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Genomics of Brain Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2018) | Viewed by 67584

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Dear Colleagues,

Brain disorders represent the third major problem of health and disability in developed countries after cardiovascular disorders and cancer. From a global health perspective, important issues to be addressed with regard to neuropsychiatric disorders (NPDs) are (i) disease burden (DALYs: disability-adjusted life years; YLDs: years lived with disability; YLLs: years of life lost); (ii) the costs (direct, indirect) of disease; (iii) disease pathogenesis; (iv) the identification of presymptomatic biomarkers; (v) novel targets for drug development; and (vi) personalized treatments with pharmacogenetic procedures for optimizing drug efficacy and safety. NPDs contribute approximately 10% of the global burden of disease. About 30% of all YLDs are assigned to NPDs, especially depression, alcohol use disorders, schizophrenia, bipolar disorder, and dementia. NPDs are the leading cause of disease burden, responsible for 7.4% of global DALYs and 22.9% of global YLDs. Within NPDs, mental disorders account for 56.7% DALYs, followed by neurological disorders (28.6%) and substance use disorder (14.7%).

A global cost of NPDs is projected to be about US$6 trillion by 2030. An estimated eight million deaths annually are attributed to mental disorders. Approximately 127 million Europeans suffer brain disorders. The total annual cost of brain disorders in Europe is about €386 billion, with €135 billion in direct medical expenditures, €179 billion in indirect costs, and €72 billion in direct non-medical costs. Mental disorders represent €240 billion (62% of the total cost, excluding dementia), followed by neurological diseases (€84 billion, 22%).

The primary cause of most brain disorders is poorly understood. In NPDs there is a convergence of multiple genomic defects distributed across the human genome with epigenetic phenomena and environmental risk factors leading to the phenotypic expression of the disease. In children, neurodevelopmental disorders are determinant for abnormal brain maturation and early mental derailment. In age-related neurodegenerative disorders, a common feature is the presence of intracellular and/or extracellular deposits of abnormally processed proteins which represent prototypical hallmarks probably contributing to premature neuronal death. A better characterization of the genomic background of mental and neurological disorders is necessary for elucidating disease-specific pathogenesis, as well as the identification of accurate biomarkers, and the implementation of novel treatments addressing pathogenic, mechanistic, metabolic, transporter and pleiotropic genes, and their products, associated with specific NPDs.

Prof. Dr. Ramón Cacabelos
Guest Editor

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Keywords

  • Alzheimer’s disease
  • Attention deficit/hyperactivity disorder
  • Autism spectrum disorders
  • Brain tumors
  • Demyelinating disorders
  • Drug addition
  • Epilepsy
  • Migraine
  • Mood disorders
  • Motor neuron disorders
  • Parkinson’s disease
  • Schizophrenia
  • Sleep disorders
  • Stroke
  • Vascular dementia

Published Papers (11 papers)

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15 pages, 1417 KiB  
Article
Deep Learning/Artificial Intelligence and Blood-Based DNA Epigenomic Prediction of Cerebral Palsy
by Ray O. Bahado-Singh, Sangeetha Vishweswaraiah, Buket Aydas, Nitish Kumar Mishra, Chittibabu Guda and Uppala Radhakrishna
Int. J. Mol. Sci. 2019, 20(9), 2075; https://doi.org/10.3390/ijms20092075 - 27 Apr 2019
Cited by 38 | Viewed by 5876
Abstract
The etiology of cerebral palsy (CP) is complex and remains inadequately understood. Early detection of CP is an important clinical objective as this improves long term outcomes. We performed genome-wide DNA methylation analysis to identify epigenomic predictors of CP in newborns and to [...] Read more.
The etiology of cerebral palsy (CP) is complex and remains inadequately understood. Early detection of CP is an important clinical objective as this improves long term outcomes. We performed genome-wide DNA methylation analysis to identify epigenomic predictors of CP in newborns and to investigate disease pathogenesis. Methylation analysis of newborn blood DNA using an Illumina HumanMethylation450K array was performed in 23 CP cases and 21 unaffected controls. There were 230 significantly differentially-methylated CpG loci in 258 genes. Each locus had at least 2.0-fold change in methylation in CP versus controls with a FDR p-value ≤ 0.05. Methylation level for each CpG locus had an area under the receiver operating curve (AUC) ≥ 0.75 for CP detection. Using Artificial Intelligence (AI) platforms/Machine Learning (ML) analysis, CpG methylation levels in a combination of 230 significantly differentially-methylated CpG loci in 258 genes had a 95% sensitivity and 94.4% specificity for newborn prediction of CP. Using pathway analysis, multiple canonical pathways plausibly linked to neuronal function were over-represented. Altered biological processes and functions included: neuromotor damage, malformation of major brain structures, brain growth, neuroprotection, neuronal development and de-differentiation, and cranial sensory neuron development. In conclusion, blood leucocyte epigenetic changes analyzed using AI/ML techniques appeared to accurately predict CP and provided plausible mechanistic information on CP pathogenesis. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders)
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48 pages, 14448 KiB  
Article
Sirtuins in Alzheimer’s Disease: SIRT2-Related GenoPhenotypes and Implications for PharmacoEpiGenetics
by Ramón Cacabelos, Juan C. Carril, Natalia Cacabelos, Aleksey G. Kazantsev, Alex V. Vostrov, Lola Corzo, Pablo Cacabelos and Dmitry Goldgaber
Int. J. Mol. Sci. 2019, 20(5), 1249; https://doi.org/10.3390/ijms20051249 - 12 Mar 2019
Cited by 65 | Viewed by 6243
Abstract
Sirtuins (SIRT1-7) are NAD+-dependent protein deacetylases/ADP ribosyltransferases with important roles in chromatin silencing, cell cycle regulation, cellular differentiation, cellular stress response, metabolism and aging. Sirtuins are components of the epigenetic machinery, which is disturbed in Alzheimer’s disease (AD), contributing to AD [...] Read more.
Sirtuins (SIRT1-7) are NAD+-dependent protein deacetylases/ADP ribosyltransferases with important roles in chromatin silencing, cell cycle regulation, cellular differentiation, cellular stress response, metabolism and aging. Sirtuins are components of the epigenetic machinery, which is disturbed in Alzheimer’s disease (AD), contributing to AD pathogenesis. There is an association between the SIRT2-C/T genotype (rs10410544) (50.92%) and AD susceptibility in the APOEε4-negative population (SIRT2-C/C, 34.72%; SIRT2-T/T 14.36%). The integration of SIRT2 and APOE variants in bigenic clusters yields 18 haplotypes. The 5 most frequent bigenic genotypes in AD are 33CT (27.81%), 33CC (21.36%), 34CT (15.29%), 34CC (9.76%) and 33TT (7.18%). There is an accumulation of APOE-3/4 and APOE-4/4 carriers in SIRT2-T/T > SIRT2-C/T > SIRT2-C/C carriers, and also of SIRT2-T/T and SIRT2-C/T carriers in patients who harbor the APOE-4/4 genotype. SIRT2 variants influence biochemical, hematological, metabolic and cardiovascular phenotypes, and modestly affect the pharmacoepigenetic outcome in AD. SIRT2-C/T carriers are the best responders, SIRT2-T/T carriers show an intermediate pattern, and SIRT2-C/C carriers are the worst responders to a multifactorial treatment. In APOE-SIRT2 bigenic clusters, 33CC carriers respond better than 33TT and 34CT carriers, whereas 24CC and 44CC carriers behave as the worst responders. CYP2D6 extensive metabolizers (EM) are the best responders, poor metabolizers (PM) are the worst responders, and ultra-rapid metabolizers (UM) tend to be better responders that intermediate metabolizers (IM). In association with CYP2D6 genophenotypes, SIRT2-C/T-EMs are the best responders. Some Sirtuin modulators might be potential candidates for AD treatment. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders)
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16 pages, 4072 KiB  
Article
HDAC Inhibitors Induce BDNF Expression and Promote Neurite Outgrowth in Human Neural Progenitor Cells-Derived Neurons
by Amir Bagheri, Parham Habibzadeh, Seyedeh Fatemeh Razavipour, Claude-Henry Volmar, Nancy T. Chee, Shaun P. Brothers, Claes Wahlestedt, Seyed Javad Mowla and Mohammad Ali Faghihi
Int. J. Mol. Sci. 2019, 20(5), 1109; https://doi.org/10.3390/ijms20051109 - 5 Mar 2019
Cited by 14 | Viewed by 5100
Abstract
Besides its key role in neural development, brain-derived neurotrophic factor (BDNF) is important for long-term potentiation and neurogenesis, which makes it a critical factor in learning and memory. Due to the important role of BDNF in synaptic function and plasticity, an in-house epigenetic [...] Read more.
Besides its key role in neural development, brain-derived neurotrophic factor (BDNF) is important for long-term potentiation and neurogenesis, which makes it a critical factor in learning and memory. Due to the important role of BDNF in synaptic function and plasticity, an in-house epigenetic library was screened against human neural progenitor cells (HNPCs) and WS1 human skin fibroblast cells using Cell-to-Ct assay kit to identify the small compounds capable of modulating the BDNF expression. In addition to two well-known hydroxamic acid-based histone deacetylase inhibitors (hb-HDACis), SAHA and TSA, several structurally similar HDAC inhibitors including SB-939, PCI-24781 and JNJ-26481585 with even higher impact on BDNF expression, were discovered in this study. Furthermore, by using well-developed immunohistochemistry assays, the selected compounds were also proved to have neurogenic potential improving the neurite outgrowth in HNPCs-derived neurons. In conclusion, we proved the neurogenic potential of several hb-HDACis, alongside their ability to enhance BDNF expression, which by modulating the neurogenesis and/or compensating for neuronal loss, could be propitious for treatment of neurological disorders. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders)
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11 pages, 788 KiB  
Article
Hippocampal LMNA Gene Expression is Increased in Late-Stage Alzheimer’s Disease
by Iván Méndez-López, Idoia Blanco-Luquin, Javier Sánchez-Ruiz de Gordoa, Amaya Urdánoz-Casado, Miren Roldán, Blanca Acha, Carmen Echavarri, Victoria Zelaya, Ivonne Jericó and Maite Mendioroz
Int. J. Mol. Sci. 2019, 20(4), 878; https://doi.org/10.3390/ijms20040878 - 18 Feb 2019
Cited by 16 | Viewed by 4265
Abstract
Lamins are fibrillary proteins that are crucial in maintaining nuclear shape and function. Recently, B-type lamin dysfunction has been linked to tauopathies. However, the role of A-type lamin in neurodegeneration is still obscure. Here, we examined A-type and B-type lamin expression levels by [...] Read more.
Lamins are fibrillary proteins that are crucial in maintaining nuclear shape and function. Recently, B-type lamin dysfunction has been linked to tauopathies. However, the role of A-type lamin in neurodegeneration is still obscure. Here, we examined A-type and B-type lamin expression levels by RT-qPCR in Alzheimer’s disease (AD) patients and controls in the hippocampus, the core of tau pathology in the brain. LMNA, LMNB1, and LMNB2 genes showed moderate mRNA levels in the human hippocampus with highest expression for the LMNA gene. Moreover, LMNA mRNA levels were increased at the late stage of AD (1.8-fold increase; p-value < 0.05). In addition, a moderate positive correlation was found between age and LMNA mRNA levels (Pearson’s r = 0.581, p-value = 0.018) within the control hippocampal samples that was not present in the hippocampal samples affected by AD. A-type and B-type lamin genes are expressed in the human hippocampus at the transcript level. LMNA mRNA levels are up-regulated in the hippocampal tissue in late stages of AD. The effect of age on increasing LMNA expression levels in control samples seems to be disrupted by the development of AD pathology. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders)
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14 pages, 1735 KiB  
Article
Metabolomic Signature in Sera of Multiple Sclerosis Patients during Pregnancy
by Claudia Rossi, Ilaria Cicalini, Mirco Zucchelli, Maria Di Ioia, Marco Onofrj, Luca Federici, Piero Del Boccio and Damiana Pieragostino
Int. J. Mol. Sci. 2018, 19(11), 3589; https://doi.org/10.3390/ijms19113589 - 14 Nov 2018
Cited by 19 | Viewed by 3645
Abstract
Multiple sclerosis (MuS) is an autoimmune disease of the central nervous system characterized by neuroinflammation, neurodegeneration, and degradation of the myelin sheath. Epidemiological studies have shown that the female gender is more susceptible than the male gender to MuS development, with a female-to-male [...] Read more.
Multiple sclerosis (MuS) is an autoimmune disease of the central nervous system characterized by neuroinflammation, neurodegeneration, and degradation of the myelin sheath. Epidemiological studies have shown that the female gender is more susceptible than the male gender to MuS development, with a female-to-male ratio of 2:1. Despite this high onset, women have a better prognosis than men, and the frequency of the relapsing phase decreases during pregnancy, while it increases soon after birth. Therefore, it is interesting to investigate hormonal fluctuations during pregnancy and whether they correlate with metabolic signatures. To gain a deeper inside into the biochemical mechanism of such a multifactorial disease, we adopted targeted metabolomics approaches for the determination of many serum metabolites in 12 pregnant women affected by MuS by mass spectrometry analysis. Our data show a characteristic hormonal fluctuation for estrogens and progesterone, as expected. They also highlight other interesting hormonal alterations for cortisol, corticosterone, 11-deoxycortisol, 4-androstene-3,17-dione, testosterone, and 17α-hydroxyprogesterone. Furthermore, a negative correlation with progesterone levels was observed for amino acids and for acylcarnitines, while an imbalance of different sphingolipids pathways was found during pregnancy. In conclusion, these data are in agreement with the characteristic clinical signs of MuS patients during pregnancy and, if confirmed, they may add an important tessera in the complex mosaic of maternal neuroprotection. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders)
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13 pages, 1677 KiB  
Communication
Insights into the Influence of Specific Splicing Events on the Structural Organization of LRRK2
by Dimitrios Vlachakis, Nikolaos E. Labrou, Costas Iliopoulos, John Hardy, Patrick A. Lewis, Hardy Rideout and Daniah Trabzuni
Int. J. Mol. Sci. 2018, 19(9), 2784; https://doi.org/10.3390/ijms19092784 - 16 Sep 2018
Cited by 3 | Viewed by 6082
Abstract
Leucine-rich repeat kinase 2 (LRRK2) is a large protein of unclear function. Rare mutations in the LRRK2 gene cause familial Parkinson’s disease (PD) and inflammatory bowel disease. Genome-wide association studies (GWAS) have revealed significant association of the abovementioned diseases at the LRRK2 locus. [...] Read more.
Leucine-rich repeat kinase 2 (LRRK2) is a large protein of unclear function. Rare mutations in the LRRK2 gene cause familial Parkinson’s disease (PD) and inflammatory bowel disease. Genome-wide association studies (GWAS) have revealed significant association of the abovementioned diseases at the LRRK2 locus. Cell and systems biology research has led to potential roles that LRRK2 may have in PD pathogenesis, especially the kinase domain (KIN). Previous human expression studies showed evidence of mRNA expression and splicing patterns that may contribute to our understanding of the function of LRRK2. In this work, we investigate and identified significant regional differences in LRRK2 expression at the mRNA level, including a number of splicing events in the Ras of complex protein (Roc) and C-terminal of Roc domain (COR) of LRRK2, in the substantia nigra (SN) and occipital cortex (OCTX). Our findings indicate that the predominant form of LRRK2 mRNA is full length, with shorter isoforms present at a lower copy number. Our molecular modelling study suggests that splicing events in the ROC/COR domains will have major consequences on the enzymatic function and dimer formation of LRRK2. The implications of these are highly relevant to the broader effort to understand the biology and physiological functions of LRRK2, and to better characterize the role(s) of LRRK2 in the underlying mechanism leading to PD. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders)
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Review

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19 pages, 324 KiB  
Review
Genetic Polymorphisms Associated with Spontaneous Intracerebral Hemorrhage
by Yi-Chun Chen, Kuo-Hsuan Chang and Chiung-Mei Chen
Int. J. Mol. Sci. 2018, 19(12), 3879; https://doi.org/10.3390/ijms19123879 - 4 Dec 2018
Cited by 19 | Viewed by 3870
Abstract
Differences in the incidence of spontaneous intracerebral hemorrhage (ICH) between ethnicities exist, with an estimated 42% of the variance explained by ethnicity itself. Caucasians have a higher proportion of lobar ICH (LICH, 15.4% of all ICH) than do Asians (3.4%). Alterations in the [...] Read more.
Differences in the incidence of spontaneous intracerebral hemorrhage (ICH) between ethnicities exist, with an estimated 42% of the variance explained by ethnicity itself. Caucasians have a higher proportion of lobar ICH (LICH, 15.4% of all ICH) than do Asians (3.4%). Alterations in the causal factor exposure between countries justify part of the ethnic variance in ICH incidence. One third of ICH risk can be explained by genetic variation; therefore, genetic differences between populations can partly explain the difference in ICH incidence. In this paper, we review the current knowledge of genetic variants associated with ICH in multiple ethnicities. Candidate gene variants reportedly associated with ICH were involved in the potential pathways of hypertension, vessel wall integrity, lipid metabolism, endothelial dysfunction, inflammation, platelet function, and coagulopathy. Furthermore, variations in APOE (in multiple ethnicities), PMF1/SLC25A44 (in European), ACE (in Asian), MTHFR (in multiple ethnicities), TRHDE (in European), and COL4A2 (in European) were the most convincingly associated with ICH. The majority of the associated genes provide small contributions to ICH risk, with few of them being replicated in multiple ethnicities. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders)
17 pages, 1361 KiB  
Review
Genomics: New Light on Alzheimer’s Disease Research
by Yeong Ju Jung, Yoon Ha Kim, Mridula Bhalla, Sung Bae Lee and Jinsoo Seo
Int. J. Mol. Sci. 2018, 19(12), 3771; https://doi.org/10.3390/ijms19123771 - 27 Nov 2018
Cited by 13 | Viewed by 6933
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that represents a major cause of death in many countries. AD is characterized by profound memory loss, disruptions in thinking and reasoning, and changes in personality and behavior followed by malfunctions in various bodily systems. [...] Read more.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease that represents a major cause of death in many countries. AD is characterized by profound memory loss, disruptions in thinking and reasoning, and changes in personality and behavior followed by malfunctions in various bodily systems. Although AD was first identified over 100 years ago, and tremendous efforts have been made to cure the disease, the precise mechanisms underlying the onset of AD remain unclear. The recent development of next-generation sequencing tools and bioinformatics has enabled us to investigate the role of genetics in the pathogenesis of AD. In this review, we discuss novel discoveries in this area, including the results of genome-wide association studies (GWAS) that have implicated a number of novel genes as risk factors, as well as the identification of epigenetic regulators strongly associated with the onset and progression of AD. We also review how genetic risk factors may interact with age-associated, progressive decreases in cognitive function in patients with AD. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders)
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33 pages, 2118 KiB  
Review
Risk Factors and Pathogenesis of HIV-Associated Neurocognitive Disorder: The Role of Host Genetics
by Ian Simon Olivier, Ramón Cacabelos and Vinogran Naidoo
Int. J. Mol. Sci. 2018, 19(11), 3594; https://doi.org/10.3390/ijms19113594 - 14 Nov 2018
Cited by 48 | Viewed by 12804
Abstract
Neurocognitive impairments associated with human immunodeficiency virus (HIV) infection remain a considerable health issue for almost half the people living with HIV, despite progress in HIV treatment through combination antiretroviral therapy (cART). The pathogenesis and risk factors of HIV-associated neurocognitive disorder (HAND) are [...] Read more.
Neurocognitive impairments associated with human immunodeficiency virus (HIV) infection remain a considerable health issue for almost half the people living with HIV, despite progress in HIV treatment through combination antiretroviral therapy (cART). The pathogenesis and risk factors of HIV-associated neurocognitive disorder (HAND) are still incompletely understood. This is partly due to the complexity of HAND diagnostics, as phenotypes present with high variability and change over time. Our current understanding is that HIV enters the central nervous system (CNS) during infection, persisting and replicating in resident immune and supporting cells, with the subsequent host immune response and inflammation likely adding to the development of HAND. Differences in host (human) genetics determine, in part, the effectiveness of the immune response and other factors that increase the vulnerability to HAND. This review describes findings from studies investigating the role of human host genetics in the pathogenesis of HAND, including potential risk factors for developing HAND. The similarities and differences between HAND and Alzheimer’s disease are also discussed. While some specific variations in host genes regulating immune responses and neurotransmission have been associated with protection or risk of HAND development, the effects are generally small and findings poorly replicated. Nevertheless, a few specific gene variants appear to affect the risk for developing HAND and aid our understanding of HAND pathogenesis. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders)
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36 pages, 1855 KiB  
Review
Pharmacoepigenomic Interventions as Novel Potential Treatments for Alzheimer’s and Parkinson’s Diseases
by Oscar Teijido and Ramón Cacabelos
Int. J. Mol. Sci. 2018, 19(10), 3199; https://doi.org/10.3390/ijms19103199 - 16 Oct 2018
Cited by 46 | Viewed by 7111
Abstract
Cerebrovascular and neurodegenerative disorders affect one billion people around the world and result from a combination of genomic, epigenomic, metabolic, and environmental factors. Diagnosis at late stages of disease progression, limited knowledge of gene biomarkers and molecular mechanisms of the pathology, and conventional [...] Read more.
Cerebrovascular and neurodegenerative disorders affect one billion people around the world and result from a combination of genomic, epigenomic, metabolic, and environmental factors. Diagnosis at late stages of disease progression, limited knowledge of gene biomarkers and molecular mechanisms of the pathology, and conventional compounds based on symptomatic rather than mechanistic features, determine the lack of success of current treatments, including current FDA-approved conventional drugs. The epigenetic approach opens new avenues for the detection of early presymptomatic pathological events that would allow the implementation of novel strategies in order to stop or delay the pathological process. The reversibility and potential restoring of epigenetic aberrations along with their potential use as targets for pharmacological and dietary interventions sited the use of epidrugs as potential novel candidates for successful treatments of multifactorial disorders involving neurodegeneration. This manuscript includes a description of the most relevant epigenetic mechanisms involved in the most prevalent neurodegenerative disorders worldwide, as well as the main potential epigenetic-based compounds under investigation for treatment of those disorders and their limitations. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders)
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9 pages, 13084 KiB  
Case Report
Whole-Exome Sequencing Implicates SCN2A in Episodic Ataxia, but Multiple Ion Channel Variants May Contribute to Phenotypic Complexity
by Neven Maksemous, Robert A. Smith, Heidi G. Sutherland, Hugo Sampaio and Lyn R. Griffiths
Int. J. Mol. Sci. 2018, 19(10), 3113; https://doi.org/10.3390/ijms19103113 - 11 Oct 2018
Cited by 8 | Viewed by 4575
Abstract
Although the clinical use of targeted gene sequencing-based diagnostics is valuable, whole-exome sequencing has also emerged as a successful diagnostic tool in molecular genetics laboratories worldwide. Molecular genetic tests for episodic ataxia type 2 (EA2) usually target only the specific calcium channel gene [...] Read more.
Although the clinical use of targeted gene sequencing-based diagnostics is valuable, whole-exome sequencing has also emerged as a successful diagnostic tool in molecular genetics laboratories worldwide. Molecular genetic tests for episodic ataxia type 2 (EA2) usually target only the specific calcium channel gene (CACNA1A) that is known to cause EA2. In cases where no mutations are identified in the CACNA1A gene, it is important to identify the causal gene so that more effective treatment can be prioritized for patients. Here we present a case of a proband with a complex episodic ataxias (EA)/seizure phenotype with an EA-affected father; and an unaffected mother, all negative for CACNA1A gene mutations. The trio was studied by whole-exome sequencing to identify candidate genes responsible for causing the complex EA/seizure phenotype. Three rare or novel variants in Sodium channel α2-subunit; SCN2A (c.3973G>T: p.Val1325Phe), Potassium channel, Kv3.2; KCNC2 (c.1006T>C: p.Ser336Pro) and Sodium channel Nav1.6; SCN8A (c.3421C>A: p.Pro1141Thr) genes were found in the proband. While the SCN2A variant is likely to be causal for episodic ataxia, each variant may potentially contribute to the phenotypes observed in this family. This study highlights that a major challenge of using whole-exome/genome sequencing is the identification of the unique causative mutation that is associated with complex disease. Full article
(This article belongs to the Special Issue Genomics of Brain Disorders)
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