Integration of genomics and metabolomics for prioritization of rare disease variants: a 2018 literature review

Graham, Emma; Lee, Jessica; Price, Magda; Tarailo‐Graovac, Maja; Matthews, Allison; Engelke, Udo F. H.; Tang, Jeffrey; Kluijtmans, Leo A. J.; Wevers, Ron A.; Wasserman, Wyeth W.; Mostafavi, Sara

doi:10.1007/s10545-018-0139-6

Cited by 38 publications

(43 citation statements)

References 76 publications

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“…Altered flux through the pathway manifests in the levels of substrates and products of nearest rate-limiting enzymes. As noted by Graham et al (2018), lack of established methods for mapping a genomic perturbation to impacted metabolites is a major challenge in genomics-metabolomics integration. Our knowledge of how any gene relates to any metabolite, and methods to gather such knowledge are still limited.…”

Section: Kilk Translation and Contextualization From Animal Models Tomentioning

confidence: 99%

Metabolomics for Animal Models of Rare Human Diseases: An Expert Review and Lessons Learned

Kilk

2019

OMICS: A Journal of Integrative Biology

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Rare diseases occur with a frequency £1:1500-1:2500 depending on the location and applicable definitions across countries. Although individually rare, they collectively affect as much as 4-8% of population imposing a large burden on public health. Rarity in prevalence means prolonged path to accurate diagnosis, lack of treatment options, and also limited chances for preclinical studies of pathogenesis. I discuss in this expert review (1) what metabolomics, as a high throughput systems sciences technology, offers for rare disease studies, (2) why animal models are important for the study of rare human diseases and what should be kept in mind while using animal models, and finally, (3) provide examples of recent research to highlight how metabolomics on animal models of rare diseases perform, and how these results can lead to the knowhow, which raises genome, metabolome, and phenotype integration to a whole new level. In sum, metabolomics has been for years in clinical use for diagnosis of certain types of rare diseases. Determination of pathogenesis of more complex diseases and testing of treatment strategies is where animal models and systems biology analytical approaches are necessary. From gathered data, it is possible to go back to diagnostic and prognostic markers for rare diseases, which so far lack reliable and robust diagnosis and therapeutic options. In the future, a major challenge is to reveal the links between genotype, metabolism, and phenotype. Rare diseases could be the key in that process.

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Section: Kilk Translation and Contextualization From Animal Models Tomentioning

confidence: 99%

Metabolomics for Animal Models of Rare Human Diseases: An Expert Review and Lessons Learned

Kilk

2019

OMICS: A Journal of Integrative Biology

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“…This is particularly true in non‐acute cases where a patient has undifferentiated symptoms, such as developmental delays or seizures, that can have a myriad of root causes including IEMs . Clinical metabolomics testing is also proving a useful complement to clinical genomic testing . It also has merit in screening for rare diseases not yet described or for which the few number of cases limits the ability to develop targeted diagnostic tests .…”

Section: Introductionmentioning

confidence: 99%

“…1 Clinical metabolomics testing is also proving a useful complement to clinical genomic testing. [2][3][4] It also has merit in screening for rare diseases not yet described or for which the few number of cases limits the ability to develop targeted diagnostic tests. 2,[5][6][7] Since no roadmap and few guideposts exist, the major goal of this review is to point out the key elements involved in developing, launching, and performing clinical metabolomics testing.…”

Section: Introductionmentioning

confidence: 99%

“…[2][3][4] It also has merit in screening for rare diseases not yet described or for which the few number of cases limits the ability to develop targeted diagnostic tests. 2,[5][6][7] Since no roadmap and few guideposts exist, the major goal of this review is to point out the key elements involved in developing, launching, and performing clinical metabolomics testing. The development of untargeted clinical metabolomics testing builds on the precedent established by untargeted clinical whole exome sequencing (WES) whose application has been used to classify genes not previously associated with epilepsy, 8 NDUFS8-related Complex I deficiency, 9 and for diagnostic evaluation of critically ill infants in pediatric and neonatal intensive care units.…”

Section: Introductionmentioning

confidence: 99%

“…Traditional diagnostic biomarker assays must identify disease with high specificity and high sensitivity to help streamline clinical care but recently 'omics tests have enabled the ability to screen and diagnose disease in an untargeted manner. 1,2,4,7 Of the 'omics technologies, genomics was the first to be accepted in the clinical space. [20][21][22][23][24][25][26][27][28][29][30] Metabolomics, a term introduced in 1998, 31 is a relatively newer technology that has been used increasingly over the past decade ( Figure 1) and may be utilized to screen for and to identify the cause of disease.…”

Section: Introductionmentioning

confidence: 99%

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Metabolomics in the clinic: A review of the shared and unique features of untargeted metabolomics for clinical research and clinical testing

et al. 2018

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Metabolomics is the untargeted measurement of the metabolome, which is composed of the complement of small molecules detected in a biological sample. As such, metabolomic analysis produces a global biochemical phenotype. It is a technology that has been utilized in the research setting for over a decade. The metabolome is directly linked to and is influenced by genetics, epigenetics, environmental factors, and the microbiome—all of which affect health. Metabolomics can be applied to human clinical diagnostics and to other fields such as veterinary medicine, nutrition, exercise, physiology, agriculture/plant biochemistry, and toxicology. Applications of metabolomics in clinical testing are emerging, but several aspects of its use as a clinical test differ from applications focused on research or biomarker discovery and need to be considered for metabolomics clinical test data to have optimum impact, be meaningful, and be used responsibly. In this review, we deconstruct aspects and challenges of metabolomics for clinical testing by illustrating the significance of test design, accurate and precise data acquisition, quality control, data processing, n‐of‐1 comparison to a reference population, and biochemical pathway analysis. We describe how metabolomics technology is integral to defining individual biochemical phenotypes, elaborates on human health and disease, and fits within the precision medicine landscape. Finally, we conclude by outlining some future steps needed to bring metabolomics into the clinical space and to be recognized by the broader medical and regulatory fields.

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Need and Challenges in Establishing Newborn Screening Programs for Inherited Metabolic Disorders in Developing Countries

et al. 2023

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Even in this post genomic era, no national level newborn screening (NBS) programs for inborn errors of metabolism (IEMs) are yet available in several developing countries including Pakistan. Through NBS, various IEMs can be screened using minute quantities of biofluids. Targeted metabolomics and genomic techniques are the main approaches used for NBS. However, lack of technical expertise and such high-end "omics" based analytical facilities, and meager funding for healthcare in developing countries are the major reasons for unavailability of NBS programs. As it is reflected by only a handful reports about IEMs from Pakistan with population of ≈220 million and consanguinity rate of about 70%, which suggests an unmet need for an NBS program owing to reasonably high prevalence of inherited diseases. Around 200 IEMs are potentially treatable if diagnosed at an earlier stage through biochemical marker and genetic screening, so such patients can get benefit from the NBS program. This overview will help to persuade the stakeholders to setup NBS programs in developing countries including Pakistan, due to multitude of benefits for IEMs; timely diagnosis and early treatment can help the patients to live a nearly healthy life, reduced suffering of the family and minimal burden on society or national healthcare system.

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Integration of genomics and metabolomics for prioritization of rare disease variants: a 2018 literature review

Cited by 38 publications

References 76 publications

Metabolomics for Animal Models of Rare Human Diseases: An Expert Review and Lessons Learned

Metabolomics for Animal Models of Rare Human Diseases: An Expert Review and Lessons Learned

Metabolomics in the clinic: A review of the shared and unique features of untargeted metabolomics for clinical research and clinical testing

Need and Challenges in Establishing Newborn Screening Programs for Inherited Metabolic Disorders in Developing Countries

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