Beryl B. Cummings
A5021127068- Genomics and Rare Diseases
- RNA Research and Splicing
- Muscle Physiology and Disorders
- RNA modifications and cancer
- Genomics and Phylogenetic Studies
- Genomic variations and chromosomal abnormalities
- Genetic Associations and Epidemiology
- Genomics and Chromatin Dynamics
- CRISPR and Genetic Engineering
- Neurogenetic and Muscular Disorders Research
- Cell Adhesion Molecules Research
- Cardiomyopathy and Myosin Studies
- Nuclear Structure and Function
- RNA and protein synthesis mechanisms
- Epigenetics and DNA Methylation
- Cancer-related molecular mechanisms research
- Genetics and Neurodevelopmental Disorders
- Nutrition, Genetics, and Disease
- Gene expression and cancer classification
- Parkinson's Disease Mechanisms and Treatments
- Peptidase Inhibition and Analysis
- Bioinformatics and Genomic Networks
- Diabetes, Cardiovascular Risks, and Lipoproteins
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Cancer-related gene regulation
Broad Institute
2016-2025
Harvard University
2015-2024
Maze (United States)
2020-2024
University of Padua
2024
Janssen (Belgium)
2022
Massachusetts General Hospital
2015-2021
Children's Hospital at Westmead
2015-2021
Kaiser Permanente South San Francisco Medical Center
2021
Massachusetts Institute of Technology
2016-2019
University of Maryland, Baltimore
2015
Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation DNA sequence changes. Here we describe aggregation analysis high-quality exome (protein-coding region) 60,706 individuals diverse ancestries generated as part Exome Aggregation Consortium (ExAC). This catalogue diversity contains an average one variant every eight bases exome, provides direct evidence presence widespread mutational recurrence. We have used this to calculate...
Abstract Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences gene disruption: crucial for function an organism will be depleted such in natural populations, whereas non-essential tolerate their accumulation. However, predicted loss-of-function enriched annotation errors, and tend to found at extremely low frequencies, so analysis requires careful variant very large sample sizes 1 . Here we describe aggregation 125,748...
Summary Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences gene disruption: critical for an organism’s function will be depleted such in natural populations, while non-essential tolerate their accumulation. However, predicted loss-of-function (pLoF) enriched annotation errors, and tend to found at extremely low frequencies, so analysis requires careful variant very large sample sizes 1 . Here, we describe aggregation...
Abstract Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression compute PrediXcan (a gene mapping approach) results using summary data (S-PrediXcan) and show its accuracy general robustness misspecified reference sets. We apply this framework 44 GTEx tissues 100+ from GWAS meta-analysis studies, creating growing public catalog of associations seeks capture the effects variation on human...
Abstract X chromosome inactivation (XCI) silences transcription from one of the two chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete humans: up one-third X-chromosomal genes are expressed both active inactive (Xa Xi, respectively) cells, with degree ‘escape’ varying individuals 1,2 . The extent which is shared tissues remains poorly characterized 3,4 , as does manifests detectable sex differences gene 5 phenotypic...
Structural variants (SVs) rearrange large segments of DNA
Worldwide, hundreds of thousands humans have had their genomes or exomes sequenced, and access to the resulting data sets can provide valuable information for variant interpretation understanding gene function. Here, we present a lightweight, flexible browser framework display large population datasets genetic variation. We demonstrate its use exome sequence from 60 706 individuals in Exome Aggregation Consortium (ExAC). The ExAC provides gene- transcript-centric displays variation, critical...
Transcriptome sequencing improves the diagnostic rate for Mendelian disease in patients whom genetic analysis has not returned a diagnosis.
Abstract A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is depletion RNA-binding protein TDP-43 from nucleus neurons in brain spinal cord 1 . major function as a repressor cryptic exon inclusion during RNA splicing 2–4 Single nucleotide polymorphisms UNC13A are among strongest hits associated with FTD ALS human genome-wide association studies 5,6 , but how those variants increase risk for disease...
Abstract The acceleration of DNA sequencing in samples from patients and population studies has resulted extensive catalogues human genetic variation, but the interpretation rare variants remains problematic. A notable example this challenge is existence disruptive dosage-sensitive disease genes, even apparently healthy individuals. Here, by manual curation putative loss-of-function (pLoF) haploinsufficient genes Genome Aggregation Database (gnomAD) 1 , we show that one explanation for...
Abstract Naturally occurring human genetic variants that are predicted to inactivate protein-coding genes provide an in vivo model of gene inactivation complements knockout studies cells and organisms. Here we report three key findings regarding the assessment candidate drug targets using loss-of-function variants. First, even essential genes, which not tolerated, can be highly successful as inhibitory drugs. Second, most sufficiently rare genotype-based ascertainment homozygous or compound...
Upstream open reading frames (uORFs) are tissue-specific cis-regulators of protein translation. Isolated reports have shown that variants create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show new upstream start codons, and disrupting stop sites existing uORFs, under strong negative selection. This selection signal is significantly stronger for arising genes intolerant to loss-of-function variants. Furthermore, creating...
Glycogen synthase 1 (GYS1), the rate-limiting enzyme in muscle glycogen synthesis, plays a central role energy homeostasis and has been proposed as therapeutic target multiple storage diseases. Despite decades of investigation, there are no known potent, selective small-molecule inhibitors this enzyme. Here, we report preclinical characterization MZ-101, small molecule that potently inhibits GYS1 vitro vivo without inhibiting GYS2, related isoform essential for synthesizing liver glycogen....
Summary Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation DNA sequence changes. Here we describe aggregation analysis high-quality exome (protein-coding region) 60,706 individuals diverse ethnicities generated as part Exome Aggregation Consortium (ExAC). The resulting catalogue diversity contains an average one variant every eight bases exome, provides direct evidence presence widespread mutational recurrence. We show that...
Multi-nucleotide variants (MNVs), defined as two or more nearby existing on the same haplotype in an individual, are a clinically and biologically important class of genetic variation. However, tools typically do not accurately classify MNVs, understanding their mutational origins remains limited. Here, we systematically survey MNVs 125,748 whole exomes 15,708 genomes from Genome Aggregation Database (gnomAD). We identify 1,792,248 across genome with constituent falling within 2 bp distance...
Objective Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management this important emerging disorder. Methods Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans . We then undertook a detailed analysis the clinical, histopathological imaging features these patients. Results All had prenatal or early onset hypotonia contractures. None...
The evolutionary history of a gene helps predict its function and relationship to phenotypic traits. Although sequence conservation is commonly used decipher assess medical relevance, methods for functional inference from comparative expression data are lacking. Here, we use RNA-seq across seven tissues 17 mammalian species show that evolution mammals accurately modeled by the Ornstein–Uhlenbeck process, proposed model continuous trait evolution. We apply this identify pathways under...
Transcriptome data can facilitate the interpretation of effects rare genetic variants. Here, we introduce ANEVA (analysis expression variation) to quantify variation in gene dosage from allelic (AE) a population. Application Genotype-Tissues Expression (GTEx) showed that this variance estimate is robust and correlated with selective constraint gene. Using these estimates outlier test (ANEVA-DOT) applied AE 70 Mendelian muscular disease patients accuracy detecting genes pathogenic variants...
Abstract Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models human gene inactivation and can be valuable indicators function the potential toxicity therapeutic inhibitors targeting these 1,2 . Gain-of-kinase-function LRRK2 are known significantly increase risk Parkinson’s disease 3,4 , suggesting that inhibition kinase activity is a promising strategy. While preclinical studies model organisms have raised some...