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Genetic Studies in Intellectual Disability and Related Disorders

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Genetic Studies in Intellectual Disability and Related Disorders Nature Reviews Genetics | AOP, published online 27 October 2015; doi:10.1038/nrg3999 REVIEWS APPLICATIONS OF NEXT-GENERATION SEQUENCING Genetic studies in intellectual disability and related disorders Lisenka E. L. M. Vissers1, Christian Gilissen1 and Joris A. Veltman1,2 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. genetic heterogeneity Epilepsy Intellectual disability (ID), the world-wide prevalence with extreme , and a genetic diag- 1 2 Group of neurological diseases of which has been estimated at 1% , is characterized by nosis is still lacking in most cases . This is concerning, that are characterized by substantial limitations in both intellectual function- as a genetic diagnosis can provide detailed information episodes of shaking, which can ing and adaptive behaviour, starting before the age of on the subtype of ID, its prognosis, possible compli- range in severity from brief, nearly undetectable to long 18 years. Most individuals with ID are identified early cations, treatment options as well as information on and vigorous. in childhood because of developmental delays, and ID the inheritance relevant for family planning. Genetic is a prominent feature of most developmental disorders. research has focused on the use of unbiased genome- Autism spectrum disorder However, a formal diagnosis of ID is made only when wide approaches because of the genetic heterogeneity (ASD). Collective term to IQ testing identifies an IQ score of less than 70. ID can of ID. These include genomic microarrays and, more describe a wide range next-generation sequencing of conditions that are occur in isolation or in combination with congeni- recently, (NGS) using exten- characterized by social deficits tal malformations or other neurological features such sive gene panels, the exome or the whole genome. With and communication difficulties, as epilepsy, sensory impairment and autism spectrum the introduction of NGS technologies, new ID genes stereotyped or repetitive disorders (ASD), and its severity (mild, moderate, severe are now being identified in rapid succession. This com- behaviour and interests, sensory issues and, in some and profound) is highly variable. bination of novel technology and increased biological cases, cognitive delays. ID can be caused by exogenous factors such as understanding is rapidly increasing the diagnostic yield maternal alcohol abuse during pregnancy, infections, of genetic tests in ID and improving the usefulness of 1Department of Human birth complications and extreme malnutrition, but genetic test results for patients and families involved. In Genetics, Donders Centre for genetics is known to have an important role in its aeti- addition, it is providing possibilities for carrier testing Neuroscience, Radboud ology. The brain is an incredibly complex organ con- and prenatal screening, as well as new targets for treat- University Medical Center, sisting of a myriad of interconnected cell types. During ment. In studying the genetics of ID, it is important Geert Grooteplein 10, 6525 GA Nijmegen, development and day‑to‑day functioning throughout to note that ID, which by definition is an early-onset The Netherlands. life, numerous proteins need to be functionally active in disorder, has a significant impact on fitness. The exact 2Department of Clinical the right amount at the right place and the correct time. effect on fitness will depend on the severity of the ID Genetics, Maastricht It is therefore not unexpected that a mutation, deletion and the presence or absence of additional clinical fea- University Medical Centre. Universiteitssingel 50, or rearrangement affecting any one of the genes encod- tures. For this reason, severe ID is mostly sporadic, 6229 ER Maastricht, ing these proteins can have severe consequences for whereas milder forms of ID can occur in families and The Netherlands. brain development or cognitive functioning. Indeed, spread through the population. This difference in fit- Correspondence to J.A.V. family and population studies of intelligence show a ness effects will impact the genetic architecture under- e-mail: joris.veltman@ high heritability, but no reliable literature exists on the lying these different forms of ID. Indeed, genomic radboudumc.nl doi:10.1038/nrg3999 heritability of ID itself. ID has become the most fre- microarray studies have revealed a strong relationship Published online quent reason for referral to paediatric genetic services. between the number of genes affected by rare copy 27 October 2015 Unfortunately, the clinical heterogeneity of ID is reflected number variants (CNVs) and the severity of the ID3. In NATURE REVIEWS | GENETICS ADVANCE ONLINE PUBLICATION | 1 © 2015 Macmillan Publishers Limited. All rights reserved REVIEWS addition, dominantly acting rare de novo mutations have Smith–Magenis syndrome, Miller–Dieker syndrome and recently been shown to be a major cause of severe ID DiGeorge syndrome23. The introduction of genomic and associated developmental disorders4–10. By contrast, microarrays allowed the genome-wide detection of more common and complex forms of inheritance are CNVs at finer resolution than was possible using the 24 Clinical heterogeneity expected to underlie the milder forms of ID. At present, light microscope . Pioneering microarray studies in The phenomenon by which the however, much less is known about the genetics under- ID showed that these CNVs occurred de novo in the same (genetic) disease can lying these mild forms of ID. The genetics of ID also germline of ~10% of patients25–28. Although these have differences in clinical differs markedly in countries with a high frequency CNVs occurred all over the genome, numerous recur- manifestation. of consanguinity, owing to a more prominent role for rent de novo CNVs have now been identified in ID as 11 23 Genetic heterogeneity recessive inheritance (see REF. 12 for a recent review). autosomal-dominant causes . Detailed clinical and The phenomenon by which In this Review, we highlight the insights obtained genetic characterization of these patients has resulted mutations in different genes from recent studies on the role of genetics in ID and in the description of many new ID syndromes, pro- can cause a similar phenotype. its impact on diagnosis, prognosis and therapy. We vided insights into the genomic architecture under- Next-generation sequencing mainly focus on the genetic aspects of ID and do not lying these genomic disorders and revealed many (NGS). A collective term extensively discuss the clinical aspects of ID (for cover- causative dosage-sensitive genes located in these CNV to describe the modern age of this topic, see REF. 13). First, we provide a brief regions29–31. Because of their superior resolution and high-throughput sequencing historical overview of genomic approaches developed to diagnostic yield, genomic microarrays rapidly replaced technologies in the G‑banded karyotyping 32 post-Sanger sequencing era. study ID. Next, we discuss results from recent genomic as the first-tier test for ID . In studies, with a focus on both dominant de novo muta- spite of these successes, the number of autosomal- Diagnostic yield tions, as well recessive forms of inheritance. In addition, dominant ID genes is still small relative to the number The percentage of patients we describe overlap with related disorders, such as ASD of X‑linked ID genes. who receive a conclusive and epilepsy, as well as ID gene networks and pathways In the meantime, over 300 genes have been identi- molecular diagnosis for their disease. in which linked genes act in concert. Finally, we outline fied for autosomal-recessive forms of ID, mostly by the future of ID research and emerging approaches for homozygosity mapping using single nucleotide polymor- Copy number variants therapy. phism (SNP) microarrays and subsequent follow‑up (CNVs). Insertions or deletions of candidate genes by Sanger sequencing. This num- larger than 1,000 nucleotides A brief historical overview in size. ber may be slightly inflated, as more than 97% of these Historically, genetic diagnosis of ID started under the genes have a role in recessive disorders that include ID De novo mutations microscope with the identification of trisomy 21 as the as one of their main features. In fact, very few recessively Genetic alterations that are cause of Down syndrome14 and a marker chromosome X inherited genes have been identified that only cause an present for the first time in one for fragile X syndrome15. Because of these discoveries and ID phenotype (known as isolated ID)12,33. family member as a result of a mutation in the germ cell of the widespread introduction of cytogenetic banding Overall, over 700 genes have now been identi- one of the parents, or in the technologies, chromosomal abnormalities were soon fied across studies of X‑linked, autosomal-dominant fertilized egg itself. recognized as a common cause of ID, explaining up to and autosomal-recessive ID, which can be used for 15% of cases16,17, and Down syndrome was recognized as the molecular diagnosis of both isolated ID and Down syndrome FIG. 1 The first recognized and most the most frequent genetic form of ID. In 1991, expansion ID‑associated disorders ( ; see Supplementary common form of a human of a CGG repeat in the fragile X mental retardation 1 information S1 (table)). aneuploidy syndrome, (FMR1) gene was identified as the cause of fragile X consisting of trisomy of syndrome18,19, with an estimated frequency of 1 in 5,000 From genes to genomes chromosome 21 and males and accounting for ~0.5% of ID20.
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