scholarly journals Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion

2021 ◽  
Author(s):  
Matthew Jensen ◽  
Anastasia Tyryshkina ◽  
Lucilla Pizzo ◽  
Corrine Smolen ◽  
Maitreya Das ◽  
...  
Keyword(s):  
Gene Expression ◽  
Developmental Delay ◽  
De Novo ◽  
Phenotypic Variability ◽  
Specific Interaction ◽  
Specific Expression ◽  
Strong Connectivity ◽  
Second Hit ◽  
Complex Disorders ◽  
Variable Expressivity

ABSTRACTRecent studies have suggested that individual variants do not sufficiently explain the variable expressivity of phenotypes observed in complex disorders. For example, the 16p12.1 deletion is associated with developmental delay and neuropsychiatric features in affected individuals, but is inherited in >90% of cases from a mildly-affected parent. While children with the deletion are more likely to carry additional “second-hit” variants than their parents, the mechanisms for how these variants contribute to phenotypic variability are unknown. We performed detailed clinical assessments, whole-genome sequencing, and RNA sequencing of lymphoblastoid cell lines for 32 individuals in five large families with multiple members carrying the 16p12.1 deletion. We found that the deletion dysregulates multiple autism and brain development genes such as FOXP1, ANK3, and MEF2. Carrier children also showed expression changes that were inherited as well as de novo compared with their parents, which matched with 39/47 observed developmental phenotypes. We identified significant enrichments for 13/25 classes of “second-hit” variants in genes with expression changes, where 7/25 variant classes were only enriched when inherited from the non-carrier parent, including missense SNVs and large deletions. In 11 instances, including for ZEB2 and SYNJ1, gene expression was synergistically altered by both the deletion and inherited “second-hits” in carrier children. Finally, brain-specific interaction network analysis showed strong connectivity between genes carrying “second-hits” and genes with transcriptome alterations, including differential expression, alternative splicing, and allele-specific expression. Our study shows that family-based assessments of transcriptome data are highly relevant towards understanding the genetic mechanisms associated with complex disorders.

scholarly journals Combinatorial patterns of gene expression changes contribute to variable expressivity of the developmental delay-associated 16p12.1 deletion

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Matthew Jensen ◽  
Anastasia Tyryshkina ◽  
Lucilla Pizzo ◽  
Corrine Smolen ◽  
Maitreya Das ◽  
...  
Keyword(s):  
Gene Expression ◽  
Developmental Delay ◽  
Gene Networks ◽  
Phenotypic Variability ◽  
Specific Interaction ◽  
Loss Of Function ◽  
Specific Expression ◽  
Second Hit ◽  
Complex Disorders ◽  
Variable Expressivity

Abstract Background Recent studies have suggested that individual variants do not sufficiently explain the variable expressivity of phenotypes observed in complex disorders. For example, the 16p12.1 deletion is associated with developmental delay and neuropsychiatric features in affected individuals, but is inherited in > 90% of cases from a mildly-affected parent. While children with the deletion are more likely to carry additional “second-hit” variants than their parents, the mechanisms for how these variants contribute to phenotypic variability are unknown. Methods We performed detailed clinical assessments, whole-genome sequencing, and RNA sequencing of lymphoblastoid cell lines for 32 individuals in five large families with multiple members carrying the 16p12.1 deletion. We identified contributions of the 16p12.1 deletion and “second-hit” variants towards a range of expression changes in deletion carriers and their family members, including differential expression, outlier expression, alternative splicing, allele-specific expression, and expression quantitative trait loci analyses. Results We found that the deletion dysregulates multiple autism and brain development genes such as FOXP1, ANK3, and MEF2. Carrier children also showed an average of 5323 gene expression changes compared with one or both parents, which matched with 33/39 observed developmental phenotypes. We identified significant enrichments for 13/25 classes of “second-hit” variants in genes with expression changes, where 4/25 variant classes were only enriched when inherited from the noncarrier parent, including loss-of-function SNVs and large duplications. In 11 instances, including for ZEB2 and SYNJ1, gene expression was synergistically altered by both the deletion and inherited “second-hits” in carrier children. Finally, brain-specific interaction network analysis showed strong connectivity between genes carrying “second-hits” and genes with transcriptome alterations in deletion carriers. Conclusions Our results suggest a potential mechanism for how “second-hit” variants modulate expressivity of complex disorders such as the 16p12.1 deletion through transcriptomic perturbation of gene networks important for early development. Our work further shows that family-based assessments of transcriptome data are highly relevant towards understanding the genetic mechanisms associated with complex disorders.

Acute Myeloid Leukemia with Translocation t(8;16) Demonstrates Specific Cytomorphological, Cytogenetic, and Gene Expression Characteristics and Can Clearly Be Discriminated from Other AML with Balanced Translocations.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2897-2897
Author(s):  
Torsten Haferlach ◽  
Helmut Loeffler ◽  
Alexander Kohlmann ◽  
Martin Dugas ◽  
Wolfgang Hiddemann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Who Classification ◽  
De Novo ◽  
Expression Patterns ◽  
Gene Expression Pattern ◽  
Support Vector ◽  
Gene Expression Patterns ◽  
Down Regulation ◽  
Specific Expression ◽  
Balanced Translocations

Abstract Balanced chromosomal rearrangements leading to fusion genes on the molecular level define distinct biological subsets in AML. The four balanced rearrangements (t(15;17), t(8;21), inv(16), and 11q23/MLL) show a close correlation to cytomorphology and gene expression patterns. We here focused on seven AML with t(8;16)(p11;p13). This translocation is rare (7/3515 cases in own cohort). It is more frequently found in therapy-related AML than in de novo AML (3/258 t-AML, and 4/3287 de novo, p=0.0003). Cytomorphologically, AML with t(8;16) is characterized by striking features: In all 7 cases the positivity for myeloperoxidase on bone marrow smears was >70% and intriguingly, in parallel >80% of blast cells stained strongly positive for non-specific esterase (NSE) in all cases. Thus, these cases can not be classified according to FAB categories. These data suggest that AML-t(8;16) arise from a very early stem cell with both myeloid and monoblastic potential. Furthermore, we detected erythrophagocytosis in 6/7 cases that was described as specific feature in AML with t(8;16). Four pts. had chromosomal aberrations in addition to t(8;16), 3 of these were t-AML all showing aberrations of 7q. Survival was poor with 0, 1, 1, 2, 20 and 18+ (after alloBMT) mo., one lost to follow-up, respectively. We then analyzed gene expression patterns in 4 cases (Affymetrix U133A+B). First we compared t(8;16) AML with 46 AML FAB M1, 41 M4, 9 M5a, and 16 M5b, all with normal karyotype. Hierachical clustering and principal component analyses (PCA) revealed that t(8;16) AML were intercalating with FAB M4 and M5b and did not cluster near to M1. Thus, monocytic characteristics influence the gene expression pattern stronger than myeloid. Next we compared the t(8;16) AML with the 4 other balanced subtypes according to the WHO classification (t(15;17): 43; t(8;21): 40; inv(16): 49; 11q23/MLL-rearrangements: 50). Using support vector machines the overall accuracy for correct subgroup assignment was 97.3% (10-fold CV), and 96.8% (2/3 training and 1/3 test set, 100 runs). In PCA and hierarchical cluster analysis the t(8;16) were grouped in the vicinity of the 11q23 cases. However, in a pairwise comparison these two subgroups could be discriminated with an accuracy of 94.4% (10-fold CV). Genes with a specific expression in AML-t(8;16) were further investigated in pathway analyses (Ingenuity). 15 of the top 100 genes associated with AML-t(8;16) were involved in the CMYC-pathway with up regulation of BCOR, COXB5, CDK10, FLI1, HNRPA2B1, NSEP1, PDIP38, RAD50, SUPT5H, TLR2 and USP33, and down regulation of ERG, GATA2, NCOR2 and RPS20. CEBP beta, known to play a role in myelomonocytic differentiation, was also up-regulated in t(8;16)-AML. Ten additional genes out of the 100 top differentially expressed genes were also involved in this pathway with up-regulation of DDB2, HIST1H3D, NSAP1, PTPNS1, RAN, USP4, TRIM8, ZNF278 and down regulation of KIT and MBD2. In conclusion, AML with t(8;16) is a specific subtype of AML with unique characteristics in morphology and gene expression patterns. It is more frequently found in t-AML, outcome is inferior in comparison to other AML with balanced translocations. Due to its unique features, it is a candidate for inclusion into the WHO classification as a specific entity.

scholarly journals Predicting tissue-specific gene expression from whole blood transcriptome

2020 ◽  
Author(s):  
Mahashweta Basu ◽  
Kun Wang ◽  
Eytan Ruppin ◽  
Sridhar Hannenhalli
Keyword(s):  
Gene Expression ◽  
Whole Blood ◽  
Specific Gene ◽  
Specific Expression ◽  
Tissue Specific ◽  
Complex Disorders ◽  
Tissue Specific Gene ◽  
Tissue Specific Expression ◽  
Specific Gene Expression ◽  
Blood Transcriptome

AbstractComplex diseases are systemic, largely mediated via transcriptional dysregulation in multiple tissues. Thus, knowledge of tissue-specific transcriptome in an individual can provide important information about an individual’s health. Unfortunately, with a few exceptions such as blood, skin, and muscle, an individual’s tissue-specific transcriptome is not accessible through non-invasive means. However, due to shared genetics and regulatory programs between tissues, the transcriptome in blood may be predictive of those in other tissues, at least to some extent. Here, based on GTEx data, we address this question in a rigorous, systematic manner, for the first time. We find that an individual’s whole blood gene expression and splicing profile can predict tissue-specific expression levels in a significant manner (beyond demographic variables) for many genes. On average, across 32 tissues, the expression of about 60% of the genes is predictable from blood expression in a significant manner, with a maximum of 81% of the genes for the musculoskeletal tissue. Remarkably, the tissue-specific expression inferred from the blood transcriptome is almost as good as the actual measured tissue expression in predicting disease state for six different complex disorders, including Hypertension and Type 2 diabetes, substantially surpassing predictors built directly from the blood transcriptome. The code for our pipeline for tissue-specific gene expression prediction – TEEBoT, is provided, enabling others to study its potential translational value in other indications.

Spatially specific expression of Hoxb4 is dependent on the ubiquitous transcription factor NFY

Development ◽  
2002 ◽  
Vol 129 (16) ◽  
pp. 3887-3899 ◽  
Author(s):  
Jonathan Gilthorpe ◽  
Marie Vandromme ◽  
Tim Brend ◽  
Alejandro Gutman ◽  
Dennis Summerbell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Binding Sites ◽  
Specific Interaction ◽  
Transcriptional Regulators ◽  
Heterologous Promoter ◽  
Specific Expression ◽  
Enhancer Activity ◽  
Hox Gene ◽  
Two Factors ◽  
Enhancer Function

Understanding how boundaries and domains of Hox gene expression are determined is critical to elucidating the means by which the embryo is patterned along the anteroposterior axis. We have performed a detailed analysis of the mouse Hoxb4 intron enhancer to identify upstream transcriptional regulators. In the context of an heterologous promoter, this enhancer can establish the appropriate anterior boundary of mesodermal expression but is unable to maintain it, showing that a specific interaction with its own promoter is important for maintenance. Enhancer function depends on a motif that contains overlapping binding sites for the transcription factors NFY and YY1. Specific mutations that either abolish or reduce NFY binding show that it is crucial for enhancer activity. The NFY/YY1 motif is reiterated in the Hoxb4 promoter and is known to be required for its activity. As these two factors are able to mediate opposing transcriptional effects by reorganizing the local chromatin environment, the relative levels of NFY and YY1 binding could represent a mechanism for balancing activation and repression of Hoxb4 through the same site.

scholarly journals Transcriptome profiles of sturgeon lateral line electroreceptor and mechanoreceptor during regeneration

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Jian Wang ◽  
Chengcheng Lu ◽  
Yifan Zhao ◽  
Zhijiao Tang ◽  
Jiakun Song ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Lateral Line ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Sensory Organs ◽  
Specific Expression ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Early Regeneration

Abstract Background The electrosensory ampullary organs (AOs) and mechanosensory neuromasts (NMs) found in sturgeon and some other non-neopterygian fish or amphibians are both originated from lateral line placodes. However, these two sensory organs have characteristic morphological and physiological differences. The molecular mechanisms for the specification of AOs and NMs are not clearly understood. Results We sequenced the transcriptome for neomycin treated sturgeon AOs and NMs in the early regeneration stages, and de novo assembled a sturgeon transcriptome. By comparing the gene expression differences among untreated AOs, NMs and general epithelia (EPs), we located some specific genes for these two sensory organs. In sturgeon lateral line, the voltage-gated calcium channels and voltage-gated potassium channels were predominant calcium and potassium channel subtypes, respectively. And by correlating gene expression with the regeneration process, we predicated several candidate key transcriptional regulation related genes might be involved in AOs and NMs regeneration. Conclusions Genes with specific expression in the two lateral line sensory organs suggests their important roles in mechanoreceptor and electroreceptor formation. The candidate transcriptional regulation related genes may be important for mechano- and electro- receptor specification, in a “dosage-related” manner. These results suggested the molecular basis for specification of these two sensory organs in sturgeon.

scholarly journals Functional assessment of the “two-hit” model for neurodevelopmental defects in Drosophila and X. laevis

2020 ◽  
Author(s):  
Lucilla Pizzo ◽  
Micaela Lasser ◽  
Tanzeen Yusuff ◽  
Matthew Jensen ◽  
Phoebe Ingraham ◽  
...  
Keyword(s):  
Xenopus Laevis ◽  
Cellular Proliferation ◽  
De Novo ◽  
Specific Interaction ◽  
Interaction Network ◽  
Patient Specific ◽  
Neurodevelopmental Outcomes ◽  
Second Hit ◽  
Complex Interactions ◽  
Pairwise Interactions

AbstractWe previously identified a deletion on chromosome 16p12.1 that is mostly inherited and associated with multiple neurodevelopmental outcomes, where severely affected probands carried an excess of rare pathogenic variants compared to mildly affected carrier parents. We hypothesized that the 16p12.1 deletion sensitizes the genome for disease, while “second hits” in the genetic background modulate the phenotypic trajectory. To test this model, we examined how neurodevelopmental defects conferred by knockdown of individual 16p12.1 homologs are modulated by simultaneous knockdown of homologs of “second hit” genes in Drosophila melanogaster and Xenopus laevis. We observed that knockdown of 16p12.1 homologs affect multiple phenotypic domains, leading to delayed developmental timing, seizure susceptibility, brain alterations, abnormal dendrite and axonal morphology, and cellular proliferation defects. In contrast to genes within the 16p11.2 deletion, which has higher de novo occurrence, 16p12.1 homologs additively interacted and were less connected to each other in a human brain-specific interaction network, suggesting that interactions with second-hit genes confer higher impact towards neurodevelopmental phenotypes. Assessment of 358 pairwise interactions in Drosophila between 16p12.1 homologs and 76 homologs of patient-specific “second-hit” genes (such as ARID1B and CACNA1A), genes within neurodevelopmental pathways (such as PTEN and UBE3A), and transcriptomic targets (such as DSCAM and TRRAP) identified both additive (47%) and epistatic (53%) effects. In 11 out of 15 families, homologs of patient-specific “second-hits” showed distinct patterns of interactions, enhancing or suppressing the phenotypic effects of one or many 16p12.1 homologs. In fact, homologs of SETD5 synergistically interacted with homologs of MOSMO in both Drosophila and X. laevis, leading to modified cellular and brain phenotypes, as well as axon outgrowth defects that were not observed with knockdown of either individual homolog. Our results suggest that several 16p12.1 genes sensitize the genome towards neurodevelopmental defects, and complex interactions with “second-hit” genes determine the ultimate phenotypic manifestation.Author SummaryCopy-number variants, or deletions and duplications in the genome, are associated with multiple neurodevelopmental disorders. The developmental delay-associated 16p12.1 deletion is mostly inherited, and severely affected children carry an excess of “second-hits” variants compared to mildly affected carrier parents, suggesting that additional variants modulate the clinical manifestation. We studied this “two-hit” model using Drosophila and Xenopus laevis, and systematically tested how homologs of “second-hit” genes modulate neurodevelopmental defects observed for 16p12.1 homologs. We observed that 16p12.1 homologs independently led to multiple neurodevelopmental features and additively interacted with each other, suggesting that interactions with “second-hit” homologs could have a higher impact towards neurodevelopmental defects than interactions between 16p12.1 homologs. We tested 358 pairwise interactions of 16p12.1 homologs with “second-hit” homologs and genes within conserved neurodevelopmental pathways, and identified interacting homologs in 11 out of 15 families studied, which modified neurodevelopmental defects of individual or multiple 16p12.1 homologs through complex interactions. Interestingly, we observed that SETD5 homologs interacted with homologs of MOSMO, which modified cellular and brain defects, and conferred neuronal phenotypes not observed with knockdown of individual homologs. We propose that the 16p12.1 deletion sensitizes the genome to multiple neurodevelopmental defects, and complex interactions with “second-hit” genes determine the final manifestation.

Long Noncoding RNAs in Erythropoiesis and Megakaryopoiesis.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2331-2331
Author(s):  
Vikram R Paralkar ◽  
Tejaswini Mishra ◽  
Jing Luan ◽  
Yu Yao ◽  
Neeraja Konuthula ◽  
...  
Keyword(s):  
Gene Expression ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Noncoding Rnas ◽  
Cell Types ◽  
Long Noncoding Rnas ◽  
Read Length ◽  
Rna Seq ◽  
Erythroid Progenitors ◽  
Specific Expression

Abstract Abstract 2331 Lnc (long noncoding) RNAs are RNA transcripts greater than 200nt that regulate gene expression independent of protein coding potential. It is estimated that thousands of lncRNAs play vital roles in diverse cellular processes and are involved in numerous diseases, including cancer. We hypothesize that multiple lncRNAs regulate erythrocyte and megakaryocyte formation by modulating gene expression. To identify lncRNAs in erythro-megakaryopoiesis, we purified two biological replicates each of murine Ter119+ erythroblasts, CD41+ megakaryocytes and bipotential megakaryocyte-erythroid progenitors (MEPs) [Lin− Kit+, Sca1−, CD16/32−, CD34−]. We performed strand-specific, paired-end, 200nt-read-length deep sequencing (RNA-Seq) to a depth of ∼200 million reads per sample using the Illumina GAII platform. We used the Tophat and Cufflinks suite of bioinformatic tools to assemble and compare de-novo transcriptomes from these three cell types, producing a high-confidence set of 69,488 transcripts. We confirmed that the RNA-seq assemblies accurately reflect gene expression predicted from prior studies. For example, Ter119+ cells were highly enriched for key erythroid transcripts encoding globins, heme synthetic enzymes and specialized membrane proteins. Megakaryocytes expressed high levels of gene encoding lineage-specific integrins and platelet markers. MEPs expressed numerous progenitor genes including Gata2, Kit and Myc. Thus, the RNA-seq data are of high-quality and sufficient complexity to accurately represent erythroid, megakaryocytic and MEP transcriptomes. We used a series of Unix-based bioinformatic filtering tools to identify lncRNAs that are expressed in these transcriptomes. We identified 605 “stringent” lncRNAs, and 813 “potential noncoding” transcripts. 47% of the lncRNAs are novel unannotated transcripts, validating the use of de-novo RNA-Seq in unique cell populations for lncRNA discovery. Among the 605 “stringent” lncRNAs, 103 are erythroid-restricted, 133 are meg-restricted and 280 are MEP-restricted, consistent with reports that lncRNAs exhibit exquisitely cell-type specific expression. Current efforts are aimed at generating a more comprehensive map of lncRNA expression at specific stages of erythroid and megakaryocyte/platelet development, and performing high throughput functional screens to analyze currently identified lncRNAs. Our studies are beginning to define new layers of gene regulation in normal erythro-megakaryopoiesis and are relevant to the pathophysiology of related disorders including various anemias, myeloproliferative and myelodysplastic syndromes and leukemias. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Ocular Manifestations of a Novel Proximal 19p13.3 Microdeletion

2018 ◽  
Vol 2018 ◽  
pp. 1-5
Author(s):  
L. Swan ◽  
D. Coman
Keyword(s):  
Short Stature ◽  
Developmental Delay ◽  
Medical Literature ◽  
De Novo ◽  
Phenotypic Variability ◽  
Clinical Manifestations ◽  
Phenotypic Heterogeneity ◽  
Facial Dysmorphism ◽  
Ocular Manifestations

Microdeletions at 19p13.3 are rarely reported in the medical literature with significant phenotypic variability. Among the reported cases, common clinical manifestations have included developmental delay, facial dysmorphism, and hypotonia. Herein we described a child with a de novo 19p13.3 microdeletion, proximal to the reported cases of 19p13.3 microdeletion/duplication, with ocular manifestations of bilateral ocular colobomata complicated with microphthalmos and cataract, associated with short stature. This case highlights the phenotypic heterogeneity of deletions in the 19p13.3 region.

scholarly journals 25 MATERNAL-TO-EMBRYONIC TRANSITION FOLLOWING NUCLEAR TRANSFER OR PARTHENOGENETIC ACTIVATION

2006 ◽  
Vol 18 (2) ◽  
pp. 121
Author(s):  
T. Brevini ◽  
S. Antonini ◽  
F. Cillo ◽  
I. Lagutina ◽  
S. Colleoni ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Pattern ◽  
Nuclear Transfer ◽  
De Novo ◽  
Gene Expression Pattern ◽  
Mrna Levels ◽  
Cell Stage ◽  
Specific Expression ◽  
Parthenogenetic Activation

The successful development of embryos generated by somatic cell nuclear transfer (SCNT) requires the ooplasm to reprogram the nucleus. This establishes the gene expression pattern necessary for full development by mechanisms that are currently being clarified. The ooplasm action on somatic nuclei shows many common aspects to the process that leads to the creation of a functional embryonic genome from the differentiated sperm and egg genomes. In order to investigate this aspect we studied a critical phase of early embryonic development: the maternal to embryonic transition (MET). We compared the pattern and level of gene expression between bovine embryos derived from in vitro fertilization (IVF), from nuclear transfer of adult fibroblasts (NT), or from parthenogenetic activation (PG). The study was performed in cattle because MET, in this species, occurs over four cell cycles, making it easier to detect even small deviations. Oocytes, matured for 22 h and fertilized in vitro or after cumulus removal, were enucleated and fused to fibroblast cells. Nuclear transfer and Met II oocytes were activated at 24-26 h of maturation with ionomycin (5 �M) for 5 min and 6DMAP (2 mM) for 4 h and then cultured in mSOFaa. Embryos were harvested at the required time for analysis at the 2-, 4-, 8-, and 16-cell; morula; and blastocyst stages and stored snap-frozen in a minimal volume of medium in groups of 5-10 embryos. Semiquantitative RT-PCR was used to study the expression of Nanog, Oct-4, Zar-1, and Par-3, because these genes are directly involved in early embryo development and have a specific expression pattern during MET. Data were analyzed with one-way ANOVA followed by Student-Newman-Keuls All Pairwise Multiple Comparison. No difference in pre-implantation development was observed among the three groups. The Nanog expression pattern was unchanged in all three groups, becoming detectable from the 8-16-cell stage onward. Oct-4 mRNA was detected at all stages in every group, but only in NT embryos did a significant increase occur at the 16-cell stage, suggesting the onset of an anticipated embryonic transcription. the Zar-1 expression pattern, with the characteristic de-novo transcription peak at the 4-cell stage, was observed in both IVF and NT embryos but not in PG embryos. In this group, Zar-1 mRNA levels were significantly higher at the 2- and 4-cell stage than in all of the following stages. The Par-3 gene showed the biggest differences among groups: IVF embryos expressed this gene from the 8-cell stage onward, whereas NT embryos showed high levels of Par-3 mRNA already at the 2-cell stage. Surprisingly, PG embryos showed no detectable Par-3 levels at any stages. The results indicate that, although in vitro development was not affected, gene-specific expression differences during MET occurred among groups. Relating the specific functions exerted by each of these genes in early development to the changes observed following the different manipulations provides useful data toward a better understanding of the role of these genes and of the mechanisms of nuclear reprogramming. This work was supported by FIRB RBNE01HPMX, FIRST 2004, and ESF-EuroStells.

scholarly journals A novel de novo KDM5C variant in a female with global developmental delay and ataxia: a case report

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Natalie C. Lippa ◽  
Subit Barua ◽  
Vimla Aggarwal ◽  
Elaine Pereira ◽  
Jennifer M. Bain
Keyword(s):  
Case Report ◽  
Intellectual Disability ◽  
Short Stature ◽  
Developmental Delay ◽  
De Novo ◽  
Phenotypic Variability ◽  
Missense Variant ◽  
Global Developmental Delay ◽  
Related Disorder ◽  
Patient Reported

Abstract Background Pathogenic variants in KDM5C are a cause of X-linked intellectual disability in males. Other features in males include short stature, dysmorphic features, seizures and spasticity. In some instances, female relatives were noted to have learning difficulties and mild intellectual disabilities, but full phenotypic descriptions were often incomplete. Recently, detailed phenotypic features of five affected females with de novo variants were described. (Clin Genet 98:43–55, 2020) Four individuals had a protein truncating variant and 1 individual had a missense variant. All five individuals had developmental delay/intellectual disability and three neurological features. Case presentation Here we report a three-year-old female with global developmental delay, hypotonia and ataxia. Through whole exome sequencing, a de novo c.1516A > G (p.Met506Val) variant in KDM5C was identified. This missense variant is in the jumonji-C domain of this multi domain protein where other missense variants have been previously reported in KDM5C related disorder. The KDM5C gene is highly intolerant to functional variation which suggests its pathogenicity. The probands motor delays and language impairment is consistent with other reported female patients with de novo variants in KDM5C. However, other features reported in females (distinctive facial features, skeletal abnormalities, short stature and endocrine features) were absent. To the best of our knowledge, our proband is the first female patient reported with a diagnosis of ataxia. Conclusions This case report provides evidence for an emerging and phenotypic variability that adds to the literature of the role of KDM5C in females with neurodevelopmental disorders as well as movement disorders.

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