Manual Chapter 09, Etiological Heterogeneity in Autism Spectrum Disorders: Role of Rare Variants

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  3. De novo Mutations (DNMs) in Autism Spectrum Disorder (ASD): Pathway and Network Analysis
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SF and the mutation p. FL was analyzed separately with an appropriate WTE7c including its alternative exon 7c. These mutations also caused a slight, non-significant shift of the I-V relationships towards more positive test potentials Fig. Current density of the variants p. Steady-state inactivation was examined using two-pulse protocols.

Data and Boltzmann fits are depicted in Fig. The voltage of half-maximal inactivation V0. Numeric values are compiled in table 2. The ASD mutants p.

Half-inactivation potentials V0. The WT with the alternative exon 7c inactivated more slowly than the WT with exon 7a. It was therefore examined using an extended test pulse duration see scale bars in Fig. Analysis of the extent of time-dependent inactivation. The complex genetic principle of origin underlying ASD is still to be elucidated [40]. So far, genome-wide association and linkage studies presented inconsistent loci, reflecting a broad etiological heterogeneity and suggesting the influence of rare variants weighted by common susceptibility alleles.

To put the spectrum and the genes into a pathophysiological context, an oligogenic model with epistasis has been assumed [41] , [42]. It describes - based on their level of biological function - a combination of multiple interacting genes resulting in ASD phenotypes. Until now, few potential pathophysiological mechanisms have been postulated [43] , [44]. GR [2]. The concept is further supported by the association of mutations in various calcium channel genes with non-idiopathic ASD [2] , [13] — [16].

We did not test for differences in the mutation frequency between ASD patients and controls. Instead, we searched for most promising candidates of putative causal variants. Subsequently, by using patch clamp, the variants were tested for putative impairment of the function of the channel complex. Electrophysiological analyses in HEK-cells by whole-cell patch-clamp recordings demonstrate that all three missense mutations significantly alter the kinetics of the currents carried by the Ca V 1.

The third mutation shows a non-significant hyperpolarizing shift in current-voltage relation and an accelerated time-dependent inactivation. Of note decelerated time-dependent inactivation and incomplete voltage-dependent inactivation behavior are the biophysical hallmarks of the TS-mutation p. We observed a low penetrance of the three mutations in the ASD families under investigation, indicating the influence of other factors on the full expression of the condition.

However, rare variants might contribute to the complex genetics and clinical heterogeneity of ASD. For comparison, an analogous sequencing approach studying CACNA1H as a candidate gene for ASD in patients revealed six non-synonymous mutations in conserved domains, all showing a low penetrance and incomplete segregation [15].

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Expression of complex genetic disorders depends on multiple factors, therefore a low penetrance of causal variants is quite common. Unaffected carriers might be subclinically affected, other risk factors might have contributed to the phenotype in the affected individuals, or the described mutations may only act as modifiers of the phenotype. For instance, Krey et al. The mutations presented here appear to follow a similar but milder mechanism of action that occurs in TS. TS presents with a multi-organ dysfunction, possibly indicating the consequences of a dramatic elevation of the intracellular calcium concentration.

Thus the mutation of the TS can be viewed as an extreme of the viable spectrum of mutations within the calcium signaling pathway. More detailed biophysical and cell-biological studies under physiological conditions are warranted for all such mutations. P-values stem from individual Student t-tests of the indicated channels. Lajonchere PI. Antonio M. We are indebted to Prof. Heusch and Prof. Lehmann-Horn for providing pcDNA3. We gratefully acknowledge the assistance by Dr. Andreas Lazar. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Abstract Autism Spectrum Disorders ASD are complex neurodevelopmental diseases clinically defined by dysfunction of social interaction.

Introduction Autism spectrum disorder ASD is defined by dysfunction of social interaction and communication, stereotypic behavior and sensory integration problems. Materials and Methods Ethics Statement Procedures were approved by the Institutional Review Board application number of the medical faculty of the University of Cologne.

Electrophysiology Whole-cell recordings in EGFP-positive cells were obtained 48—72 h after transfection. Download: PPT. Figure 1. Table 1. Figure 4. Table 2. Discussion The complex genetic principle of origin underlying ASD is still to be elucidated [40]. Supporting Information. Table S1. Table S2. References 1. View Article Google Scholar 2. Cell 19— View Article Google Scholar 3. J Bioenerg Biomembr — View Article Google Scholar 4. Biophys J — View Article Google Scholar 5. Ludwig A, Flockerzi V, Hofmann F Regional expression and cellular localization of the alpha1 and beta subunit of high voltage-activated calcium channels in rat brain.

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In the group of non-syndromic ASD the indication for genetic investigation is currently less clear. In this group the simultaneous effect of the different common and rare variants should be estimated, which is currently dubious. Polygenic risk scores are emerging as a tool to predict disease risk in multifactorial diseases, but have many potential bias De La Vega and Bustamante, ; Torkamani et al. Even so polygenic risk score show promise, for example earlier studies showed that ASD polygenic risk score is positively correlated with general cognitive ability Clarke et al.

However, we are far away from everyday clinical utilization. Certain limitations of the study should be mentioned. The size of the cohort is perhaps the most important one. As we looked specifically for rare variants in a relatively small cohort, the probability of finding variants with very low MAF is low.

This could explain our result, that only five gene had significantly more rare variant burden than expected by spontaneous mutation rate, gene size and genic intolerance. This can result in false negative findings. False positive findings may also arise due to small sample size, however, this is mitigated by the fact, that well established ASD-genes were included in the panel. However, this approach has also disadvantages.

Autism Spectrum Disorder: The Cell Danger Response

The low number of total variant detected made impossible to analyze ethnicity and cryptic relatedness from the genetic data. On the other hand selection of a gene panel always contains a bias, since the number of genes linked to ASD is around according to the SFARI database 5. However, many of these do not have an associated Mendelian disorder. Finally we did not carry out functional experiments in this study, so cannot distinct clearly between rare non-functional and rare functional variants. We used protein prediction scores to assess the probability of functional impact of a variant.

In this study, we performed an analysis of rare single nucleotide and small INDEL variants in a Hungarian ASD cohort, detected by NGS panel testing, in order to identify syndromic autism cases and to assess the contribution of rare variants in formerly established ASD genes on a cohort level. Our study indicates that NGS panel gene sequencing can be useful in dedicated cases, where the clinical picture suggests a clinically defined syndromic autism i. However, the necessity of unselected NGS panel screening in the clinic remains controversial, because of uncertain clinical utility, and difficulties of the variant interpretation.

The detected rare variants may still significantly influence autism risk and subphenotypes in a polygenic model. However, to detect the effects of these variants large cohorts are needed. As knowledge will increase about the contribution of these rare variants on the phenotype, an individual assessment might also be beneficial in the future for personalized management of patients with ASD.

Written informed consent was obtained from the parents of the patient, or over 18 years of age, directly from the patients. NV and PB performed data collection and physical examination of the patients. KP performed the next generations sequencing. CP performed the neuropsychological testing of the patients.

De novo Mutations (DNMs) in Autism Spectrum Disorder (ASD): Pathway and Network Analysis

MM coordinated the research team, led the manuscript preparation, and revised and corrected the manuscript. All authors read and approved the final manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

We are grateful for the children for their participation in this study, and also for their parents. Table summarizes the number of different variant types, detected in the investigated genes. Next generation sequencing is not suitable for detection of repeat expansion events. Adzhubei, I. A method and server for predicting damaging missense mutations.

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