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Essential Genetic Findings in Neurodevelopmental Disorders Ana R Cardoso et al. Human Genomics (2019) 13:31 https://doi.org/10.1186/s40246-019-0216-4 REVIEW Open Access Essential genetic findings in neurodevelopmental disorders Ana R. Cardoso1,2,3, Mónica Lopes-Marques1,2,3, Raquel M. Silva4,5, Catarina Serrano1,2,3, António Amorim1,2,3, Maria J. Prata1,2,3 and Luísa Azevedo1,2,3* Abstract Neurodevelopmental disorders (NDDs) represent a growing medical challenge in modern societies. Ever-increasing sophisticated diagnostic tools have been continuously revealing a remarkably complex architecture that embraces genetic mutations of distinct types (chromosomal rearrangements, copy number variants, small indels, and nucleotide substitutions) with distinct frequencies in the population (common, rare, de novo). Such a network of interacting players creates difficulties in establishing rigorous genotype-phenotype correlations. Furthermore, individual lifestyles may also contribute to the severity of the symptoms fueling a large spectrum of gene-environment interactions that have a key role on the relationships between genotypes and phenotypes. Herein, a review of the genetic discoveries related to NDDs is presented with the aim to provide useful general information for the medical community. Keywords: Neurodevelopmental disorders, Brain-related genes, Deleterious mutations, de novo mutations, Polymorphisms, Risk alleles, Gene interaction Introduction NDDs include, for example, autism spectrum disorder, in- Neurodevelopment is the biological process resulting in tellectual disability, attention deficit hyperactivity disorder, the development and maturation of the nervous system. schizophrenia, and bipolar disorder [7, 9, 10]. The pre- In humans, the process starts at the third week of valence of these disorders constitutes a serious health embryonic growth with the formation of the neural tube problem in modern days. Previous reviews in distinct po- [1–5]. From the ninth week onward, the brain orderly pulations indicated a median global estimate of 62/10,000 maturates and acquires its typical structure, under a for autism [11], 10.37/1000 for intellectual disability tightly orchestrated chain of events that includes abundant [12], and a median lifetime prevalence of 4/1000 for cell proliferation, migration, and differentiation [1, 4, 5]. schizophrenia [13]. Any disruption to such orderly and complex chain of Multiple causes have been associated with NDDs, events may lead to dysfunctional brain development, and including genetic, environmental, infectious, and trau- consequently to a neurodevelopmental phenotype. Under matic, among others, which in general do not operate the designation neurodevelopmental disorders (NDDs) alone but instead interacting between each other [6]. falls a group of complex and heterogeneous disorders Importantly, the co-occurrence of distinct NDD entities showing symptoms associated to abnormal brain develop- has been often reported in the literature (e.g., [14]) ment that may give rise to impaired cognition, communi- suggesting the existence of shared underlying biological/ cation, adaptive behavior, and psychomotor skills [6–8]. cellular mechanisms [15, 16]. This review intends to focus on the molecular * Correspondence: [email protected] mechanisms associated with the most common neuro- 1i3S - Instituto de Investigação e Inovação em Saúde, Population Genetics and Evolution Group, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 developmental illnesses, for which the precise etiology Porto, Portugal remains still largely unknown, but yet the genetic 2 IPATIMUP - Institute of Molecular Pathology and Immunology, University of component has been increasingly deciphered with the Porto, Rua Júlio Amaral de Carvalho 45, 4200-135 Porto, Portugal Full list of author information is available at the end of the article massive sequencing of genomes of affected individuals. © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Cardoso et al. Human Genomics (2019) 13:31 Page 2 of 7 Gene/variant discovery by genome/exome screenings disorders [38–41]. Very recently, Short et al. [41]esti- Although the genetic etiology of NDDs is far from being mated that pathogenic de novo variants in fetal brain completely known, significant advances have been made regulatory elements account for about 1–3% of exome- in the last years, achieved hand-in-hand with progresses negative NDD probands. Therefore, WGS should be in ascertaining specific biological pathways underlying the considered whenever exome analyses do not provide evi- molecular mechanisms of these illnesses. The current dence regarding putative causative mutations in NDD mutational spectrum of NDDs includes many hundreds of phenotypes. genes related to neurodevelopmental pathways such as those associated with chromatin remodeling, synaptic Polymorphic variants and risk assessment function, and transcriptional regulation [17–19]. There is It is widely acknowledged that common genetic varia- convincing evidence for the huge genetic heterogeneity tions play an important role in the majority of complex not only within but also between and across different disorders; actually, both rare and common alleles can NDDs, once it is documented a considerable overlap of contribute towards disease susceptibility [42]. Usually, vari- genes involved in more than one NDD, and the number of ants with high frequency in the general population confer known causative genes continues to increase. low relative risk [43, 44] while rare alleles highly penetrant Whole exome sequencing (WES) has revealed to be may confer high risk [44]. Similarly to what is commonly among the most useful approaches in the identification of found in other complex genetic disorders, the risk of devel- novelcausalmutations[20–32] in particular WES-Trio oping NDDs seems to be highly influenced by the com- (proband and parents) studies due to be based on the bined effect of common variants [45]. Up to now, comparison of the genotypes of an affected child and their thousands of common low-risk genetic variants that col- parents, allowing thus the identification both of de novo lectively can contribute to NDD susceptibility have been mutations as inherited risk variants with variable pene- described [46]. Although the specific common risk alleles trance. The success of the WES approach was clearly may differ between distinct NDDs, given their overall rele- demonstrated in a recent study based in consanguineous vance here, we selected two single nucleotide polymor- families with NDDs, in which 14 new candidate genes phisms (SNPs), highly polymorphic and showing replicated not previously associated with NDD disorders were evidence of being associated with NDDs [47–51]todissect identified (GRM7, STX1A, CCAR2, EEF1D, GALNT2, their patterns of population distribution. In Fig. 1 is plotted SLC44A1, LRRIQ3, AMZ2, CLMN, SEC23IP, INIP, the frequency of the assumed risk allele at each SNP across NARG2, FAM234B,andTRAP1) all in patients who five major human populations. were homozygous for truncating mutations in each of The rs12704290 is an intronic variant located at the genes [31]. Importantly, the same study allowed the GRM3, the gene that encodes the glutamate metabo- identification of a de novo dominant truncating muta- tropic receptor 3 involved in the glutamatergic neuro- tion at the PARD6A (p.Arg312Term), a gene never yet transmission. At this position, the assumed risk allele is associated with any human disease but whose mouse rs12704290-G, which has been associated with a signifi- homolog had been demonstrated to control glial-guided cant increased risk to schizophrenia [48, 50]. This allele neuronal migration [33]. Although future studies still need is highly frequent across the five major human popula- to address whether PARD6A plays a similar functional role tions (Fig. 1), reaching the highest frequency in Africans present in humans, this illustrates the importance of WES (0.976) whereas the lowest is typically observed in in revealing new candidate genes that may have a critical Europeans (0.872). role in the neurodevelopment. The other common variant, rs7794745, is localized Intronic mutations can also be identified through in the CNTNAP2 gene, which encodes a neurexin WES. In 2017, Prchalova et al. [34] reported on an adult family protein involved in cell-cell adhesion [53]. The female with severe intellectual disability, epilepsy, and allele rs7794745-T was previously associated with an autistic features among other symptoms in whom the increased risk of developing autism spectrum disorder WES analysis led to the detection of an intronic muta- [47, 49, 51] and is highly frequent in all human popu- tion in the SYNGAP1 gene that was experimentally dem- lations (Fig. 1). The presence of risk alleles showing onstrated to interfere with mRNA splicing. SYNGAP1 high frequencies in different human populations led encodes the Ras/Rap GTP-activating protein, which has to the question on whether they were ancestral or de- a critical
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