Mosaic Trisomy 12 Associated with Overgrowth Detected in Fibroblast Cell Lines

2019 ◽  
Vol 157 (3) ◽  
pp. 153-157 ◽  
Author(s):  
Yanca Gasparini ◽  
Marília M. Montenegro ◽  
Gil M. Novo-Filho ◽  
José R.M. Ceroni ◽  
Rachel S. Honjo ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Cytogenetic Analysis ◽  
Gene Dosage ◽  
Skin Pigmentation ◽  
Facial Asymmetry ◽  
Fibroblast Cell ◽  
Relevant Information ◽  
Gene Dosage Effects ◽  
Trisomy 12 ◽  
Mosaic Trisomy

Mosaic trisomy 12 is a rare anomaly, and only 9 cases of live births with this condition have been reported in the literature. The clinical phenotype is variable, including neuropsychomotor developmental delay, congenital heart disease, microcephaly, cutaneous spots, facial asymmetry, prominent ears, hypotonia, retinopathy, and sensorineural hearing loss. A 2-year-old female presented with neuropsychomotor developmental delay, prominent forehead, dolichocephaly, patchy skin pigmentation, and unexpected overgrowth at birth. Cytogenetic analysis of her peripheral blood showed normal results, suggesting the presence of a chromosomal alteration in other tissues. Further studies using G-banding and FISH performed on fibroblasts from both hyper- and hypopigmented regions identified a 47,XX,+12/46,XX karyotype. To the best of our knowledge, no patients with mosaic trisomy 12 associated with overgrowth have been reported to date. Congenital overgrowth and neonatal overgrowth have been frequently linked to Pallister-Killian syndrome (PKS; OMIM 601803). This case suggests the possibility of an association of genes present in the 12p region with fetal overgrowth, considering that chromosomal duplications could lead to an increase in the production of aberrant transcripts and disturbing gene dosage effects. This case highlights the importance of cytogenetic analysis in different tissues to provide relevant information to the specific genotype/phenotype correlation.

scholarly journals Proteogenomic Subtyping of Chronic Lymphocytic Leukemia Identifies a Novel Poor Outcome Subgroup with a Distinct Drug Response Profile

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-11
Author(s):  
Sophie A. Herbst ◽  
Mattias Vesterlund ◽  
Rozbeh Jafari ◽  
Ioannis Siavelis ◽  
Matthias Stahl ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Drug Response ◽  
Gene Dosage ◽  
Lymphocytic Leukemia ◽  
Protein Abundance ◽  
Advisory Committees ◽  
Gene Dosage Effects ◽  
Trisomy 12 ◽  
Support Research

Background: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western world and shows a very heterogeneous clinical course. While the genetic landscape of CLL has been well characterized during recent years it can only partially explain the underlying biology of this heterogeneity. Proteogenomics could offer a valuable tool to fill this gap and improve the understanding of CLL biology. Methods: Here, we performed a large proteogenomic analysis (n=263) of three clinically annotated CLL cohorts: For the discovery cohort (Germany_1: n=68) we performed in-depth HiRIEF LC-MS based proteomics (more than 9000 proteins quantified) alongside genome-, transcriptome and ex-vivo drug response-profiling with 43 clinically established drugs. The proteome of two additional validation cohorts (Germany_2: n=44, Sweden_1: n=89), were characterized by data-independent acquisition (DIA) mass spectrometry. Results: To connect the CLL genotype with the molecular phenotype, we investigated associations between recurrent genetic alterations of CLL, mRNA expression and protein abundance. We found that trisomy 12, IGHV status and SF3B1 mutations had the greatest impact on protein abundances. CLL specific recurrent chromosomal deletions and gains (trisomy 12, del17p, del13q, del11q, gain8q24) consistently impacted on gene expression and protein abundance through gene dosage effects. We explored functional consequences of these gene dosage effects and found that the additional copy of chromosome 12 increased the abundance of central B-cell receptor (BCR) protein complexes through cis- and trans-effects, which could explain the increased response of trisomy 12 patient samples to BCR inhibition. Somatic mutations of TP53, ATM and XPO1 were associated with less, but specific and biologically-relevant protein abundance changes. p53 for instance, was the most upregulated protein in TP53 mutated samples, owing to the known stabilisation of mutant p53. This effect was not detectable on transcript level. ATM and XPO1 protein abundances were significantly lower in ATM and XPO1 mutated cases, indicating loss-of-function phenotypes of these mutations. To understand global similarities and differences between CLL patients on the proteomic level, we performed unsupervised clustering and identified clinically meaningful subgroups. Unsupervised clustering of the proteomics data identified six subgroups with contrasting clinical behaviour. TP53 mutations, IGHV status, trisomy 12 and their interactions explained five subgroups. These results show that quantitative mass spectrometry-based proteomics distinguished clinically relevant subgroups of CLL. Most importantly, we identified a previously unappreciated subgroup of CLL, comprising 20% of all cases, which could be uncovered by proteomic profiling and showed no association with frequent genetic or transcriptional alterations. This new CLL subgroup was characterized by accelerated disease progression, SF3B1 mutation-independent splicing alterations, metabolomic reprogramming and increased vulnerability to inhibitors of metabolic enzymes and the proteasome. Surprisingly, major BCR signaling proteins were downregulated in this subgroup, suggesting less dependence on BCR activity. In accordance with this observation, an unsupervised analysis revealed that low levels of many BCR signaling proteins (e.g. PLCG2 and PIK3CD) were associated with short time to next treatment. The existence of this subgroup could be confirmed in the validation cohorts. Finally, we performed an unsupervised multi-omics factor analysis (MOFA) across all omics data sets in parallel. This unsupervised analysis confirmed the existence of the above identified CLL subgroups and an important role of SF3B1 mutation-independent splicing alterations in CLL. Conclusion: Our integrative multi-omics analysis provides the first comprehensive overview of the interplay between genetic variants, the transcriptome, and the proteome, along with functional consequences for drug response and clinical outcome in CLL. Importantly, we identified a new subgroup with accelerated disease progression, a distinct proteomic signature and a clinically exploitable drug sensitivity profile. Figure Disclosures Mueller-Tidow: BiolineRx: Research Funding; Daiichi Sankyo: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMBF: Research Funding; Wilhelm-Sander-Stiftung: Research Funding; Jose-Carreras-Siftung: Research Funding; Bayer AG: Research Funding; Deutsche Krebshilfe: Research Funding; Deutsche Forschungsgemeinschaft: Research Funding; Janssen-Cilag Gmbh: Membership on an entity's Board of Directors or advisory committees. Dreger:Neovii: Research Funding; Roche: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy; Gilead: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; AbbVie: Consultancy, Speakers Bureau. Stilgenbauer:Pharmacyclics: Consultancy, Honoraria, Other, Research Funding; Novartis: Consultancy, Honoraria, Other, Research Funding; Mundipharma: Consultancy, Honoraria, Other, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Genzyme: Consultancy, Honoraria, Other: travel support, Research Funding; Genentech: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Other: travel support, Research Funding; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding. Tausch:Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding. Dietrich:Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Genetics advances and learning disability

2000 ◽  
Vol 176 (1) ◽  
pp. 12-19 ◽  
Author(s):  
Walter J. Muir
Keyword(s):  
Learning Disability ◽  
Gene Dosage ◽  
Genetic Disorders ◽  
Molecular Medicine ◽  
Gene Dosage Effects ◽  
Dosage Effects ◽  
Rapid Changes ◽  
Basic Understanding ◽  
Genetic Mechanisms ◽  
Dynamic Mutations

BackgroundMedicine is rapidly becoming molecular medicine, and little escapes the grasp of modern genetics. Most disorders associated with learning disability have at least a genetic component influencing their expression; in many disorders, disturbances of genetic mechanisms play a pivotal role.AimsDynamic mutations, imprinting mechanisms and gene-dosage effects are explained with reference to genetic disorders that lead to learning disability.MethodA review of recent important studies in the genetics of learning disability.ResultsA host of new genetic connections to conditions associated with learning disability have been made.ConclusionsA basic understanding of these genetic connections is important for all learning disability psychiatrists if they are to follow the rapid changes – already beginning to influence our practice – that hold immense promise for the future.

scholarly journals A high-resolution allelotype of B-cell chronic lymphocytic leukemia (B-CLL)

Blood ◽  
2002 ◽  
Vol 100 (5) ◽  
pp. 1787-1794 ◽  
Author(s):  
Urban Novak ◽  
Elisabeth Oppliger Leibundgut ◽  
Jörg Hager ◽  
Dominique Mühlematter ◽  
Martine Jotterand ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Chromosomal Aberrations ◽  
Cytogenetic Analysis ◽  
Prognostic Significance ◽  
Genetic Alterations ◽  
Lymphocytic Leukemia ◽  
Accurate Information ◽  
Trisomy 12 ◽  
Cell Chronic Lymphocytic Leukemia

The most frequent chromosomal aberrations in B-cell chronic lymphocytic leukemia (B-CLL) are deletions on 13q, 11q, and 17p, and trisomy 12, all of which are of prognostic significance. Conventional cytogenetic analysis and fluorescence in situ hybridization (FISH) are used for their detection, but cytogenetic analysis is hampered by the low mitotic index of B-CLL cells, and FISH depends on accurate information about candidate regions. We used a set of 400 highly informative microsatellite markers covering all chromosomal arms (allelotyping) and automated polymerase chain reaction (PCR) protocols to screen 46 patients with typical B-CLL for chromosomal aberrations. For validation, we compared data with our conventional karyotype results and fine mapping with conventional single-site PCR. All clonal cytogenetic abnormalities potentially detectable by our microsatellite PCR (eg, del13q14 and trisomy 12) were picked up. Allelotyping revealed additional complex aberrations in patients with both normal and abnormal B-CLL karyotypes. Aberrations detectable in the samples with our microsatellite panel were found on almost all chromosomal arms. We detected new aberrant loci in typical B-CLL, such as allelic losses on 1q, 9q, and 22q in up to 25% of our patients, and allelic imbalances mirroring chromosomal duplications, amplifications, or aneuploidies on 2q, 10p, and 22q in up to 27% of our patients. We conclude that allelotyping with our battery of informative microsatellites is suitable for molecular screening of B-CLL. The technique is well suited for analyses in clinical trials, it provides a comprehensive view of genetic alterations, and it may identify new loci with candidate genes relevant in the molecular biology of B-CLL.

scholarly journals Dopaminergic Gene Dosage in Autism versus Developmental Delay: From Complex Networks to Machine Learning approaches

2020 ◽  
Author(s):  
André Santos ◽  
Francisco Caramelo ◽  
Joana Barbosa de Melo ◽  
Miguel Castelo-Branco
Keyword(s):  
Machine Learning ◽  
Autism Spectrum Disorders ◽  
Network Analysis ◽  
Developmental Delay ◽  
Gene Dosage ◽  
Genetic Alterations ◽  
Autism Spectrum ◽  
Compact Set ◽  
Neural Basis ◽  
Spectrum Disorders

AbstractThe neural basis of behavioural changes in Autism Spectrum Disorders (ASD) remains a controversial issue. One factor contributing to this challenge is the phenotypic heterogeneity observed in ASD, which suggests that several different system disruptions may contribute to diverse patterns of impairment between and within study samples. Here, we took a retrospective approach, using SFARI data to study ASD by focusing on participants with genetic imbalances targeting the dopaminergic system. Using complex network analysis, we investigated the relations between participants, Gene Ontology (GO) and gene dosage related to dopaminergic neurotransmission from a polygenic point of view. We converted network analysis into a machine learning binary classification problem to differentiate ASD diagnosed participants from DD (developmental delay) diagnosed participants. Using 1846 participants to train a Random Forest algorithm, our best classifier achieved on average a diagnosis predicting accuracy of 85.18% (sd 1.11%) on a test sample of 790 participants using gene dosage features. In addition, we observed that if the classifier uses GO features it was also able to infer a correct response based on the previous examples because it is tied to a set of biological process, molecular functions and cellular components relevant to the problem. This yields a less variable and more compact set of features when comparing with gene dosage classifiers. Other facets of knowledge-based systems approaches addressing ASD through network analysis and machine learning, providing an interesting avenue of research for the future, are presented through the study.Lay SummaryThere are important issues in the differential diagnosis of Autism Spectrum Disorders. Gene dosage effects may be important in this context. In this work, we studied genetic alterations related to dopamine processes that could impact brain development and function of 2636 participants. On average, from a genetic sample we were able to correctly separate autism from developmental delay with an accuracy of 85%.

scholarly journals Infantile tremor syndrome

2017 ◽  
Vol 4 (6) ◽  
pp. 2228
Author(s):  
Apoorva Sree Puttagunta ◽  
Shruthi T. K. ◽  
Shubha S. ◽  
Rajakumar P. S.
Keyword(s):  
Developmental Delay ◽  
Scalp Hair ◽  
Skin Pigmentation ◽  
Natural Course ◽  
Involuntary Movements ◽  
The Subject ◽  
Breast Fed

Infantile tremor syndrome (ITS) is defined by the tetrad of pallor, developmental delay/regression, skin pigmentation, and brown scanty scalp hair. Involuntary movements in the form of tremors supervene in the natural course of the illness in a significant number of cases. The disorder is common in exclusively breast-fed infants of vegetarian mothers. Most of the children eventually recover but are frequently left with long-term cognitive and language neurodeficits. This review attempts to provide comprehensive and up-to-date information on the subject incorporating recently published studies. 

scholarly journals Gene dosage effects on transmission ratio distortion and fertility in mice that carry t haplotypes

1989 ◽  
Vol 54 (3) ◽  
pp. 221-225 ◽  
Author(s):  
Lee M. Silver
Keyword(s):  
Gene Dosage ◽  
Transmission Ratio Distortion ◽  
Transmission Ratio ◽  
Double Dose ◽  
Absolute Level ◽  
T Complex ◽  
Gene Dosage Effects ◽  
Ratio Distortion ◽  
The Individual ◽  
Very High

SummaryComplete t haplotypes can be transmitted at distorted ratios from heterozygous +/t male mice as a consequence of t-specific alleles at a series of t complex distorter loci (Tcd-1t through Tcd-4t) and a t complex responder locus. Partial t haplotypes that lack the Tcd-2t allele cannot be transmitted at the very high ratios characteristic of complete t haplotypes. The breeding studies reported here tested the possibility that the absence of Tcd-2t could be compensated for by the presence of double doses of other Tcdt alleles. The results indicate that a double dose of Tcd-4t alone will not work, but that a double dose of both Tcd-1t and Tcd-4t can promote a very high transmission ratio in the absence of Tcd-2t. These results suggest that the extent to which transmission ratios are distorted is dependent upon the absolute level of expression of the individual Tcd genes. Further studies of genotypic effects on transmission ratio distortion, as well as fertility, lead to the suggestion of a fifth t complex distorter (Tcd-5) locus within t haplotypes.

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