Congenital cerebral palsy: genetic cause and nosological integrity

2021 ◽  
Vol 15 (3-4) ◽  
pp. 65-77
Author(s):  
P. I. Sokolov ◽  
N. V. Chebanenko ◽  
V. P. Zykov ◽  
I. V. Kanivets ◽  
A. G. Prityko ◽  
...  
Keyword(s):  
Cerebral Palsy ◽  
De Novo ◽  
Muscle Tone ◽  
Copy Number Variations ◽  
Genetic Determinism ◽  
Nucleotide Polymorphisms ◽  
Reproductive Ability ◽  
Genetically Determined ◽  
Genomic Anomalies

The review provides an analysis of 73 full-text articles, the source of which was the Medline, OMIM, NCBI, Pubmed, Scopus, eLibrary.ru databases. The data of studies of the main pathogenetic mechanisms of the formation of the cerebral palsy (CP) phenotype, such as chromosomal aberrations, copy number variations, single nucleotide polymorphisms, associated with the development of the CP phenotype, are reviewed and analyzed. Epigenetic effects on the genome, as well as the effects of the genome on the mechanisms of epigenomic regulation, are examined in detail. The data on the genetic determinism of concomitant pathology and reactivity to therapeutic tactics are presented. Based on the study of data from numerous studies, the authors draw the following conclusions:1) the pathogenesis of the phenotype of CP includes a large number of genes that determine violations of cellular metabolism, neuroontogenesis, brain resistance to hypoxia, etc;2) genes whose abnormalities form a syndromic pathology are involved in the pathogenesis of CP;3) the multidirectionality and breadth of the effects of the gene pool with the outcome in a syndrome-specific distinctive picture of the CP allows us to propose the concept of a neurotropic genome;4) the mechanisms of gene involvement can vary from aberrations to epigenetic imbalances;5) different groups of genes can differentially influence the formation of individual syndromes in the phenotype of CP;6) there are data indicating a genetic determinism of the tendency to contracture, pharmacoreactivity to drugs that reduce muscle tone, reactivity to habilitation effects;7) genomic-epigenomic interactions normally ensure the body’s adaptation to environmental conditions, and with pathology, they increase the likelihood of regulatory breakdowns that lead to the formation of a CP phenotype;8) the exclusion from the diagnosis of CP of genetically determined cases of phenotype development is incorrect.The authors present two anthropogenic reasons for the increase in the frequency of occurrence of de novo identified gene abnormalities:1) anthropogenic impact on the environment, increasing the number of anomalies of the genome de novo; 2) iatrogenic effects of technologies for preserving life, vitality and reproductive ability of carriers of genomic anomalies. This effect leads to the fixation of anomalies in the genome of the population.A paradox is formulated, according to which, in the presence of technologies capable of preserving the life of carriers of genomic anomalies, in vivo technologies for genome correction are only just beginning to be put into practice. Based on this, it is concluded that it is necessary to intensify the development of methods for prenatal diagnosis and gene therapy of CP.

scholarly journals De novo and rare inherited copy-number variations in the hemiplegic form of cerebral palsy

2017 ◽  
Vol 20 (2) ◽  
pp. 172-180 ◽  
Author(s):  
Mehdi Zarrei ◽  
Darcy L Fehlings ◽  
Karizma Mawjee ◽  
Lauren Switzer ◽  
Bhooma Thiruvahindrapuram ◽  
...  
Keyword(s):  
Cerebral Palsy ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variations

scholarly journals Pathogenic convergence of CNVs in genes functionally associated to a severe neuromotor developmental delay syndrome

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Juan L. García-Hernández ◽  
Luis A. Corchete ◽  
Íñigo Marcos-Alcalde ◽  
Paulino Gómez-Puertas ◽  
Carmen Fons ◽  
...  
Keyword(s):  
Cerebral Palsy ◽  
De Novo ◽  
Snp Array ◽  
Unknown Origin ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Test Case ◽  
Severe Motor ◽  
Neurological Phenotype ◽  
Snp Array Analysis

Abstract Background Complex developmental encephalopathy syndromes might be the consequence of unknown genetic alterations that are likely to contribute to the full neurological phenotype as a consequence of pathogenic gene combinations. Methods To identify the additional genetic contribution to the neurological phenotype, we studied as a test case a boy, with a KCNQ2 exon-7 partial duplication, by single-nucleotide polymorphism (SNP) microarray to detect copy-number variations (CNVs). Results The proband presented a cerebral palsy like syndrome with a severe motor and developmental encephalopathy. The SNP array analysis detected in the proband several de novo CNVs, nine partial gene losses (LRRC55, PCDH9, NALCN, RYR3, ELAVL2, CDH13, ATP1A2, SLC17A5, ANO3), and two partial gene duplications (PCDH19, EFNA5). The biological functions of these genes are associated with ion channels such as calcium, chloride, sodium, and potassium with several membrane proteins implicated in neural cell-cell interactions, synaptic transmission, and axon guidance. Pathogenically, these functions can be associated to cerebral palsy, seizures, dystonia, epileptic crisis, and motor neuron dysfunction, all present in the patient. Conclusions Severe motor and developmental encephalopathy syndromes of unknown origin can be the result of a phenotypic convergence by combination of several genetic alterations in genes whose physiological function contributes to the neurological pathogenic mechanism.

scholarly journals Pathogenic convergence of CNVs in genes functionally associated to a severe neuromotor developmental delay syndrome

2020 ◽  
Author(s):  
Juan L. García-Hernández ◽  
Luis A. Corchete ◽  
Íñigo Marcos-Alcalde ◽  
Paulino Gómez-Puertas ◽  
Carmen Fons ◽  
...  
Keyword(s):  
Cerebral Palsy ◽  
De Novo ◽  
Snp Array ◽  
Unknown Origin ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Test Case ◽  
Severe Motor ◽  
Neurological Phenotype ◽  
Snp Array Analysis

Abstract Background Complex developmental encephalopathy syndromes might be the consequence of unknown genetic alterations are likely to contribute to the full neurological phenotype as a consequence of pathogenic gene combinations. Methods To identify the additional genetic contribution to the neurological phenotype, we studied as a test case a boy, with a KCNQ2 exon-7 partial duplication, by single nucleotide polymorphism (SNP) microarray to detect copy-number variations (CNVs). Results The proband presented a cerebral palsy like syndrome with a severe motor and developmental encephalopathy. The SNP array analysis detected in the proband several de novo CNVs, nine partial gene losses (LRRC55, PCDH9, NALCN, RYR3, ELAVL2, CDH13, ATP1A2, SLC17A5, ANO3), and two partial gene duplications (PCDH19, EFNA5). The biological functions of these genes are associated with ion channels such as calcium, chloride, sodium, and potassium; and with several membrane proteins implicated in neural cell-cell interactions, synaptic transmission and axon guidance. Pathogenically, these functions can be associated to cerebral palsy, seizures, dystonia, epileptic crisis, and motor neuron dysfunction, all present in the patient. Conclusions Severe motor and developmental encephalopathy syndromes of unknown origin can be the result of a phenotypic convergence by combination of several genetic alterations in genes whose physiological function contributes to the neurological pathogenic mechanism.

scholarly journals In vivo and in vitro ageing results in accumulation of de novo copy number variations in bulls

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Tamas Revay ◽  
Olutobi Oluwole ◽  
Tom Kroetsch ◽  
W. Allan King
Keyword(s):  
Copy Number ◽  
De Novo ◽  
Copy Number Variations ◽  
In Vitro Ageing

scholarly journals An Overview of Genetic and Environmental Risk of Autism Spectrum Disorder

2019 ◽  
pp. 37-44 ◽  
Author(s):  
Jianjun Ou ◽  
Ruiting Liu ◽  
Yidong Shen ◽  
Kun Xia ◽  
Jingping Zhao
Keyword(s):  
Autism Spectrum Disorder ◽  
Environmental Factors ◽  
Rare Variants ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Spectrum Disorder ◽  
Nucleotide Polymorphisms ◽  
Genetic And Environmental Factors

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder typically diagnosed in children in the first few years of life. Genetic studies have demonstrated a moderate to high heritability of ASD, but only a limited number of single nucleotide polymorphisms (SNPs) have been identified. Meanwhile, numerous single de novo rare variants and copy number variations have been detected in patients with ASD, which are likely caused by environmental factors. Here we provide an overview of genetic and environmental factors that may contribute to the risk of ASD and we recommend that further study should be focused on both genes and environmental factors, as well as their interactions with the expectation that epigenetic studies will lead to understanding the link between the environment and risk of ASD.

scholarly journals Pathogenic convergence of CNVs in genes functionally associated to a severe neuromotor developmental delay syndrome

2021 ◽  
Author(s):  
Juan L. García-Hernández ◽  
Luis A. Corchete ◽  
Íñigo Marcos-Alcalde ◽  
Paulino Gómez-Puertas ◽  
Carmen Fons ◽  
...  
Keyword(s):  
Cerebral Palsy ◽  
De Novo ◽  
Snp Array ◽  
Unknown Origin ◽  
Genetic Alterations ◽  
Copy Number Variations ◽  
Test Case ◽  
Severe Motor ◽  
Neurological Phenotype ◽  
Snp Array Analysis

Abstract Background: Complex developmental encephalopathy syndromes might be the consequence of unknown genetic alterations are likely to contribute to the full neurological phenotype as a consequence of pathogenic gene combinations. Methods: To identify the additional genetic contribution to the neurological phenotype, we studied as a test case a boy, with a KCNQ2 exon-7 partial duplication, by single nucleotide polymorphism (SNP) microarray to detect copy-number variations (CNVs). Results: The proband presented a cerebral palsy like syndrome with a severe motor and developmental encephalopathy. The SNP array analysis detected in the proband several de novo CNVs, nine partial gene losses (LRRC55, PCDH9, NALCN, RYR3, ELAVL2, CDH13, ATP1A2, SLC17A5, ANO3), and two partial gene duplications (PCDH19, EFNA5). The biological functions of these genes are associated with ion channels such as calcium, chloride, sodium, and potassium; and with several membrane proteins implicated in neural cell-cell interactions, synaptic transmission and axon guidance. Pathogenically, these functions can be associated to cerebral palsy, seizures, dystonia, epileptic crisis, and motor neuron dysfunction, all present in the patient. Conclusions: Severe motor and developmental encephalopathy syndromes of unknown origin can be the result of a phenotypic convergence by combination of several genetic alterations in genes whose physiological function contributes to the neurological pathogenic mechanism.

scholarly journals Genome wide transcriptome analysis reveals vital role of heat responsive genes in regulatory mechanisms of lentil (Lens culinaris Medikus)

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Dharmendra Singh ◽  
Chandan Kumar Singh ◽  
Jyoti Taunk ◽  
Vasudha Jadon ◽  
Madan Pal ◽  
...  
Keyword(s):  
Heat Stress ◽  
Transcriptome Analysis ◽  
Pollen Germination ◽  
De Novo ◽  
Nucleotide Polymorphisms ◽  
Sensitive Genotype ◽  
Tolerant Genotype

Abstract The present study reports the role of morphological, physiological and reproductive attributes viz. membrane stability index (MSI), osmolytes accumulations, antioxidants activities and pollen germination for heat stress tolerance in contrasting genotypes. Heat stress increased proline and glycine betaine (GPX) contents, induced superoxide dismutase (SOD), ascorbate peroxidase (APX) and glutathione peroxidase (GPX) activities and resulted in higher MSI in PDL-2 (tolerant) compared to JL-3 (sensitive). In vitro pollen germination of tolerant genotype was higher than sensitive one under heat stress. In vivo stressed pollens of tolerant genotype germinated well on stressed stigma of sensitive genotype, while stressed pollens of sensitive genotype did not germinate on stressed stigma of tolerant genotype. De novo transcriptome analysis of both the genotypes showed that number of contigs ranged from 90,267 to 104,424 for all the samples with N50 ranging from 1,755 to 1,844 bp under heat stress and control conditions. Based on assembled unigenes, 194,178 high-quality Single Nucleotide Polymorphisms (SNPs), 141,050 microsatellites and 7,388 Insertion-deletions (Indels) were detected. Expression of 10 genes was evaluated using quantitative Real Time Polymerase Chain Reaction (RT-qPCR). Comparison of differentially expressed genes (DEGs) under different combinations of heat stress has led to the identification of candidate DEGs and pathways. Changes in expression of physiological and pollen phenotyping related genes were also reaffirmed through transcriptome data. Cell wall and secondary metabolite pathways are found to be majorly affected under heat stress. The findings need further analysis to determine genetic mechanism involved in heat tolerance of lentil.

scholarly journals SCHIZOPHRENIA: THE SEARCH FOR GENETIC RISK FACTORS

2019 ◽  
pp. 241-252
Author(s):  
V. Pomohaibo ◽  
O. Berezan ◽  
A. Petrushov
Keyword(s):  
Genetic Risk ◽  
Clinical Effect ◽  
De Novo ◽  
Genetic Model ◽  
Copy Number Variations ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Risk Alleles

The risk of schizophrenia is caused by mutations in brain expressed genes. Four groups of mutations are distinguished: single-nucleotide polymorphisms, single-nucleotide variants, small insertions/deletions and copy number variations. Each individual disruptive allele has a weak clinical effect, but their certain complex causes schizophrenia hereditary liability. Currently almost 30 alleles with SNPs were identified, but theirs can be several thousands. It was showed that 2546 genes with SNVs and InDel have a higher probability of being associated with schizophrenia. It was identified more than 20 schizophrenia risk loci with CNVs that are distributed over the genome-wide.It was noted that the genetic mechanism of schizophrenia is extremely complex and far from understanding. Satisfactory genetic model of this disease does not exist for the present. It is proposed a classification of schizophrenia risk alleles according to their frequency: common, rare and de novo.

scholarly journals CEREBRAL PALSY BIOMARKER

2021 ◽  
Author(s):  
Aleksandr S. Golota
Keyword(s):  
Risk Factors ◽  
Cerebral Palsy ◽  
Genetic Susceptibility ◽  
Epidemiological Studies ◽  
Copy Number Variations ◽  
Clinical Risk Factors ◽  
Nucleotide Polymorphisms ◽  
Clinical Risk ◽  
New Findings ◽  
Gene Expression Studies

Cerebral palsy is a neurological disorder that is attributed to non-progressive injury or malformation that occurred in the developing fetal or infant brain. The motor disorders in cerebral palsy are often accompanied by disturbances of sensation, perception, cognition, communication, behaviour, and by epilepsy. Cerebral palsy is a complex disorder that is likely to be of multifactorial origin. Epidemiological studies have shown that the origins of most CP are prior to labor. A number of clinical risk factors for cerebral palsy have been described in the literature including preterm birth, low birth weight, inflammation, maternal infection during pregnancy and placenta pathology. Hypoxia at birth may be primary or secondary to preexisting pathology, but the currently known clinical risk factors do not explain the majority of cases. Many of these risk factors may have a genetic component. Several single nucleotide polymorphisms, DNA copy number variations and epigenetic patterns increase genetic susceptibility for cerebral palsy. Whole genome sequencing and gene expression studies may extend the percentage of cases with a genetic pathway. Clinical risk factors could act as triggers for CP where there is genetic susceptibility. These new findings should refocus research about the causes of these complex and varied neurodevelopmental disorders on the search for biomarkers of the risk of cerebral palsy. Genomics, proteomics and metabolomics have huge potential for deepening our understanding of many complex diseases by identifying diagnostic and prognostic panels of biomarkers, especially in various neurological disorders, including cerebral palsy.

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