Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria

Sloan, Jennifer L.; Johnston, Jennifer J.; Manoli, Irini; Chandler, Randy J.; Krause, Caitlin; Carrillo-Carrasco, Nuria; Chandrasekaran, Suma; Sysol, Justin R.; O’Brien, Kevin; Hauser, Natalie; Sapp, Julie C.; Dorward, Heidi; Huizing, Marjan; Barshop, Bruce A.; Berry, Susan A.; James, Philip; Champaigne, Neena L.; Lonlay, Pascale de; Valayannopoulos, Vassilli; Geschwind, Michael D.; Gavrilov, Dimitar; Nyhan, William L.; Biesecker, Leslie G.; Venditti, Charles P.

doi:10.1038/ng.908

Cited by 88 publications

(100 citation statements)

References 13 publications

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“…One-way ANOVA with post hoc Tukey test was used as statistical test (*p < 0.05; ***p < 0.001). (legend continued on next page) promotes adhesion between dendrites and axons via alpha neurexins in the adult brain (Petrenko et al, 1996), alterations in ACSF3 have been linked to mental retardation and the development of seizures (Sloan et al, 2011). Interestingly, TRNP1 has recently been discovered as a DNA-binding protein with essential modulating functions during tangential and radial migration of neuroblasts within the developing cerebral cortex (Stahl et al, 2013), corroborating the identification of distinct origin-dependent identities in fNSC-iPSC-NPCs.…”

Section: Identification Of Origin-dependent Cell Identities In Humanmentioning

confidence: 92%

Origin-Dependent Neural Cell Identities in Differentiated Human iPSCs In Vitro and after Transplantation into the Mouse Brain

et al. 2014

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The differentiation capability of induced pluripotent stem cells (iPSCs) toward certain cell types for disease modeling and drug screening assays might be influenced by their somatic cell of origin. Here, we have compared the neural induction of human iPSCs generated from fetal neural stem cells (fNSCs), dermal fibroblasts, or cord blood CD34(+) hematopoietic progenitor cells. Neural progenitor cells (NPCs) and neurons could be generated at similar efficiencies from all iPSCs. Transcriptomics analysis of the whole genome and of neural genes revealed a separation of neuroectoderm-derived iPSC-NPCs from mesoderm-derived iPSC-NPCs. Furthermore, we found genes that were similarly expressed in fNSCs and neuroectoderm, but not in mesoderm-derived iPSC-NPCs. Notably, these neural signatures were retained after transplantation into the cortex of mice and paralleled with increased survival of neuroectoderm-derived cells in vivo. These results indicate distinct origin-dependent neural cell identities in differentiated human iPSCs both in vitro and in vivo.

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Section: Identification Of Origin-dependent Cell Identities In Humanmentioning

confidence: 92%

Origin-Dependent Neural Cell Identities in Differentiated Human iPSCs In Vitro and after Transplantation into the Mouse Brain

et al. 2014

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“…It has been shown that this error is common, with up to 20% of variants listed in databases as pathogenic actually being benign (Bell et al 2011). Further clinical research on this participant led to the surprising result that she had severely abnormal blood and urine levels of malonic and methylmalonic acid (Sloan et al 2011). This novel approach to translational research was a powerful confirmation that the mutation was indeed pathogenic, but there was another, even more important conclusion.…”

Section: Clinical and Translational Researchmentioning

confidence: 99%

“…An example of this type of sequence-based hypothesisgenerating clinical research started with a collaborative project in which we showed that mutations in the gene ACSF3 caused the biochemical phenotype of combined malonic and methylmalonic acidemia (Sloan et al 2011). At that time, the disorder was believed to be a classic pediatric, autosomal-recessive severe metabolic disorder with decompensation and sometimes death.…”

Section: Clinical and Translational Researchmentioning

confidence: 99%

Hypothesis-generating research and predictive medicine

Biesecker

2013

Genome Res.

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Genomics has profoundly changed biology by scaling data acquisition, which has provided researchers with the opportunity to interrogate biology in novel and creative ways. No longer constrained by low-throughput assays, researchers have developed hypothesis-generating approaches to understand the molecular basis of nature-both normal and pathological. The paradigm of hypothesis-generating research does not replace or undermine hypothesis-testing modes of research; instead, it complements them and has facilitated discoveries that may not have been possible with hypothesistesting research. The hypothesis-generating mode of research has been primarily practiced in basic science but has recently been extended to clinical-translational work as well. Just as in basic science, this approach to research can facilitate insights into human health and disease mechanisms and provide the crucially needed data set of the full spectrum of genotype-phenotype correlations. Finally, the paradigm of hypothesis-generating research is conceptually similar to the underpinning of predictive genomic medicine, which has the potential to shift medicine from a primarily population-or cohort-based activity to one that instead uses individual susceptibility, prognostic, and pharmacogenetic profiles to maximize the efficacy and minimize the iatrogenic effects of medical interventions.The goal of this article is to describe how recent technological changes provide opportunities to undertake novel approaches to biomedical research and to practice genomic preventive medicine. Massively parallel sequencing is the primary technology that will be addressed here (Mardis 2008), but the principles apply to many other technologies, such as proteomics, metabolomics, transcriptomics, etc. Readers of this journal are well aware of the precipitous fall of sequencing costs over the last several decades. The consequence of this fall is that we are no longer in a scientific and medical world where the throughput (and the costs) of testing is the key limiting factor around which these enterprises are organized. Once one is released from this limiting factor, one may ask whether these enterprises should be reorganized. Here I outline the principles of how these enterprises are organized, show how highthroughput biology can allow alternative organizations of these enterprises to be considered, and show how biology and medicine are in many ways similar. The discussion includes three categories of enterprises: basic research, clinical research, and medical practice.

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“…The first maps to two genomic locations, an intron of ACSF3 (Acyl-CoA synthetase family member 3) and an exon of hypothetical transcript AK126744. No function has been attributed to AK126744, and while ACSF3 dysfunction is causal for combined malonic and methylmalonic aciduria (30), its possible relationship colorectal adenoma is unclear. However, both regions are annotated as transcribed, giving validity to the existence of an RNA product with this sequence.…”

Section: Discussionmentioning

confidence: 99%

Discovery and Validation of Circulating Biomarkers of Colorectal Adenoma by High-Depth Small RNA Sequencing

Roberts

Hardigan

Moore

et al. 2018

Clinical Cancer Research

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Purpose Colorectal cancer (CRC) is the third most common cancer worldwide, causing ~700,000 deaths each year. The majority of CRCs begin as adenomas. Definitive screening for colorectal adenomas is currently accomplished through colonoscopy but, owing largely to costs and invasiveness, is typically limited to patient groups at higher risk by virtue of age or family history. We sought to determine if blood-based small RNA markers could detect colorectal adenoma. Experimental Design We applied high-depth small RNA sequencing to plasma from a large (n=189) cohort of patients, balanced for age, sex, and ancestry. Our analytical methodology allowed for the detection of both microRNAs and other small RNA species. We replicated sequencing results by qPCR on plasma samples from an independent cohort (n=140). Results We found several small RNA species with significant associations to colorectal adenoma, including both microRNAs and non-microRNA small RNAs. These associations were robust to correction for patient covariates, including age. Among the adenoma-associated small RNAs, two, a miR-335-5p isoform and an un-annotated small RNA, validated by qPCR in an independent cohort. A classifier trained on measures of these two RNAs in the discovery cohort yields an AUC of 0.755 (0.775 with age) for adenoma detection in the independent cohort. This classifier accurately detects adenomas in patients under 50 and is robust to sex or ancestry. Conclusions Circulating small RNAs (including but not limited to miRNAs) discovered by sequencing and validated by qPCR identify patients with colorectal adenomas effectively.

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Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria

Cited by 88 publications

References 13 publications

Origin-Dependent Neural Cell Identities in Differentiated Human iPSCs In Vitro and after Transplantation into the Mouse Brain

Origin-Dependent Neural Cell Identities in Differentiated Human iPSCs In Vitro and after Transplantation into the Mouse Brain

Hypothesis-generating research and predictive medicine

Discovery and Validation of Circulating Biomarkers of Colorectal Adenoma by High-Depth Small RNA Sequencing

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