A5005494787- Genomics and Rare Diseases
- Genetic Associations and Epidemiology
- CRISPR and Genetic Engineering
- Cardiomyopathy and Myosin Studies
- Cancer Genomics and Diagnostics
- Genomic variations and chromosomal abnormalities
- Prenatal Screening and Diagnostics
- Pluripotent Stem Cells Research
- Congenital heart defects research
- Genomics and Chromatin Dynamics
- BRCA gene mutations in cancer
- DNA Repair Mechanisms
- Single-cell and spatial transcriptomics
- Gene expression and cancer classification
- Biomedical Ethics and Regulation
- Reproductive Biology and Fertility
- Genetics and Neurodevelopmental Disorders
- Pregnancy and preeclampsia studies
- Neonatal Health and Biochemistry
- Biotin and Related Studies
- Colorectal Cancer Screening and Detection
- Biomedical Text Mining and Ontologies
- Genetic factors in colorectal cancer
- DNA and Nucleic Acid Chemistry
- Genetic Syndromes and Imprinting
Brotman Baty Institute
2024
University of Washington
2021-2024
Brigham and Women's Hospital
2018-2021
Harvard University
2021
McGill University
2013-2016
The greatest opportunity for lifelong impact of genomic sequencing is during the newborn period. "BabySeq Project" a randomized trial that explores medical, behavioral, and economic impacts integrating into care healthy sick newborns.Families newborns are enrolled from Boston Children's Hospital Brigham Women's nurseries, half to receive report includes monogenic disease variants, recessive carrier variants childhood onset or actionable disorders, pharmacogenomic variants. All families...
<h3>Importance</h3> Newborn genomic sequencing (nGS) may provide health benefits throughout the life span, but there are concerns that it could also have an unfavorable (ie, negative) psychosocial effect on families. <h3>Objective</h3> To assess of nGS families from BabySeq Project, a randomized clinical trial evaluating care newborns well-baby nurseries and intensive units. <h3>Design, Setting, Participants</h3> In this conducted May 14, 2015, to 21, 2019, at units 3 Boston, Massachusetts,...
Clinical classification of genomic variants identified on sequencing is often challenging, with many classified as Variants Uncertain Significance (VUS) account insufficient evidence. Advances in and gene synthesis has made feasible multiplexed assays variant effect (MAVEs), which quantify the functional impact thousands a single experiment. These evidence they generate have potential to empower more accurate clinical classification. However, there are outstanding challenges opportunities...
Abstract Despite widespread advances in DNA sequencing, the functional consequences of most genetic variants remain poorly understood. Multiplexed Assays Variant Effect (MAVEs) can measure function at scale, and are beginning to address this problem. However, MAVEs cannot readily be applied ∼10% human genes encoding secreted proteins. We developed a flexible, scalable cell surface display method, Surface Tethering Extracellular Proteins (MultiSTEP), protein variant effects. used MultiSTEP...
Multiplexed Assays of Variant Effects (MAVEs) can test all possible single variants in a gene interest. The resulting saturation-style data may help resolve variant classification disparities between populations, especially for uncertain significance (VUS).
Failure of homologous synapsis during meiotic prophase triggers transcriptional repression. Asynapsis the X and Y chromosomes their consequent silencing is essential for spermatogenesis. However, asynapsis portions autosomes in heterozygous translocation carriers may be detrimental progression. In fact, a wide range phenotypic outcomes from arrest to normal spermatogenesis have been described causes such variation remain elusive. To better understand consequences male Robertsonian...
Standard transgenic cell line generation requires screening 100-1000s of colonies to isolate correctly edited cells. We describe CRISPRa On-Target Editing Retrieval (CRaTER) which enriches for cells with on-target knock-in a cDNA-fluorescent reporter transgene by transient activation the targeted locus followed flow sorting recover show CRaTER recovers rare heterozygous, biallelic-editing transcriptionally-inactive MYH7 in human induced pluripotent stem (hiPSCs), enriching on average 25-fold...
Pathogenic autosomal-dominant missense variants in
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked genetic condition affecting estimated 400-500 million people worldwide and one of the causes chronic hemolytic anemia drug-, food-, or infection-induced anemia. Most G6PD-deficient individuals are asymptomatic unless exposed to a triggering event (eg, fava beans, certain drugs), which can result in life-threatening acute In neonates, G6PD increases risk for severe hyperbilirubinemia kernicterus, associated with increased...
Multiplexed Assays of Variant Effects (MAVEs) can test all possible single variants in a gene interest. The resulting saturation-style functional data may help resolve variant classification disparities between populations, especially for Variants Uncertain Significance (VUS). We analyzed clinical significance classifications 213,663 individuals European-like genetic ancestry versus 206,975 non-European-like from All Us and the Genome Aggregation Database. Then, we incorporated clinically...
ObjectivesThe challenges of understanding how interventions influence follow-up medical care are magnified during genomic testing because few patients have received it to date and the scope information provides is complex often unexpected. We tested a novel strategy for quantifying downstream healthcare utilization after more comprehensively efficiently identify related services. also evaluated effectiveness different methods collecting these data.MethodsWe developed risk-based approach...
Here, we report a newborn female infant from the well-baby cohort of BabySeq Project who was identified with compound heterozygous BTD gene variants. The two variants included well-established pathogenic variant (c.1612C>T, p.Arg538Cys) that causes profound biotinidase deficiency (BTD) in homozygosity. In addition, novel splice (c.44+1G>A, p.?) invariant donor region intron 1, potentially predictive loss function. predicted to impact splicing exon 1; however, given absence any reported...
Genomic medicine aims to use patient-level genetic data improve clinical care. However, the majority of clinically encountered variants are classified as uncertain significance (VUS), which cannot be used for making decisions given their unknown relationship disease.
Genetic testing has the potential to personalize healthcare and improve health outcomes. However, disparities in access genomic medicine variant interpretation have emerged as critical issues. These are particularly evident when classifying variants with unclear clinical significance, referred Variants of Uncertain Significance (VUS). VUS complicate implementation precision raise questions about how these may affect individuals from different genetic ancestries.
Standard transgenic cell line generation requires screening 100-1000s of colonies to isolate correctly edited cells. We describe CR ISPR a On- T arget E diting R etrieval (CRaTER) which enriches for cells with on-target knock-in cDNA-fluorescent reporter transgene by transient activation the targeted locus followed flow sorting recover show CRaTER recovers rare heterozygous, biallelic-editing transcriptionally-inactive MYH7 in human induced pluripotent stem (hiPSCs), enriching on average...
A variant can be pathogenic or benign with relation to a human disease. Current classification categories from reflect probabilistic summary of current understanding. primary metric clinical utility for multiplexed assays effect (MAVE) is the number variants that reclassified uncertain significance (VUS). However, we hypothesized this measure underrepresents information gained MAVEs and an theory approach which includes data does not reclassify will better true gain. We used evaluate gain, in bits,