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Recent advancements in genomics, such as whole-exome or whole-genome sequencing, have enabled scientists to identify numerous mutations underlying neurodevelopmental disorders. Given the few hundred risk genes that have been discovered, the etiological variability and the heterogeneous clinical presentation, the need for genotype—along with phenotype-based diagnosis of individual patients has become a requisite.
In this review we look at recent advancements in genomic analysis and their translation into clinical practice.
Understanding Developmental Disorders: A Causal Modelling Approach (Cognitive Development)
The past decade has seen a rapid development of precise technological and methodological advancements in genetics and genomics, thus allowing an unprecedented identification of mutations that are involved in complex neurodevelopmental conditions. Understanding the etiology of NDDs faces many challenges that range from delineating the heritable genetic components to defining individual factors that predispose to NDD risk and identifying the precise mechanisms through which these factors together lead to the disorder 2.
In addition, the clinical heterogeneity of NDDs make diagnosing a lengthy and costly process, complicating the quest for personalized medicine. However, the identification of bona fide genetic risk factors and the use of functional genomics to progress from mutation to phenotype represent a solid foundation for the development of individualized therapeutic approaches.
In this review, we begin by mentioning some features of these disorders and continue by emphasizing the importance of genomics in determining the etiology of NDDs. We then describe advantages and limitations in the use of animal or stem cell models to study patient-specific genetic mutations. Finally, we discuss successful examples of translational research creating an evidence-based framework of how personalized medicine can advance the treatment of NDDs.
NDDs are a group of early onset neurological disorders, including autism spectrum disorders ASD , intellectual disability ID and language disorders among others. ASDs are characterized by early dysfunction in social interactions, communication deficits, and the presence of repetitive and restricted behaviors 3. ASDs, with an estimated prevalence of 1 in 68 births 3 , represent an issue of public concern. Evidence suggests that the causes involve both genetic and environmental factors 7.
Patients diagnosed with ASD often present with other comorbidities such as intellectual disability ID 8 , epilepsy 9 , and motor abnormalities Epileptic seizures are due to abnormal neuronal activity such as excessive excitation or hypersynchronization, which can occur as a result of developmental defects or due to brain insults e. With over 65 million people affected worldwide, epilepsy is the most common, chronic neurological disorder Although in many cases seizures can be controlled by existing anti-epileptic drugs, the treatment gap is still large Genetic underpinnings for epilepsies have been long recognized and over the past 20 years a significant number of epilepsy-risk genes have been identified 16 , On average, a newborn acquires between 50 and new genetic variants, resulting in 0.
Given such a high individual variability, a plethora of variants associated with NDDs have been found in hundreds of different genes, ranging from single nucleotide changes single nucleotide variants SNV to loss or gain of up to thousands of nucleotides copy number variants CNV. Sequencing of the human and other mammalian genomes has provided an important set of tools to start understanding the human genetic variation.
The first steps to elucidate the genetic heterogeneity of NDDs were done by using karyotyping or fluorescence in situ hybridization FISH. As the need for more accurate detection of nucleotide variations in the context of developmental disabilities grew, chromosome microarray CMA technology was developed and rapidly implemented as part of first-line evaluation for children with a NDD 19 , CMA set the stage for genetic variation detection, but the advent of whole-genome and whole-exome sequencing WGS and WES led to the identification of many inherited and de novo germline variants that significantly contribute to total NDD risk 21 , 22 , 23 , 24 Fig.
These mutations emphasize the convergence on specific biological pathways due to their enrichment in certain gene sets including genes regulated by the fragile X protein Finally, germline mutations do not explain all NDD cases, indicating that other genetic defects also come into play. For example, postzygotic i. Along with the previously identified CNVs, such mutations have meaningful implications for risk prediction, diagnosis and patient management Mutations are identified in a series of genes with predisposition to NDDs pink ovals.
ASO antisense oligonucleotides—gray panel and BCAA branched chain amino acids—beige panel are two examples of personalized therapies probed in mouse models. Drug repurposing blue panel enables the usage of the same drug for different diseases due to novel mechanisms identified. Thus, the abovementioned technologies represent powerful tools for the molecular genetic dissection of patients affected by NDDs. Their introduction into clinical practice and association with routine phenotype-driven diagnosis holds promise for personalized diagnosis and therapy of NDDs.
The early occurrence of genetic glitches and the relatively late onset of symptoms that enable the diagnosis of NDDs, represent a major pitfall in identifying the cause and delivering the right kind of therapy. To complicate things further, for most NDDs, therapies hinge largely on behavioral or educational interventions 33 and on treating associated rather than core symptoms of the disorder.
Thus, for the majority of people with NDDs, the outcomes are poor or very poor in adulthood Given such challenges, we must ask how genetics may contribute to their improvement. First and foremost, genetic testing can lead to active monitoring and early intervention, even before the onset of the disorder.
Furthermore, knowing the genetic cause of a disorder may reveal the role of a specific biological pathway in its onset. Thus, targeted pharmacological interventions could be made with already existing drugs. Similarly, WES with targeted gene analysis e. Lastly, since NDDs are associated with cognitive and behavioral abnormalities, genetic information can guide the choice of behavioral treatment However, despite these advantages, the multiple guidelines proposing the use of genetic testing for individuals with NDDs are not implemented routinely in clinical practice This lack of use is either due to scarcity of resources or due to a lack of medical staff prepared to analyze and interpret genetic results.
To circumvent this issue, a proper dissemination of up-to-date findings about NDD genetics to clinical staff is desirable. In addition, genetic counseling should inform parents about recurrence risk assessment. Several systems cells, rodents, primates have been used to generate models of NDDs that can partially reproduce disease features and can be of interest for understanding underlying mechanisms Fig. However, mice also present with important limitations.
For example, assessment of higher brain functions, such as language and facial recognition, is difficult in large screens. To overcome some of these limitations, non-human primates can be employed to model complex behavior and higher cortical functions 45 , whereas zebrafish and invertebrates can be used for high-throughput genetic screens Alongside animal models, in vitro reprograming of stem cells has enabled the generation and analysis of human neurons.
The experimental tractability, the ability to model diseases directly from affected individuals and the unlimited source of cells are just some of the advantages of stem cell-based models. Conversely, the high heterogeneity among iPSC clones, the immature identity of neurons differentiated in vitro, the lack of high-order connectivity and the difficulty to model lamination in a 2D system are some of the obvious shortcomings of iPSC-derived disease models.
Axiomatically, the biggest advantage of genetic studies is to provide clues about the underlying neurobiology of NDDs and to transition those clues into clinical practice Fig. At present, the available treatments for NDDs consist of a combination of behavioral therapies 57 and drugs approved for ameliorating comorbidities such as irritability and anxiety, while in many cases the core symptoms of NDDs remain unsolved.
However, the combination of genetics and functional analysis led to the discovery of several molecular pathways involved in NDDs that were targeted to evaluate novel therapeutic strategies. Particularly, inhibiting the mechanistic target of rapamycin mTOR rescues physiological, morphological and behavioral abnormalities in mice modeling diseases associated with protein translation defects such as TSC 58 , PTEN- associated macrocephaly 59 or 15q duplication syndrome Multiple clinical trials are investigating the pharmacokinetics and pharmacodynamics of rapamaycin and its analogs sirolimus, everolimus for treating TSC with associated ASD 61 , Likewise, increasing levels of IGF1 -like growth factor 1 and brain-derived neurotrophic factor via transcriptional modulation improves physiological and behavioral anomalies in RS mouse models 63 , 64 and IGF1 administration leads to a higher endurance to social and cognitive testing in patients with RS 65 or PMDS However, contrary to what was predicted by a decade of studies in FXS animal models, administration of mavoglurant, an mGluR5 antagonist 68 , or arbaclofen, a GABA B receptor agonist 69 , 70 , to adolescents and adults with FXS showed no significant improvement in behavioral traits in a randomized, double-blind, placebo-controlled phase 2 trial.
Conversely, in a mouse model of PMDS with complete deletion of Shank3 , researchers reported decreased mGluR5 signaling in the striatum and cortex. Administration of a benzamide derivative resulted in augmentation of mGluR5 activity and rescue of functional and behavioral defects in mice. Thus, pharmacological treatments aimed at increasing mGluR5 activity may represent an option for patients with S HANK3 mutations 71 , Hence, genetically discriminating between different forms of NDDs and identifying the convergence of the common molecular pathways underlying NDD pathophysiology are important goals Fig.
Recently, new therapeutic strategies have been designed based on genetic findings. Using antisense oligonucleotides ASOs Fig. Following a similar rationale, ASOs are used for restoring normal levels of MeCP2 and rescuing neurological deficits in mice carrying an extra copy of Mecp2 Replacing a defective gene may also be achieved by gene therapy using adeno-associated virus AAV vectors However, making ASOs and AAV amenable to translation into clinical trials is challenging due to their safety, pharmacokinetics and distribution in the brain The Bckdk mouse model displays an abnormal brain amino acid profile and dietary supplementation with the missing BCAAs reverses certain neurological phenotypes Fig.
In addition to identifying new targets for therapy, genetic findings are useful for personalizing existing pharmacotherapy or behavioral interventions. In this sense, WES with targeted gene analysis e. In the case of people with SHANK3 deletions, they tend to have more advanced receptive communication skills than verbal language ability 79 and therefore could benefit from assistive communication strategies that may not have been in mind unless the genetic cause of their ASD was known.
Recently, a very common trend uses genetic findings for the application of targeted drug repurposing based on single gene defects Fig. Such an approach already shows promise for personalizing therapies for epilepsy cases arising from gain-of-function mutations in ion-channel subunit genes e.
Nonetheless, important barriers remain in order to translate these approaches to non-ion channel epilepsy genes and loss-of-function mutations 80 , Likewise, recent observations indicate that metformin, a worldwide first-line therapy for type 2 diabetes, rescues core phenotypes in adult FXS mice due to normalization of ERK signaling, eIF4E phosphorylation and matrix metalloproteinase 9 expression MMP-9 Given that the previously mentioned clinical trials with mGluR5 antagonists have failed, metformin represents a new therapeutic avenue for clinical studies involving FXS patients.
Administration of oxytocin, which is a peptide usually administered to initiate uterine contractions that also appears to be involved in modulating social behavior, improves ASD-like social deficits in several mouse models 83 and in a Shank3 -deficient rat 84 , but the clinical effectiveness of oxytocin on ASD should still be considered tentative due to mixed findings The quick development of novel and efficient sequencing technologies made the identification of genetic causes for a number of NDDs possible.
Using these techniques, an underlying genetic cause of many NDD cases can be identified. This progress allows the design of personalized therapeutic strategies and the implementation of genetic counseling. Furthermore, studies employing animal and human cell models carrying specific genetic glitches are underscoring potential novel therapeutic approaches. In the past few years, potential treatments derived from genetic and functional analysis made it to clinical trials.
Although several clinical trials have failed, the treatment of some NDDs seems much closer. Due to the very complex nature of NDDs, interdisciplinary approaches combining genetics, functional genomics, robust biological models and objective measures of response, such as biomarkers 86 , as well as the capability of researchers and clinicians to work side by side, will be essential. Data for this review was collected by typing the following keywords into PubMed: genomics, genetics, personalized therapy, neurodevelopmental disorders all in combination with NDDs, ASD, ID.
Shashi, V. The utility of the traditional medical genetics diagnostic evaluation in the context of next-generation sequencing for undiagnosed genetic disorders. Advancing the understanding of autism disease mechanisms through genetics. Elsabbagh, M.
Understanding Developmental Disorders : John Morton :
Global prevalence of autism and other pervasive developmental disorders. Autism Res 5 , — Amir, R. Verkerk, A. Identification of a gene FMR-1 containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65 , — Kandt, R. Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease.
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