Genome and RNA sequencing in patients with methylmalonic aciduria of unknown cause

Abdrabo, Lina Sobhi; Watkins, David; Wang, Sophie Ran; Lafond-Lapalme, Joël; Rivière, Jean‐Baptiste; Rosenblatt, David S.

doi:10.1038/s41436-019-0640-9

Cited by 4 publications

(6 citation statements)

References 18 publications

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“…Specific mutations in MMADHC can also lead to a combined phenotype of MMA and homocystinuria or isolated homocystinuria 8 . In the rare case of inconclusive genetic results, complementation studies, the propionate incorporation assayor enzyme activity measurements in fibroblasts can aid in the diagnostic process 3,9,10 . Many of the known MMUT mutations have been functionally tested with the aforementioned assays, allowing the historic classification as a mut 0 subtype (no response to hydroxocobalamin supplementation in the propionate incorporation assay) or a mut − subtype (increased propionate incorporation upon addition of hydroxocobalamin to the cell culture medium) 11,12 …”

Section: Guidelinesmentioning

confidence: 99%

“…MMA, methylmalonic acidaemia; PA, propionic acidaemia incorporation assayor enzyme activity measurements in fibroblasts can aid in the diagnostic process. 3,9,10 Many of the known MMUT mutations have been functionally tested with the aforementioned assays, allowing the historic classification as a mut 0 subtype (no response to hydroxocobalamin supplementation in the propionate incorporation assay) or a mut − subtype (increased propionate incorporation upon addition of hydroxocobalamin to the cell culture medium). 11,12 In the case of PA, there is no evidence that identification of the underlying gene defect (in PCCA or PCCB) can guide management or prognosis, as no genotype-phenotype correlation is known.…”

Section: Bone Healthmentioning

confidence: 99%

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Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision

Forny

Hörster

Ballhausen³

et al. 2021

J of Inher Metab Disea

159

207

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Isolated methylmalonic acidaemia (MMA) and propionic acidaemia (PA) are rare inherited metabolic diseases. Six years ago, a detailed evaluation of the available evidence on diagnosis and management of these disorders has been published for the first time. The article received considerable attention, illustrating the importance of an expert panel to evaluate and compile recommendations to guide rare disease patient care. Since that time, a growing body of evidence on transplant outcomes in MMA and PA patients and use of precursor free amino acid mixtures allows for updates of the guidelines. In this article, we aim to incorporate this newly published knowledge and provide a revised version of the guidelines. The analysis was performed by a panel of multidisciplinary health care experts, who followed an updated guideline development methodology (GRADE). Hence, the full body of evidence up until autumn 2019 was re‐evaluated, analysed and graded. As a result, 21 updated recommendations were compiled in a more concise paper with a focus on the existing evidence to enable well‐informed decisions in the context of MMA and PA patient care.

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Section: Guidelinesmentioning

confidence: 99%

Section: Bone Healthmentioning

confidence: 99%

Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision

Forny

Hörster

Ballhausen³

et al. 2021

J of Inher Metab Disea

159

207

View full text Add to dashboard Cite

show abstract

“…While MMA is the name‐giving biomarker of MMUT, it is usually not found to be elevated in individuals with PA. However, mild elevation of MMA in urine of a PA patient has been reported 29 . We hypothesize that we observed an organ‐specific effect: while body fluids receive metabolites from many different cell types and organs, we exclusively investigated renal tubular cells.…”

Section: Discussionmentioning

confidence: 97%

“…However, mild elevation of MMA in urine of a PA patient has been reported. 29 We hypothesize that we observed an organ-specific effect: while body fluids receive metabolites from many different cell types and organs, we exclusively investigated renal tubular cells. MMA might furthermore impact on organic acid transport in renal tubular cells.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial damage in renal epithelial cells is potentiated by protein exposure in propionic aciduria

Schumann

Belche

Schaller

et al. 2021

J of Inher Metab Disea

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“…There is growing evidence that RNA-seq can substantially improve diagnostic yield across a variety of disease subtypes (3, 10, 13-15) through identification of variants impacting splicing, or leading to impairment of transcript expression or stability (16). However, there remain several hurdles to the effective and routine integration of RNA-seq into diagnostic pipelines.…”

Section: Introductionmentioning

confidence: 99%

MRSD: a novel quantitative approach for assessing suitability of RNA-seq in the clinical investigation of mis-splicing in Mendelian disease

Rowlands

Taylor

Rice

et al. 2021

Preprint

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BackgroundRNA-sequencing of patient biosamples is a promising approach to delineate the impact of genomic variants on splicing, but variable gene expression between tissues complicates selection of appropriate tissues. Relative expression level is often used as a metric to predict RNA-sequencing utility. Here, we describe a gene- and tissue-specific metric to inform the feasibility of RNA-sequencing, overcoming some issues with using expression values alone.ResultsWe derive a novel metric, Minimum Required Sequencing Depth (MRSD), for all genes across three human biosamples (whole blood, lymphoblastoid cell lines (LCLs) and skeletal muscle). MRSD estimates the depth of sequencing required from RNA-sequencing to achieve user-specified sequencing coverage of a gene, transcript or group of genes of interest. MRSD predicts levels of splice junction coverage with high precision (90.1-98.2%) and overcomes transcript region-specific sequencing biases. Applying MRSD scoring to established disease gene panels shows that LCLs are the optimum source of RNA, of the three investigated biosamples, for 69.3% of gene panels. Our approach demonstrates that up to 59.4% of variants of uncertain significance in ClinVar predicted to impact splicing could be functionally assayed by RNA-sequencing in at least one of the investigated biosamples.ConclusionsWe demonstrate the power of MRSD as a metric to inform choice of appropriate biosamples for the functional assessment of splicing aberrations. We apply MRSD in the context of Mendelian genetic disorders and illustrate its benefits over expression-based approaches. We anticipate that the integration of MRSD into clinical pipelines will improve variant interpretation and, ultimately, diagnostic yield.

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Genome and RNA sequencing in patients with methylmalonic aciduria of unknown cause

Cited by 4 publications

References 18 publications

Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision

Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision

Mitochondrial damage in renal epithelial cells is potentiated by protein exposure in propionic aciduria

MRSD: a novel quantitative approach for assessing suitability of RNA-seq in the clinical investigation of mis-splicing in Mendelian disease

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