scholarly journals Identification of novel CSNK2A1 variants and the genotype–phenotype relationship in patients with Okur–Chung neurodevelopmental syndrome: a case report and systematic literature review

2021 ◽  
Vol 49 (5) ◽  
pp. 030006052110170
Author(s):  
Ruo-hao Wu ◽  
Wen-ting Tang ◽  
Kun-yin Qiu ◽  
Xiao-juan Li ◽  
Dan-xia Tang ◽  
...  
Keyword(s):  
De Novo ◽  
Facial Dysmorphism ◽  
Comprehensive Overview ◽  
Protein Coding ◽  
Coding Regions ◽  
Gtp Binding ◽  
Phenotypic Spectrum ◽  
Whole Exome ◽  
First Time ◽  
Binding Loop

De novo germline variants of the casein kinase 2α subunit (CK2α) gene ( CSNK2A1) have been reported in individuals with the congenital neuropsychiatric disorder Okur–Chung neurodevelopmental syndrome (OCNS). Here, we report on two unrelated children with OCNS and review the literature to explore the genotype–phenotype relationship in OCNS. Both children showed facial dysmorphism, growth retardation, and neuropsychiatric disorders. Using whole-exome sequencing, we identified two novel de novo CSNK2A1 variants: c.479A>G p.(H160R) and c.238C>T p.(R80C). A search of the literature identified 12 studies that provided information on 35 CSNK2A1 variants in various protein-coding regions of CK2α. By quantitatively analyzing data related to these CSNK2A1 variants and their corresponding phenotypes, we showed for the first time that mutations in protein-coding CK2α regions appear to influence the phenotypic spectrum of OCNS. Mutations altering the ATP/GTP-binding loop were more likely to cause the widest range of phenotypes. Therefore, any assessment of clinical spectra for this disorder should be extremely thorough. This study not only expands the mutational spectrum of OCNS, but also provides a comprehensive overview to improve our understanding of the genotype–phenotype relationship in OCNS.

Novel De NovoEFTUD2 Mutations in 2 Cases With MFDM, Initially Suspected to Have Alternative Craniofacial Diagnoses

2018 ◽  
Vol 56 (5) ◽  
pp. 674-678 ◽  
Author(s):  
Jennie C. Lacour ◽  
Lori McBride ◽  
Hugo St. Hilaire ◽  
Gerhard S. Mundinger ◽  
Michael Moses ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Elongation Factor ◽  
Elongation Factor Tu ◽  
De Novo Mutations ◽  
Gtp Binding ◽  
Phenotypic Spectrum ◽  
Whole Exome ◽  
Mandibulofacial Dysostosis

We report 2 cases of mandibulofacial dysostosis with microcephaly (MFDM) with different and novel de novo mutations in the elongation factor Tu GTP binding domain containing 2 gene. Both cases were initially thought to have alternative disorders but were later correctly diagnosed through whole-exome sequencing. These cases expand upon our knowledge of the phenotypic spectrum in patients with MFDM, which will aid in defining the full phenotype of this disorder and increase awareness of this condition.

scholarly journals Human to yeast pathway transplantation: cross-species dissection of the adenine de novo pathway regulatory node

2017 ◽  
Author(s):  
Neta Agmon ◽  
Jasmine Temple ◽  
Zuojian Tang ◽  
Tobias Schraink ◽  
Maayan Baron ◽  
...  
Keyword(s):  
Yeast Strain ◽  
Transcriptional Control ◽  
De Novo ◽  
Enzyme Level ◽  
Yeast Cells ◽  
Protein Coding ◽  
Coding Regions ◽  
Human Proteins ◽  
Human Ortholog ◽  
Yeast Genes

AbstractPathway transplantation from one organism to another represents a means to a more complete understanding of a biochemical or regulatory process. The purine biosynthesis pathway, a core metabolic function, was transplanted from human to yeast. We replaced the entireSaccharomyces cerevisiaeadenine de novo pathway with the cognate human pathway components. A yeast strain was “humanized” for the full pathway by deleting all relevant yeast genes completely and then providing the human pathway in trans using a neochromosome expressing the human protein coding regions under the transcriptional control of their cognate yeast promoters and terminators. The “humanized” yeast strain grows in the absence of adenine, indicating complementation of the yeast pathway by the full set of human proteins. While the strain with the neochromosome is indeed prototrophic, it grows slowly in the absence of adenine. Dissection of the phenotype revealed that the human ortholog ofADE4, PPAT, shows only partial complementation. We have used several strategies to understand this phenotype, that point toPPAT/ADE4as the central regulatory node. Pathway metabolites are responsible for regulatingPPAT’sprotein abundance through transcription and proteolysis as well as its enzymatic activity by allosteric regulation in these yeast cells. Extensive phylogenetic analysis of PPATs from diverse organisms hints at adaptations of the enzyme-level regulation to the metabolite levels in the organism. Finally, we isolated specific mutations in PPAT as well as in other genes involved in the purine metabolic network that alleviate incomplete complementation byPPATand provide further insight into the complex regulation of this critical metabolic pathway.

scholarly journals Case Report: Identification of a de novo Microdeletion 1q44 in a Patient With Seizures and Developmental Delay

2021 ◽  
Vol 12 ◽  
Author(s):  
Yiehen Tung ◽  
Haiying Lu ◽  
Wenxin Lin ◽  
Tingting Huang ◽  
Samuel Kim ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Clinical Symptoms ◽  
Karyotype Analysis ◽  
Microdeletion Syndrome ◽  
Phenotypic Spectrum ◽  
Whole Exome ◽  
Number Variation ◽  
History Of

Objective: 1q44 microdeletion syndrome is difficult to diagnose due to the wide phenotypic spectrum and strong genetic heterogeneity. We explore the correlation between the chromosome microdeletions and phenotype in a child with 1q44 microdeletion syndrome, we collected the clinical features of the patient and combined them with adjacent copy number variation (CNV) regions previously reported.Methods: We collected the full medical history of the patient and summarized her clinical symptoms. Whole-exome sequencing (WES) and CapCNV analysis were performed with DNA extracted from both the patient's and her parents' peripheral blood samples. Fluorescent quantitative PCR (q-PCR) was performed for the use of verification to the CNV regions.Results: A 28.7 KB microdeletion was detected in the 1q44 region by whole-exome sequencing and low-depth whole-genome sequencing. The deleted region included the genes COX20 and HNRNPU. As verification, karyotype analysis showed no abnormality, and the results of qPCR were consistent with that of whole-exome sequencing and CapCNV analysis.Conclusion: The patient was diagnosed with 1q44 microdeletion syndrome with clinical and genetic analysis. Analyzing both whole-exome sequencing and CapCNV analysis can not only improve the diagnostic rate of clinically suspected syndromes that present with intellectual disability (ID) and multiple malformations but also support further study of the correlation between CNVs and clinical phenotypes. This study lays the foundation for the further study of the pathogenesis of complex diseases.

scholarly journals Pandoravirus celtis illustrates the microevolution processes at work in the giant Pandoraviridae genomes

2018 ◽  
Author(s):  
Matthieu Legendre ◽  
Jean-Marie Alempic ◽  
Nadège Philippe ◽  
Audrey Lartigue ◽  
Sandra Jeudy ◽  
...  
Keyword(s):  
De Novo ◽  
Gene Repertoire ◽  
Protein Coding ◽  
Genomic Changes ◽  
Coding Regions ◽  
Protein Coding Genes ◽  
Intergenic Regions ◽  
Mere Existence ◽  
Increasing Functions ◽  
Similar Gene

AbstractWith genomes of up to 2.7 Mb propagated in µm-long oblong particles and initially predicted to encode more than 2000 proteins, members of the Pandoraviridae family display the most extreme features of the known viral world. The mere existence of such giant viruses raises fundamental questions about their origin and the processes governing their evolution. A previous analysis of six newly available isolates, independently confirmed by a study including 3 others, established that the Pandoraviridae pan-genome is open, meaning that each new strain exhibits protein-coding genes not previously identified in other family members. With an average increment of about 60 proteins, the gene repertoire shows no sign of reaching a limit and remains largely coding for proteins without recognizable homologs in other viruses or cells (ORFans). To explain these results, we proposed that most new protein-coding genes were created de novo, from pre-existing non-coding regions of the G+C rich pandoravirus genomes. The comparison of the gene content of a new isolate, P. celtis, closely related (96% identical genome) to the previously described P. quercus is now used to test this hypothesis by studying genomic changes in a microevolution range. Our results confirm that the differences between these two similar gene contents mostly consist of protein-coding genes without known homologs (ORFans), with statistical signatures close to that of intergenic regions. These newborn proteins are under slight negative selection, perhaps to maintain stable folds and prevent protein aggregation pending the eventual emergence of fitness-increasing functions. Our study also unraveled several insertion events mediated by a transposase of the hAT family, 3 copies of which are found in P. celtis and are presumably active. Members of the Pandoraviridae are presently the first viruses known to encode this type of transposase.

scholarly journals Structure and Phylogeny of the Curly Birch Chloroplast Genome

2021 ◽  
Vol 12 ◽  
Author(s):  
Konstantin A. Shestibratov ◽  
Oleg Yu. Baranov ◽  
Eugenia N. Mescherova ◽  
Pavel S. Kiryanov ◽  
Stanislav V. Panteleev ◽  
...  
Keyword(s):  
Chloroplast Genome ◽  
Genetic Markers ◽  
De Novo ◽  
Functional Organization ◽  
Protein Coding ◽  
Organelle Genomes ◽  
Genes Encoding ◽  
Cpdna Sequence ◽  
Ssr Loci ◽  
First Time

Curly birch [Betula pendula var. carelica (Merckl.) Hämet-Ahti] is a relatively rare variety of silver birch (B. pendula Roth) that occurs mainly in Northern Europe and northwest part of Russia (Karelia). It is famous for the beautiful decorative texture of wood. Abnormal xylogenesis underlying this trait is heritable, but its genetic mechanism has not yet been fully understood. The high number of potentially informative genetic markers can be identified through sequencing nuclear and organelle genomes. Here, the de novo assembly, complete nucleotide sequence, and annotation of the chloroplast genome (plastome) of curly birch are presented for the first time. The complete plastome length is 160,523 bp. It contains 82 genes encoding structural and enzymatic proteins, 37 transfer RNAs (tRNAs), and eight ribosomal RNAs (rRNAs). The chloroplast DNA (cpDNA) is AT-rich containing 31.5% of A and 32.5% of T nucleotides. The GC-rich regions represent inverted repeats IR1 and IR2 containing genes of rRNAs (5S, 4.5S, 23S, and 16S) and tRNAs (trnV, trnI, and trnA). A high content of GC was found in rRNA (55.2%) and tRNA (53.2%) genes, but only 37.0% in protein-coding genes. In total, 384 microsatellite or simple sequence repeat (SSR) loci were found, mostly with mononucleotide motifs (92% of all loci) and predominantly A or T motifs (94% of all mononucleotide motifs). Comparative analysis of cpDNA in different plant species revealed high structural and functional conservatism in organization of the angiosperm plastomes, while the level of differences depends on the phylogenetic relationship. The structural and functional organization of plastome in curly birch was similar to cpDNA in other species of woody plants. Finally, the identified cpDNA sequence variation will allow to develop useful genetic markers.

scholarly journals De novo, systemic, deleterious amino acid substitutions are common in large cytoskeleton-related protein coding regions

2016 ◽  
Vol 6 (2) ◽  
pp. 211-216
Author(s):  
Rebecca J. Stoll ◽  
Grace R. Thompson ◽  
Mohammad D. Samy ◽  
George Blanck
Keyword(s):  
Amino Acid ◽  
De Novo ◽  
Amino Acid Substitutions ◽  
Related Protein ◽  
Protein Coding ◽  
Coding Regions

scholarly journals Extreme purifying selection against point mutations in the human genome

2021 ◽  
Author(s):  
Noah Dukler ◽  
Mehreen R Mughal ◽  
Ritika Ramani ◽  
Yi-Fei Huang ◽  
Adam Siepel
Keyword(s):  
Human Genome ◽  
De Novo ◽  
Point Mutations ◽  
Purifying Selection ◽  
Selection Coefficient ◽  
Sequencing Data ◽  
Protein Coding ◽  
Coding Regions ◽  
Protein Coding Genes ◽  
Selective Effects

Genome sequencing of tens of thousands of human individuals has recently enabled the measurement of large selective effects for mutations to protein-coding genes. Here we describe a new method, called ExtRaINSIGHT, for measuring similar selective effects at individual sites in noncoding as well as in coding regions of the human genome. ExtRaINSIGHT estimates the prevalance of strong purifying selection, or "ultraselection" (λs), as the fractional depletion of rare single-nucleotide variants (minor allele frequency <0.1%) in a target set of genomic sites relative to matched sites that are putatively neutrally evolving, in a manner that controls for local variation and neighbor-dependence in mutation rate. We show using simulations that, above an appropriate threshold, λs is closely related to the average site-specific selection coefficient against heterozygous point mutations, as predicted at mutation-selection balance. Applying ExtRaINSIGHT to 71,702 whole genome sequences from gnomAD v3, we find particularly strong evidence of ultraselection in evolutionarily ancient miRNAs and neuronal protein-coding genes, as well as at splice sites. Moreover, our estimated selection coefficient against heterozygous amino-acid replacements across the genome (at 1.4%) is substantially larger than previous estimates based on smaller sample sizes. By contrast, we find weak evidence of ultraselection in other noncoding RNAs and transcription factor binding sites, and only modest evidence in ultraconserved elements and human accelerated regions. We estimate that ~0.3-0.5% of the human genome is ultraselected, with one third to one half of ultraselected sites falling in coding regions. These estimates suggest ~0.3-0.4 lethal or nearly lethal de novo mutations per potential human zygote, together with ~2 de novo mutations that are more weakly deleterious. Overall, our study sheds new light on the genome-wide distribution of fitness effects for new point mutations by combining deep new sequencing data sets and classical theory from population genetics.

CNV Analysis in Monozygotic Twin Pairs Discordant for Urorectal Malformations

2013 ◽  
Vol 16 (4) ◽  
pp. 802-807 ◽  
Author(s):  
Friederike Baudisch ◽  
Markus Draaken ◽  
Enrika Bartels ◽  
Eberhard Schmiedeke ◽  
Soyhan Bagci ◽  
...  
Keyword(s):  
De Novo ◽  
Bladder Exstrophy ◽  
Anorectal Malformations ◽  
Monozygotic Twin ◽  
Regulatory Elements ◽  
Copy Number Variations ◽  
Molecular Karyotyping ◽  
Genetic Changes ◽  
Coding Regions ◽  
Whole Exome

Early post-twinning mutational events can account for discordant phenotypes in monozygotic (MZ) twin pairs. Such mutational events may comprise genomic alterations of different sizes, ranging from single nucleotides to large copy-number variations (CNVs). Anorectal malformations (ARM) and the bladder exstrophy-epispadias complex (BEEC) represent the most severe end of the urorectal malformation spectrum. Recently, CNV studies in patients with sporadic ARM and the BEEC have identified de novo events that occur in specific chromosomal regions. We hypothesized that early arising, post-twinning CNVs might contribute to discordance in MZ twin pairs with ARM or the BEEC; knowledge of such CNVs might help to identify additional chromosomal regions involved in the development of these malformations. We investigated four discordant MZ twin pairs (three ARM and one BEEC) using molecular karyotyping arrays comprising 1,140,419 markers with a median marker spacing of 1.5 kb. Filtering the coding regions for possible disease-causing post-twinning de novo CNVs present only in the affected twin, but not in the unaffected twin or the parents, identified a total of 136 CNVs. These 136 CNVs were then filtered against publicly available databases and finally re-evaluated visually. No potentially causative CNV remained after applying these filter criteria. Our results suggest that post-twinning CNV events that affect coding regions of the genome did not contribute to the discordant phenotypes in MZ twin pairs that we investigated. Possible causes for the discordant phenotypes include changes in regulatory elements or smaller genetic changes within coding regions which may be detectable by whole-exome sequencing.

scholarly journals Severe neurodevelopmental disease caused by a homozygous TLK2 variant

2019 ◽  
Vol 28 (3) ◽  
pp. 383-387 ◽  
Author(s):  
Ana Töpf ◽  
Yavuz Oktay ◽  
Sunitha Balaraju ◽  
Elmasnur Yilmaz ◽  
Ece Sonmezler ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Missense Variant ◽  
Cerebellar Vermis ◽  
Language Delay ◽  
Facial Dysmorphism ◽  
Neurodevelopmental Disease ◽  
Whole Exome ◽  
Neurodevelopmental Phenotype

Abstract A distinct neurodevelopmental phenotype characterised mainly by mild motor and language delay and facial dysmorphism, caused by heterozygous de novo or dominant variants in the TLK2 gene has recently been described. All cases reported carried either truncating variants located throughout the gene, or missense changes principally located at the C-terminal end of the protein mostly resulting in haploinsufficiency of TLK2. Through whole exome sequencing, we identified a homozygous missense variant in TLK2 in a patient showing more severe symptoms than those previously described, including cerebellar vermis hypoplasia and West syndrome. Both parents are heterozygous for the variant and clinically unaffected highlighting that recessive variants in TLK2 can also be disease causing and may act through a different pathomechanism.

scholarly journals NOVOMIR: De Novo Prediction of MicroRNA-Coding Regions in a Single Plant-Genome

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Jan-Hendrik Teune ◽  
Gerhard Steger
Keyword(s):  
Noncoding Rna ◽  
De Novo ◽  
Plant Genome ◽  
Messenger Rnas ◽  
Protein Coding ◽  
Rna Molecules ◽  
Coding Regions ◽  
Mirna Genes ◽  
Genomic Scale ◽  
Eukaryotic Genomes

MicroRNAs (miRNA) are small regulatory, noncoding RNA molecules that are transcribed as primary miRNAs (pri-miRNA) from eukaryotic genomes. At least in plants, their regulatory activity is mediated through base-pairing with protein-coding messenger RNAs (mRNA) followed by mRNA degradation or translation repression. We describeNOVOMIR, a program for the identification of miRNA genes in plant genomes. It uses a series of filter steps and a statistical model to discriminate a pre-miRNA from other RNAs and does rely neither on prior knowledge of a miRNA target nor on comparative genomics. The sensitivity and specificity ofNOVOMIR for detection of premiRNAs fromArabidopsis thalianais ~0.83 and ~0.99, respectively. Plant pre-miRNAs are more heterogeneous with respect to size and structure than animal pre-miRNAs. Despite these difficulties,NOVOMIR is well suited to perform searches for pre-miRNAs on a genomic scale.NOVOMIR is written in Perl and relies on two additional, free programs for prediction of RNA secondary structure (RNALFOLD, RNASHAPES).

Sign in / Sign up

Export Citation Format

Share Document