Abstract 17081: End Stage Mitochondrial Cardiomyopathy And Heart Transplantation Due To Pathogenic Biallelic C1QBP Variants

Circulation ◽  
2021 ◽  
Vol 144 (Suppl_2) ◽  
Author(s):  
Nicholas S Wilcox ◽  
Stuart Prenner ◽  
Marisa Cevasco ◽  
Courtney Condit ◽  
Amy Goldstein ◽  
...  
Keyword(s):  
Mitochondrial Genome ◽  
Heart Transplantation ◽  
Genome Sequencing ◽  
Large Scale ◽  
De Novo ◽  
Late Onset ◽  
Genetic Disorder ◽  
Disease Onset ◽  
Serum Lactate ◽  
Metabolic Decompensation

Case Presentation: A 29-year-old male with LVH diagnosed in childhood was admitted with acute HF. TTE showed LVEF 5-10% and LV thrombi for which he was anticoagulated. He received inappropriate ICD shocks due to T wave oversensing, leading to cardiogenic shock requiring VA-ECMO support. Serum lactate peaked at 17 mmol/L due to cardiac and metabolic decompensation. He underwent heart transplantation (HT) on hospital day (HD) 8 and tolerated standard immunosuppression. First endomyocardial biopsy showed acute cellular rejection requiring pulse steroids. He was discharged on HD 33. Trio whole exome and mitochondrial genome sequencing revealed biallelic variants in complement component 1Q subcomponent-binding protein ( C1QBP ), due to a maternally inherited likely pathogenic variant c.612C>G (p.F204L in exon 5) and an apparently de novo deletion of 17p13.2, spanning exons 4-6 of C1QBP and exon 6 of the RPAIN gene. Mitochondrial genome sequencing of the explanted heart revealed multiple large-scale mitochondrial DNA deletions at 33% heteroplasmy. Discussion: C1QBP variants are associated with mitochondrial and multi-organ dysfunction. Only 12 patients exhibiting biallelic C1QBP variants are reported. Four died in the peripartum period due to fetal hydrops or HF; 5 exhibited early-onset cardiomyopathy (CM); 3 others had late-onset ophthalmoplegia without CM. The p.F204L variant has been reported in 1 patient with compound C1QBP p.F204L/p.C186S heterozygosity who died from hydrops fetalis and a second with p.F204L homozygosity with late-onset ophthalmoplegia and skeletal myopathy without CM. Differences in the size, heteroplasmy, and tissue distribution of mitochondrial genome secondary deletions may explain variability in disease onset and progression. We present the first patient with biallelic pathogenic C1QBP gene variants with mitochondrial CM to undergo HT and highlight the diagnosis and management of an exceptionally uncommon genetic disorder.

scholarly journals P4-097: RARE VARIANTS IN FAMILIAL LATE-ONSET ALZHEIMER'S DISEASE IDENTIFIED FROM LARGE SCALE WHOLE GENOME SEQUENCING

2019 ◽  
Vol 15 ◽  
pp. P1312-P1312
Author(s):  
Badri N. Vardarajan ◽  
James Jaworski ◽  
Gary W. Beecham ◽  
Sandra Barral ◽  
Dolly Reyes-Dumeyer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Large Scale ◽  
Rare Variants ◽  
Late Onset ◽  
Whole Genome

scholarly journals MitoZ: A toolkit for mitochondrial genome assembly, annotation and visualization

2018 ◽  
Author(s):  
Guanliang Meng ◽  
Yiyuan Li ◽  
Chentao Yang ◽  
Shanlin Liu
Keyword(s):  
Mitochondrial Genome ◽  
Open Source Software ◽  
Large Scale ◽  
High Throughput Sequencing ◽  
De Novo ◽  
Ecological Studies ◽  
Free Open Source Software ◽  
Sequencing Technologies ◽  
Evolutionary Studies ◽  
Free Open Source

AbstractMitochondrial genome (mitogenome) plays important roles in evolutionary and ecological studies. It becomes routine to utilize multiple genes on mitogenome or the entire mitogenomes to investigate phylogeny and biodiversity of focal groups with the onset of High Throughput Sequencing technologies. We developed a mitogenome toolkit MitoZ, consisting of independent modules ofde novoassembly, findMitoScaf, annotation and visualization, that can generate mitogenome assembly together with annotation and visualization results from HTS raw reads. We evaluated its performance using a total of 50 samples of which mitogenomes are publicly available. The results showed that MitoZ can recover more full-length mitogenomes with higher accuracy compared to the other available mitogenome assemblers. Overall, MitoZ provides a one-click solution to construct the annotated mitogenome from HTS raw data and will facilitate large scale ecological and evolutionary studies. MitoZ is free open source software distributed under GPLv3 license and available athttps://github.com/linzhi2013/MitoZ.

A Novel Variant in FOXC1 Associated With Atypical Axenfeld-Rieger Syndrome

2021 ◽  
Author(s):  
Rui Wang ◽  
Wei-Qian Wang ◽  
Xiao-Qin Li ◽  
Juan Zhao ◽  
Kun Yang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
De Novo ◽  
Late Onset ◽  
Genetic Disorder ◽  
Genetic Diagnosis ◽  
Pathogenic Variant ◽  
Rieger Syndrome ◽  
Craniofacial Dysmorphism ◽  
Whole Exome ◽  
Novel Variant

Abstract Background Mutations in the Forkhead Box C1 (FOXC1) are known to cause autosomal dominant hereditary Axenfeld-Rieger syndrome, which is a genetic disorder characterized by ocular and systemic features including glaucoma, variable dental defects, craniofacial dysmorphism and hearing loss. Due to late-onset of ocular disorders and lack of typical presentation, therefore, clinical diagnosis present a huge challenge. Results In this study, we described a pathogenic variant in FOXC1 in one 5 year-old boy who is presented with hypertelorism, pupil deformation in both eyes, conductive hearing loss, and dental defects. By whole exome sequencing, we identified a 3bp deletion in FOXC1, c.516_518delGCG (p.Arg173del) as the disease-causing variant, which was de novo and not detected in the parents, and could be classified as a “pathogenic variant” according to the American College of Medical Genetics and Genomics guidelines. After confirmation of this FOXC1 variant, clinical data on Axenfeld-Rieger syndrome-associated clinical features were collected and analyzed. Although the affected individual present hearing loss, however, the hearing loss is conductive and is reversible during the follow-up, which might not linked to the FOXC1 variant and is coincidental. Conclusions Routine examination of FOXC1 is necessary for the genetic diagnosis of hypertelorism-associated syndrome. These findings may assist clinicians in reaching correct clinical and molecular diagnoses, and providing appropriate genetic counseling.

scholarly journals A novel variant in FOXC1 associated with atypical Axenfeld-Rieger syndrome

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Rui Wang ◽  
Wei-Qian Wang ◽  
Xiao-Qin Li ◽  
Juan Zhao ◽  
Kun Yang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
De Novo ◽  
Late Onset ◽  
Genetic Disorder ◽  
Genetic Diagnosis ◽  
Rieger Syndrome ◽  
Craniofacial Dysmorphism ◽  
Whole Exome ◽  
Ocular Disorders ◽  
Novel Variant

AbstractMutations in the Forkhead Box C1 (FOXC1) are known to cause autosomal dominant hereditary Axenfeld-Rieger syndrome, which is a genetic disorder characterized by ocular and systemic features including glaucoma, variable dental defects, craniofacial dysmorphism and hearing loss. Due to late-onset of ocular disorders and lack of typical presentation, clinical diagnosis presents a huge challenge. In this study, we described a pathogenic in-frame variant in FOXC1 in one 5-year-old boy who is presented with hypertelorism, pupil deformation in both eyes, conductive hearing loss, and dental defects. By whole exome sequencing, we identified a 3 bp deletion in FOXC1, c.516_518delGCG (p.Arg173del) as the disease-causing variant, which was de novo and not detected in the parents, and could be classified as a “pathogenic variant” according to the American College of Medical Genetics and Genomics guidelines. After confirmation of this FOXC1 variant, clinical data on Axenfeld-Rieger syndrome-associated clinical features were collected and analyzed. Furthermore, Although the affected individual present hearing loss, however, the hearing loss is conductive and is reversible during the follow-up, which might not linke to the FOXC1 variant and is coincidental. Routine examination of FOXC1 is necessary for the genetic diagnosis of hypertelorism-associated syndrome. These findings may assist clinicians in reaching correct clinical and molecular diagnoses, and providing appropriate genetic counseling.

scholarly journals Haplocheck: Phylogeny-based Contamination Detection in Mitochondrial and Whole-Genome Sequencing Studies

2020 ◽  
Author(s):  
Hansi Weissensteiner ◽  
Lukas Forer ◽  
Liane Fendt ◽  
Azin Kheirkhah ◽  
Antonio Salas ◽  
...  
Keyword(s):  
Mitochondrial Genome ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Large Scale ◽  
Nuclear Dna ◽  
Nuclear Genome ◽  
Whole Genome ◽  
Sequencing Studies ◽  
Project Data ◽  
The Impact

AbstractWithin-species contamination is a major issue in sequencing studies, especially for mitochondrial studies. Contamination can be detected by analysing the nuclear genome or by inspecting the heteroplasmic sites in the mitochondrial genome. Existing methods using the nuclear genome are computationally expensive, and no suitable tool for detecting contamination in large-scale mitochondrial datasets is available. Here we present haplocheck, a tool that requires only the mitochondrial genome to detect contamination in both mitochondrial and whole-genome sequencing studies. Haplocheck is able to distinguish between contaminated and real heteroplasmic sites using the mitochondrial phylogeny. By applying haplocheck to the 1000 Genomes Project data, we show (1) high concordance in contamination estimates between mitochondrial and nuclear DNA and (2) quantify the impact of mitochondrial copy numbers on the mitochondrial based contamination results. Haplocheck complements leading nuclear DNA based contamination tools, and can therefore be used as a proxy tool in nuclear genome studies.Haplocheck is available both as a command-line tool at https://github.com/genepi/haplocheck and as a cloud web-service producing interactive reports that facilitates the navigation through the phylogeny of contaminated samples.

Hyperthyroidism under Immunosuppression after Heart Transplantation as a Late-onset of Amiodarone-treatment

2016 ◽  
Vol 64 (S 01) ◽  
Author(s):  
S. Schmidt ◽  
M. Rybczynski ◽  
F. Wagner ◽  
H. Reichenspurner ◽  
M. Barten
Keyword(s):  
Heart Transplantation ◽  
Late Onset ◽  
Amiodarone Treatment

0306 Exploring the feasibility of using copy number variants as genetic markers through large-scale whole genome sequencing experiments

2016 ◽  
Vol 94 (suppl_5) ◽  
pp. 146-146
Author(s):  
D. M. Bickhart ◽  
L. Xu ◽  
J. L. Hutchison ◽  
J. B. Cole ◽  
D. J. Null ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genetic Markers ◽  
Genome Sequencing ◽  
Copy Number ◽  
Large Scale ◽  
Copy Number Variants ◽  
Whole Genome

Target-Templated de novo Design of Macrocyclic D-/L-Peptides: Inhibitors of the PD-1/PD-L1 Interaction

2020 ◽  
Author(s):  
Salvador Guardiola ◽  
Monica Varese ◽  
Xavier Roig ◽  
Jesús Garcia ◽  
Ernest Giralt
Keyword(s):  
Protein Interactions ◽  
Cyclic Peptides ◽  
General Framework ◽  
Large Scale ◽  
De Novo ◽  
Inhibitory Effect ◽  
Original Text ◽  
Protein Protein Interactions ◽  
Retraction Notice ◽  
Pharmaceutical Properties

<p>NOTE: This preprint has been retracted by consensus from all authors. See the retraction notice in place above; the original text can be found under "Version 1", accessible from the version selector above.</p><p><br></p><p>------------------------------------------------------------------------</p><p><br></p><p>Peptides, together with antibodies, are among the most potent biochemical tools to modulate challenging protein-protein interactions. However, current structure-based methods are largely limited to natural peptides and are not suitable for designing target-specific binders with improved pharmaceutical properties, such as macrocyclic peptides. Here we report a general framework that leverages the computational power of Rosetta for large-scale backbone sampling and energy scoring, followed by side-chain composition, to design heterochiral cyclic peptides that bind to a protein surface of interest. To showcase the applicability of our approach, we identified two peptides (PD-<i>i</i>3 and PD-<i>i</i>6) that target PD-1, a key immune checkpoint, and work as protein ligand decoys. A comprehensive biophysical evaluation confirmed their binding mechanism to PD-1 and their inhibitory effect on the PD-1/PD-L1 interaction. Finally, elucidation of their solution structures by NMR served as validation of our <i>de novo </i>design approach. We anticipate that our results will provide a general framework for designing target-specific drug-like peptides.<i></i></p>

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