Mitochondrial <scp>D</scp><scp>NA</scp> Analysis from Exome Sequencing Data Improves Diagnostic Yield in Neurological Diseases

Poole, Olivia V.; Pizzamiglio, Chiara; Murphy, David; Falabella, Micol; Macken, William L.; Bugiardini, Enrico; Woodward, Cathy E.; Labrum, Robyn; Efthymiou, Stéphanie; Salpietro, Vincenzo; Kobylecki, Christopher; Kaiyrzhanov, Rauan; Maroofian, Reza; Amato, Anthony A.; Gregory, Allison; Hayflick, Susan J.; Genomics, Queen Square; Jonvik, Hallgeir; Wood, Nicholas; Houlden, Henry; Vandrovcová, Jana; Hanna, Michael G.; Pittman, Alan; Pitceathly, Robert D S

doi:10.1002/ana.26063

Cited by 15 publications

(8 citation statements)

References 17 publications

(31 reference statements)

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“…30 31 Additionally, mutation of the neighboring subunit of the first complex ( MT-ND5) has been previously brought in connection with Leigh syndrome where the patient's family history was positive for CVS. 32 Completion of the medical history further supports the mitochondrial origin of her symptoms because vomiting episodes were triggered or aggravated by infection, starvation, and also by a protein-rich diet. 33 34 Since CVS does not belong to the previously reported symptoms of mT18 and the proband's asymptomatic mother carries the same heteroplasmic MT-ND6 mutation ( Fig.…”

Section: Discussionmentioning

confidence: 88%

A Patient Diagnosed with Mosaic Trisomy 18 Presenting New Symptoms: Diaphragmatic Relaxation and Cyclic Vomiting Syndrome. Updated Review of Mosaic Trisomy 18 Cases

et al. 2022

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Although data on T18 are widespread, there is a lack of knowledge on mosaic trisomy 18 (mT18). A current review of mT18 symptomatology, long-term follow-up, and potential health risks is lacking for health care professionals. Our paper addresses these, emphasizing the importance of regular tumor screening as a key message for mT18 patient follow-up. We also present the case of a female patient with mT18 who presented with diaphragmatic relaxation and cyclic vomiting syndrome (CVS), which had previously not been reported in this genetic condition. On further investigating the etiology of CVS, we revealed a novel mitochondrial mutation in the MT-ND6 gene in heteroplasmic form. Based on the literature, we hypothesize that the mitochondrial mutation together with mT18 could result in CVS.

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Section: Discussionmentioning

confidence: 88%

A Patient Diagnosed with Mosaic Trisomy 18 Presenting New Symptoms: Diaphragmatic Relaxation and Cyclic Vomiting Syndrome. Updated Review of Mosaic Trisomy 18 Cases

et al. 2022

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“…Interestingly, low-level heteroplasmic variants (VL <10%) have shown matrilineal inheritance [ 55 , 56 ] with increased relevance in aging [ 57 ], and in clinical settings, particularly cancer [ 58 , 59 ]. Nonetheless, the reliability of these low-level variants has been a matter of debate [ 60 , 61 , 62 ] and, thus, current guidelines/workflows suggest a heteroplasmy threshold of 10%, based on the limitations of Sanger sequencing and electrophoresis technology [ 35 , 37 , 63 , 64 , 65 , 66 ].…”

Section: Discussionmentioning

confidence: 99%

From Forensics to Clinical Research: Expanding the Variant Calling Pipeline for the Precision ID mtDNA Whole Genome Panel

Cortes-Figueiredo

Carvalho

Fonseca

et al. 2021

IJMS

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Despite a multitude of methods for the sample preparation, sequencing, and data analysis of mitochondrial DNA (mtDNA), the demand for innovation remains, particularly in comparison with nuclear DNA (nDNA) research. The Applied Biosystems™ Precision ID mtDNA Whole Genome Panel (Thermo Fisher Scientific, USA) is an innovative library preparation kit suitable for degraded samples and low DNA input. However, its bioinformatic processing occurs in the enterprise Ion Torrent Suite™ Software (TSS), yielding BAM files aligned to an unorthodox version of the revised Cambridge Reference Sequence (rCRS), with a heteroplasmy threshold level of 10%. Here, we present an alternative customizable pipeline, the PrecisionCallerPipeline (PCP), for processing samples with the correct rCRS output after Ion Torrent sequencing with the Precision ID library kit. Using 18 samples (3 original samples and 15 mixtures) derived from the 1000 Genomes Project, we achieved overall improved performance metrics in comparison with the proprietary TSS, with optimal performance at a 2.5% heteroplasmy threshold. We further validated our findings with 50 samples from an ongoing independent cohort of stroke patients, with PCP finding 98.31% of TSS’s variants (TSS found 57.92% of PCP’s variants), with a significant correlation between the variant levels of variants found with both pipelines.

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“…New sequencing platforms have revolutionized diagnostics of such diseases, mainly exome and wholegenome approaches, including mitochondrial heteroplasmy [33]. Nevertheless, a holistic -omics approach is needed to generate more comprehensive results, also requiring new bioinformatics tools to properly analyze them [34][35][36][37][38].…”

Section: Structural Genomicsmentioning

confidence: 99%

Analyzing Modern Biomolecules: The Revolution of Nucleic-Acid Sequencing – Review

et al. 2021

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Recent developments have revolutionized the study of biomolecules. Among them are molecular markers, amplification and sequencing of nucleic acids. The latter is classified into three generations. The first allows to sequence small DNA fragments. The second one increases throughput, reducing turnaround and pricing, and is therefore more convenient to sequence full genomes and transcriptomes. The third generation is currently pushing technology to its limits, being able to sequence single molecules, without previous amplification, which was previously impossible. Besides, this represents a new revolution, allowing researchers to directly sequence RNA without previous retrotranscription. These technologies are having a significant impact on different areas, such as medicine, agronomy, ecology and biotechnology. Additionally, the study of biomolecules is revealing interesting evolutionary information. That includes deciphering what makes us human, including phenomena like non-coding RNA expansion. All this is redefining the concept of gene and transcript. Basic analyses and applications are now facilitated with new genome editing tools, such as CRISPR. All these developments, in general, and nucleic-acid sequencing, in particular, are opening a new exciting era of biomolecule analyses and applications, including personalized medicine, and diagnosis and prevention of diseases for humans and other animals.

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Mitochondrial DNA Analysis from Exome Sequencing Data Improves Diagnostic Yield in Neurological Diseases

Cited by 15 publications

References 17 publications

A Patient Diagnosed with Mosaic Trisomy 18 Presenting New Symptoms: Diaphragmatic Relaxation and Cyclic Vomiting Syndrome. Updated Review of Mosaic Trisomy 18 Cases

A Patient Diagnosed with Mosaic Trisomy 18 Presenting New Symptoms: Diaphragmatic Relaxation and Cyclic Vomiting Syndrome. Updated Review of Mosaic Trisomy 18 Cases

From Forensics to Clinical Research: Expanding the Variant Calling Pipeline for the Precision ID mtDNA Whole Genome Panel

Analyzing Modern Biomolecules: The Revolution of Nucleic-Acid Sequencing – Review

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