An increasing number of therapeutic options is being developed for ID. In addition, preventative strategies should be aimed at reducing the number of de novo mutations in the offspring.

Abstract

Genetic factors play a major part in intellectual disability (ID), but genetic studies have been complicated for a long time by the extreme clinical and genetic heterogeneity. Recently, progress has been made using different next-generation sequencing approaches in combination with new functional readout systems. This approach has provided novel insights into the biological pathways underlying ID, improved the diagnostic process and offered new targets for therapy. In this Review, we highlight the insights obtained from recent studies on the role of genetics in ID and its impact on diagnosis, prognosis and therapy. We also discuss the future directions of genetics research for ID and related neurodevelopmental disorders.

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Figure 1: Increase of genes linked to isolated ID and ID-associated disorders.
Figure 2: Diagnostic yield for ID over time.
Figure 3: Genic overlap for neurodevelopmental disorders.

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Acknowledgements

We thank Hans-Hilger Ropers and Arjan de Brouwer for fruitful scientific discussions, and Rolph Pfundt for discussion and expertise on diagnostic relevant ID genes. This work was in part financially supported by grants from the Netherlands Organization for Scientific Research (916-14-043 to C.G. and 918-15-667 to J.A.V.) and the European Research Council (ERC; starting grant DENOVO 281964 to J.A.V.).

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Correspondence to Joris A. Veltman.

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Supplementary information S1 (table)

Genes linked to isolated ID and ID-associated disorders (PDF 473 kb)

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Glossary

Epilepsy

Group of neurological diseases that are characterized by episodes of shaking, which can range in severity from brief, nearly undetectable to long and vigorous.

Autism spectrum disorder

(ASD). Collective term to describe a wide range of conditions that are characterized by social deficits and communication difficulties, stereotyped or repetitive behaviour and interests, sensory issues and, in some cases, cognitive delays.

Clinical heterogeneity

The phenomenon by which the same (genetic) disease can have differences in clinical manifestation.

Genetic heterogeneity

The phenomenon by which mutations in different genes can cause a similar phenotype.

Next-generation sequencing

(NGS). A collective term to describe the modern high-throughput sequencing technologies in the post-Sanger sequencing era.

Diagnostic yield

The percentage of patients who receive a conclusive molecular diagnosis for their disease.

Copy number variants

(CNVs). Insertions or deletions larger than 1,000 nucleotides in size.

De novo mutations

Genetic alterations that are present for the first time in one family member as a result of a mutation in the germ cell of one of the parents, or in the fertilized egg itself.

Down syndrome

The first recognized and most common form of a human aneuploidy syndrome, consisting of trisomy of chromosome 21 and representing 6–8% of all intellectual disability (ID) cases. The syndrome is generally associated with physical growth delays, characteristic facial features and mild to moderate ID.

Fragile X syndrome

Genetic disorder characterized by intellectual disability (ID), elongated face, large or protruding ears, macroorchidism, stereotypic movements and social anxiety.

Prader–Willi syndrome

Genetic condition that is characterized by hypotonia, feeding difficulties, poor growth, delayed development and behavioural problems. In infancy, patients develop an insatiable appetite that leads to chronic hyperphagia and obesity.

Angelman syndrome

Complex genetic disorder that primarily affects the nervous system and is characterized by delayed development, intellectual disability, speech impairment, epilepsy and problems with movement and balance. Patients typically have a happy, excitable, demeanour.

Williams syndrome

Genetic condition that is characterized by mild to moderate intellectual disability, cardiovascular disease, distinctive facial features and a typical outgoing, engaging personality.

Smith–Magenis syndrome

Developmental disorder that is characterized by mild to moderate intellectual disability, delayed speech and language skills, distinctive facial features, sleep disturbances and behavioural problems.

Miller–Dieker syndrome

Genetic condition that is characterized by a pattern of abnormal brain development known as lissencephaly, which leads to severe intellectual disability, developmental delay, seizures, spasticity, hypotonia and feeding difficulties.

DiGeorge syndrome

Genetic disorder that is characterized by a heart defect, learning difficulties and cleft palate, among other symptoms.

G-banded karyotyping

Visualization of the chromosome count present in the nucleus of a eukaryotic cell after Giemsa staining, followed by trypsin digestion, using a light microscope. The staining results in a recognizable pattern of light (euchromatic) and dark (heterochromatic) stained bands.

Homozygosity mapping

A method to map human recessive disease traits with DNA of inbred children.

Schinzel–Giedion syndrome

A rare genetic disorder of congenital hydronephrosis, skeletal dysplasia and severe developmental retardation.

Kabuki syndrome

A rare genetic condition that is characterized by distinctive facial features, skeletal anomalies and intellectual disability.

Bohring–Opitz syndrome

A rare genetic disorder that is characterized by facial anomalies, multiple malformations, failure to thrive and severe intellectual disabilities.

Single nucleotide variants

(SNVs). Differences in the nucleotide composition at single positions in the genome.

Neurodevelopmental disorders

Term generally used to collectively describe disorders affecting neurodevelopment, including autism spectrum disorder, epilepsy, schizophrenia and intellectual disability.

Structural variants

Genomic regions of at least 1 kb in size that alter the normal chromosomal composition, such as inversions, translocations or copy number variants.

Induced pluripotent stem cells

(iPSCs). Adult cells that have been reprogrammed to stem cells and can thus be differentiated into different cell types.

Kleefstra syndrome

Genetic condition characterized by the core phenotype of developmental delay, intellectual disability, speech impairment, (childhood) hypotonia and distinct facial features, including synophrys, hypertelorism, midface hypoplasia, anteverted nares, prognathism, rolled out (everted) lips and macroglossia.

Coffin–Siris syndrome

A rare genetic disorder that causes developmental delays and absence of the fifth finger and toe nails.

Degron consensus sequence

Specific sequence of amino acids in a protein that directs the starting place of degradation.

Somatic mutations

Mutations that are present in a proportion of cells of the body except sperm and egg cells.

Schizophrenia

Psychotic disorder marked by severely impaired thinking, emotions and behaviour, including the inability to filter sensory stimuli and enhanced perceptions of sounds and colours.

Loss-of-function

(LoF). A mutation expected to result in reduced or abolished protein function.

Digenic and oligogenic inheritance

A form of disease inheritance in which mutations in two (digenic) or more (oligogenic) unlinked genes must be present in a single individual to cause disease, whereas each mutation individually is insufficient to cause a phenotype.

Expressivity

The severity of the disease in individuals who have both the risk variant and the disease.

Penetrance

The proportion of patients with a specific phenotype among all carriers of a specific genotype.

Incidental findings

Medically relevant genetic variants unrelated to the clinical indication for which the genetic test was requested.

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Vissers, L., Gilissen, C. & Veltman, J. Genetic studies in intellectual disability and related disorders. Nat Rev Genet 17, 9–18 (2016). https://doi.org/10.1038/nrg3999

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