Eric Minikel
Harvard University
Publications 25
Antisense oligonucleotides (ASOs) designed to lower prion protein (PrP) expression in the brain through RNAse H1-mediated degradation of PrP RNA are in development as prion disease therapeutics. ASOs were previously reported to sequence-independently interact with PrP and inhibit prion accumulation in cell culture, yet in vivo studies using a new generation of ASOs found that only PrP-lowering sequences were effective at extending survival. Cerebrospinal fluid (CSF) PrP has been proposed as a ph...
#1Gregory J. RaymondH-Index: 30
#2Hien ZhaoH-Index: 4
Last.Sonia M. VallabhH-Index: 4
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#1Sonia M. Vallabh (Broad Institute)H-Index: 4
#2Chloe K. Nobuhara (Harvard University)H-Index: 6
Last.Stuart L. Schreiber (Broad Institute)H-Index: 49
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Reduction of native prion protein (PrP) levels in the brain is an attractive strategy for the treatment or prevention of human prion disease. Clinical development of any PrP-reducing therapeutic will require an appropriate pharmacodynamic biomarker: a practical and robust method for quantifying PrP, and reliably demonstrating its reduction in the central nervous system (CNS) of a living patient. Here we evaluate the potential of ELISA-based quantification of human PrP in human cerebrospinal flui...
5 CitationsSource
#1Eric Minikel (Broad Institute)H-Index: 12
#2Eric Kuhn (Broad Institute)H-Index: 16
Last.Steven A. Carr (Broad Institute)H-Index: 18
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Therapies currently in preclinical development for prion disease seek to lower prion protein (PrP) expression in the brain. Trials of such therapies are likely to rely on quantification of PrP in cerebrospinal fluid (CSF) as a pharmacodynamic biomarker and possibly as a trial endpoint. Studies using PrP ELISA kits have reproducibly shown that CSF PrP is lowered in the symptomatic phase of disease, a potential confounder for reading out the effect of PrP-lowering drugs in symptomatic patients. To...
1 CitationsSource
#1Nicola Whiffin (NIHR: National Institute for Health Research)H-Index: 18
#2Angharad M. Roberts (NIHR: National Institute for Health Research)H-Index: 7
Last.James S. WareH-Index: 29
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2 CitationsSource
#1Manuel A. Rivas (Stanford University)H-Index: 29
#2Brandon E. Avila (Broad Institute)H-Index: 2
Last.M. J. Daly (Broad Institute)H-Index: 178
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As part of a broader collaborative network of exome sequencing studies, we developed a jointly called data set of 5,685 Ashkenazi Jewish exomes. We make publicly available a resource of site and allele frequencies, which should serve as a reference for medical genetics in the Ashkenazim (hosted in part at, also available in gnomAD at We estimate that 34% of protein-coding alleles present in the Ashkenazi Jewish population at frequ...
18 CitationsSource
#1Nicola Whiffin (Imperial College London)H-Index: 18
#2Eric Minikel (Broad Institute)H-Index: 12
Last.James S. WareH-Index: 29
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Whole-exome and whole-genome sequencing have transformed the discovery of genetic variants that cause human Mendelian disease, but discriminating pathogenic from benign variants remains a daunting challenge. Rarity is recognized as a necessary, although not sufficient, criterion for pathogenicity, but frequency cutoffs used in Mendelian analysis are often arbitrary and overly lenient. Recent very large reference datasets, such as the Exome Aggregation Consortium (ExAC), provide an unprecedented ...
111 CitationsSource
#1Xiaolei Zhang (NIH: National Institutes of Health)H-Index: 4
#2Eric Minikel (Broad Institute)H-Index: 12
Last.Ben Weisburd (Broad Institute)H-Index: 7
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This software repository provides a pipeline for converting raw ClinVar data files into analysis-friendly tab-delimited tables, and also provides these tables for the most recent ClinVar release. Separate tables are generated for genome builds GRCh37 and GRCh38 as well as for mono-allelic variants and complex multi-allelic variants. Additionally, the tables are augmented with allele frequencies from the ExAC and gnomAD datasets as these are often consulted when analyzing ClinVar variants. Overal...
13 CitationsSource
#1Colleen M. Carlston (ARUP Laboratories)H-Index: 3
#2Anne H. O’Donnell-Luria (Broad Institute)H-Index: 13
Last.Rong Mao (ARUP Laboratories)H-Index: 25
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The clinical interpretation of genetic variants has come to rely heavily on reference population databases such as the Exome Aggregation Consortium (ExAC) database. Pathogenic variants in genes associated with severe, pediatric-onset, highly penetrant, autosomal dominant conditions are assumed to be absent or rare in these databases. Exome sequencing of a six-year-old female patient with seizures, developmental delay, dysmorphic features and failure to thrive identified an ASXL1 variant previous...
17 CitationsSource