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

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.

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Lessons Learned from CNV Analysis of Major Birth Defects

International Journal of Molecular Sciences ◽

10.3390/ijms21218247 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8247

Author(s):

Alina Christine Hilger ◽

Gabriel Clemens Dworschak ◽

Heiko Martin Reutter

Keyword(s):

Birth Defects ◽

Copy Number ◽

Congenital Malformations ◽

De Novo ◽

Copy Number Variations ◽

Lessons Learned ◽

Organ System ◽

Molecular Karyotyping ◽

The Past ◽

Single Organ

The treatment of major birth defects are key concerns for child health. Hitherto, for the majority of birth defects, the underlying cause remains unknown, likely to be heterogeneous. The implicated mortality and/or reduced fecundity in major birth defects suggest a significant fraction of mutational de novo events among the affected individuals. With the advent of systematic array-based molecular karyotyping, larger cohorts of affected individuals have been screened over the past decade. This review discusses the identification of disease-causing copy-number variations (CNVs) among individuals with different congenital malformations. It highlights the differences in findings depending on the respective congenital malformation. It looks at the differences in findings of CNV analysis in non-isolated complex congenital malformations, associated with central nervous system malformations or intellectual disabilities, compared to isolated single organ-system malformations. We propose that the more complex an organ system is, and the more genes involved during embryonic development, the more likely it is that mutational de novo events, comprising CNVs, will confer to the expression of birth defects of this organ system.

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A Case With 4 de Novo Copy Number Variations With Clinical Features That Overlap 1q43q44 Microdeletion and 3q29 Microduplication Syndromes

Child Neurology Open ◽

10.1177/2329048x18798200 ◽

2018 ◽

Vol 5 ◽

pp. 2329048X1879820

Author(s):

Miriam Kessi ◽

Jing Peng ◽

Lifen Yang ◽

Haolin Duan ◽

Yulin Tang ◽

...

Keyword(s):

Intellectual Disability ◽

Corpus Callosum ◽

Copy Number ◽

De Novo ◽

Copy Number Variations ◽

Language Delay ◽

Global Developmental Delay ◽

Recurrent Infections ◽

Dental Anomalies ◽

Microdeletion Syndrome

1q43q44 microdeletion syndrome is characterized by intellectual disability/global developmental delay, epilepsy, dysmorphic facies, stereotypic movement, language delay, recurrent infections, dental anomalies, and hand and foot anomalies. Microcephaly and corpus callosum dysplasia are present in some cases depending on gene content. 3q29 microduplication syndrome is characterized by intellectual disability, language delay, microcephaly, and dental anomalies. We report the first case with 4 de novo copy number variations with clinical features which overlap 1q43q44 microdeletion and 3q29 microduplication syndromes. Our case presented with global developmental delay, epilepsy, recurrent infections, stereotypic movements, speech delay, microcephaly, facial dysmorphism, bilateral clinodactyly, and small puffy feet with metatarsus varus; however, she had no corpus callosum dysplasia. Our case highlights the role of multiple copy number variations in the occurrence of a certain phenotype. Moreover, it supports the theory that the loss of HNRNPU gene function cannot explain the occurrence of microcephaly and abnormalities of the corpus callosum in 1q43q44 microdeletion syndrome.

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Copy number variations in cryptogenic cerebral palsy

Neurology ◽

10.1212/wnl.0000000000001494 ◽

2015 ◽

Vol 84 (16) ◽

pp. 1660-1668 ◽

Cited By ~ 42

Author(s):

R. Segel ◽

H. Ben-Pazi ◽

S. Zeligson ◽

A. Fatal-Valevski ◽

A. Aran ◽

...

Keyword(s):

Cerebral Palsy ◽

Copy Number ◽

Copy Number Variations

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Detection and reconstruction of tandemly organized de novo copy number variations

BMC Bioinformatics ◽

10.1186/1471-2105-11-s11-s12 ◽

2010 ◽

Vol 11 (S11) ◽

Cited By ~ 5

Author(s):

Dan He ◽

Nicholas Furlotte ◽

Eleazar Eskin

Keyword(s):

Copy Number ◽

De Novo ◽

Copy Number Variations

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Associations between Familial Rates of Psychiatric Disorders and De Novo Genetic Mutations in Autism

Autism Research and Treatment ◽

10.1155/2017/9371964 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Kyleen Luhrs ◽

Tracey Ward ◽

Caitlin M. Hudac ◽

Jennifer Gerdts ◽

Holly A. F. Stessman ◽

...

Keyword(s):

Psychiatric Disorders ◽

Copy Number ◽

Depressive Disorders ◽

De Novo ◽

Familial Risk ◽

Autism Spectrum ◽

Copy Number Variations ◽

Genetic Etiology ◽

Additive Contribution ◽

Familial Risk Factors

The purpose of this study was to examine the confluence of genetic and familial risk factors in children with Autism Spectrum Disorder (ASD) with distinct de novo genetic events. We hypothesized that gene-disrupting mutations would be associated with reduced rates of familial psychiatric disorders relative to structural mutations. Participants included families of children with ASD in four groups: de novo duplication copy number variations (DUP, n=62), de novo deletion copy number variations (DEL, n=74), de novo likely gene-disrupting mutations (LGDM, n=267), and children without a known genetic etiology (NON, n=2111). Familial rates of psychiatric disorders were calculated from semistructured interviews. Results indicated overall increased rates of psychiatric disorders in DUP families compared to DEL and LGDM families, specific to paternal psychiatric histories, and particularly evident for depressive disorders. Higher rates of depressive disorders in maternal psychiatric histories were observed overall compared to paternal histories and higher rates of anxiety disorders were observed in paternal histories for LGDM families compared to DUP families. These findings support the notion of an additive contribution of genetic etiology and familial factors are associated with ASD risk and highlight critical need for continued work targeting these relationships.

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Increased Frequency of Copy Number Variations Revealed by Array Comparative Genomic Hybridization in the Offspring of Male Mice Exposed to Low Dose-Rate Ionizing Radiation

International Journal of Molecular Sciences ◽

10.3390/ijms222212437 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12437

Author(s):

Keiji Ogura ◽

Yoshiko Ayabe ◽

Chihiro Harada ◽

Ignacia Braga Tanaka ◽

Satoshi Tanaka ◽

...

Keyword(s):

Ionizing Radiation ◽

Dose Rate ◽

Copy Number ◽

Array Comparative Genomic Hybridization ◽

Low Dose ◽

De Novo ◽

Copy Number Variations ◽

Comparative Genomic ◽

Male Mice ◽

Low Dose Rate

There is very little information on the transgenerational or genetic effects of low dose-rate ionizing radiation. We report the detection of the transgenerational effects of chronic low dose-rate irradiation in mice, at the molecular level in the whole genome, using array comparative genomic hybridization technology. We observed that the number of the mice with de novo copy number variations (specifically, deletions) was significantly increased in the offspring of C57BL/6J male mice exposed to 20 mGy/day gamma-rays for 400 days (total dose: 8000 mGy), as compared to non-irradiated controls. We did not detect any difference in the size of the de novo deletions between the irradiated and the non-irradiated groups. An analysis of the life span of the offspring suggested a possibility that de novo copy-number variations may be associated with shorter life spans.

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