High‐Throughput Assays to Assess the Functional Impact of Genetic Variants: A Road Towards Genomic‐Driven Medicine

Ipe, Joseph; Swart, Marelize; Burgess, KS; Skaar, Todd C.

doi:10.1111/cts.12440

Cited by 34 publications

(34 citation statements)

References 109 publications

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“…Some aspects of MAVEs, namely library synthesis and sequencing, are relatively well established and have been described extensively. 12,13,[31][32][33] Here, we focus on the aspects that are critical for the goal of prospectively interpreting human genetic variation.…”

Section: Annotating Every Possible Variant In Disease-related Functiomentioning

confidence: 99%

Variant Interpretation: Functional Assays to the Rescue

Starita

Ahituv

Dunham

et al. 2017

The American Journal of Human Genetics

322

294

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Classical genetic approaches for interpreting variants, such as case-control or co-segregation studies, require finding many individuals with each variant. Because the overwhelming majority of variants are present in only a few living humans, this strategy has clear limits. Fully realizing the clinical potential of genetics requires that we accurately infer pathogenicity even for rare or private variation. Many computational approaches to predicting variant effects have been developed, but they can identify only a small fraction of pathogenic variants with the high confidence that is required in the clinic. Experimentally measuring a variant's functional consequences can provide clearer guidance, but individual assays performed only after the discovery of the variant are both time and resource intensive. Here, we discuss how multiplex assays of variant effect (MAVEs) can be used to measure the functional consequences of all possible variants in disease-relevant loci for a variety of molecular and cellular phenotypes. The resulting large-scale functional data can be combined with machine learning and clinical knowledge for the development of ''lookup tables'' of accurate pathogenicity predictions. A coordinated effort to produce, analyze, and disseminate large-scale functional data generated by multiplex assays could be essential to addressing the variant-interpretation crisis.

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Section: Annotating Every Possible Variant In Disease-related Functiomentioning

confidence: 99%

Variant Interpretation: Functional Assays to the Rescue

Starita

Ahituv

Dunham

et al. 2017

The American Journal of Human Genetics

322

294

View full text Add to dashboard Cite

show abstract

“…While many causative sequence changes likely affect gene expression via impacting function of cis‐regulatory elements, predicting which of the trait‐associated genetic variants will ultimately modulate cis‐regulatory function is challenging. Some of these challenges can be addressed experimentally using high‐throughput reporter or mutagenesis assays in cell culture models . However, given the high cell‐type selectivity of many regulatory elements and the fact that multiple cell types contribute to the craniofacial complex as development proceeds, the choice of cell culture models for such assays will be crucial to capture relevant putative regulatory variants.…”

Section: Moving Forward: Challenges and Opportunitiesmentioning

confidence: 99%

“…Some of these challenges can be addressed experimentally using high-throughput reporter or mutagenesis assays in cell culture models. 29 However,…”

Section: Moving Forward: Challeng E S and Opp Ortunitie Smentioning

confidence: 99%

Hunting for genes that shape human faces: Initial successes and challenges for the future

Weinberg

Roosenboom

Shaffer

et al. 2019

Orthod Craniofacial Res

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Structured Abstract There is ample evidence from heritability studies, genetic syndromes and experimental animal models that facial morphology is strongly influenced by genes. In this brief review, we present an up‐to‐date overview of the efforts to identify genes associated with the size and shape of human facial features. We discuss recent methodological advances that have led to breakthroughs, but also the multitude of challenges facing the field. We offer perspective on possible applications of this line of research, particularly in the context of the precision genomics movement.

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“…With this in mind, Ipe et al . provide a very comprehensive overview of numerous technologies and resources that illuminate the functional relevance of genomic variations …”

Section: Building Confidencementioning

confidence: 99%

Translating Precision

Pacanowski

2017

Clinical Translational Sci

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High‐Throughput Assays to Assess the Functional Impact of Genetic Variants: A Road Towards Genomic‐Driven Medicine

Cited by 34 publications

References 109 publications

Variant Interpretation: Functional Assays to the Rescue

Variant Interpretation: Functional Assays to the Rescue

Hunting for genes that shape human faces: Initial successes and challenges for the future

Translating Precision

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