selecting the right genes to report in newborn genomic ... · selecting the right genes to report...
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Selecting the right genes to report in newborn genomic sequencing: The BabySeq Project
Ozge Ceyhan Birsoy, Ph.D. Partners HealthCare Laboratory for Molecular Medicine Broad Institute Clinical Research Sequencing Platform
Brigham and Women’s Hospital & Harvard Medical School
Genomic sequencing in newborns
Opportunities Challenges
The BabySeq Project
NIH funded 5 year study to explore the impact of genomic sequencing of newborns (gNBS) on families and providers
Develop laboratory processes to perform and interpret results of genomic sequencing in newborns
Medical Individual and public health?
Behavioral Physician and parent behavior?
Economic The healthcare system?
Medical Record Review
240 Newborns in NICU at BCH and Parents
•Standard NBS •Family History
•Standard NBS •Family History
•Genome Report Optional:
•Indication-Based Analysis
•Standard NBS •Family History
•Genome Report
240 Healthy Newborns at BWH and Parents
•Standard NBS •Family History
10-month Follow-up Consultation and Exam with Study Physician and Genetic Counselor
Pre-Enrollment Genetic Counseling, Consent, Blood Draw, Family History with Genetic Counselor
Consultation and Results Disclosure with Genetic Counselor and Study Physician. Consultation Note and Testing Reports placed in Medical Record
and sent to other care providers.
Outcom
es collected. Study Physicians and GC
s available for questions from
parents, NIC
U M
Ds and outside M
Ds
Randomization Randomization
Project Overview
Two reporting strategies
Genomic Newborn Sequencing Report
Indication Based Analysis
Risk for childhood-onset disease
Carrier status for childhood-onset disease
Pharmacogenomic (relevant to pediatrics)
Blood type
Genes associated with the infant’s clinical features
Option to query PGx variants related to the infant’s care
Well newborn nursery
NICU
Pathogenic Likely pathogenic Uncertain significance Likely benign Benign
Genomic Newborn Sequencing Report
Indication Based Analysis
Criteria for including a variant in a BabySeq report
Criteria for including a gene in a BabySeq report
Strong Moderate Limited
GNSR IBA Specific disease suspected
Gene-disease evidence level
High Moderate Low Penetrance
Childhood Age of onset Adulthood
>5 million variants
≥10% in WGS Cases
HGMD ClinVar >5%
Novel LOF
Medical exome
>1%
Gene exclusions
Variant exclusions
~200
-300
var
iant
s <60 variants 20-40
variants 10-30
variants
Data Set A ≥ 10% MAF WGS Cases Excludes common technical FPs Common indels wrong nomenclature Exceptions FV, HFE, SERPINA1
Data Set B - Gene Exclusions Evidence for gene-disease association = none, limited, or disputed Non medically relevant phenotype
Initial Filters Curated Exclusion Datasets
A B C
MedSeq Genome Filtering Approach Applied to BabySeq
Data Set C - Variant Exclusions Benign interpretation LOF but LOF not disease mechanism GWAS or PGx association only
Being addressed for BabySeq before launch
Heidi Rehm
Identifying genes to be reported on GNSR
~4,000 disease-associated genes
Evidence-based gene-disease association review Evidence for causing disease
Age of onset Penetrance
Inheritance pattern Phenotype category Carrier phenotype
GNSR criteria: High evidence to cause highly penetrant childhood-onset disease
Evidence level for a causal role in disease
Criteria
DEFINITIVE Role of gene in disease repeatedly demonstrated for multiple
pathogenic variants AND Upheld ≥3 years
STRONG Multiple families with pathogenic variants AND
Supporting functional data AND ≥2 independent reports
MODERATE ≥3 families with reasonably pathogenic variants reported AND Supporting functional data
LIMITED <3 families with reasonably pathogenic variants reported OR Multiple variants without sufficient evidence for pathogenicity
NO EVIDENCE No reported evidence for a causal role in disease
DISPUTED Valid evidence refuting a role in disease equivalent or stronger than evidence supporting this role
EVIDENCE AGAINST Evidence refuting role in disease significantly outweighs evidence supporting this
ClinGen Clinical Validity Classifications
Curating age of onset, penetrance and actionability
Age of onset: Has the disease / gene / variant ever been reported in childhood?
Actionability during childhood: Would surveillance/intervention during childhood be beneficial to prevent
disease or improve outcome? How severe is the outcome? Nature of the surveillance/intervention method?
Penetrance : High: ≥80% of reported individuals are symptomatic Moderate: 20-80% of reported individuals are symptomatic Low: <20% of reported individuals are symptomatic With assigned confidence scores
1,566 gene-disease associations curated so far
Evidence level for causal role in disease
Earliest reported age of onset
Penetrance
906 genes meet GNSR reporting criteria
34%
33%
22%
10% 0.1%
84%
13% 3% 0.3%
81%
4% 5%
10%
Should they be reported in GNSR?
Moderate evidence/penetrance
but “clinically actionable” in
childhood
Carriers at risk for adult-onset
disease
Mixed presentation
Will be reported Will not be reported Need to discuss!
Childhood-onset Strong evidence High penetrance
Adult-onset Limited evidence Low penetrance
Carriers status if heterozygotes are at risk for adult-onset disease
Gene Disease Evidence Inh Age of onset
Penetrance Carrier phenotype
FH Fumarase deficiency Strong AR Childhood High HLRCC
FH Hereditary leiomyomatosis and renal cell cancer
Strong AD Adulthood Moderate N/A
Indication Based Analysis
Indication-based gene list
Literature HGMD OMIM
GeneReviews GeneTests
Expert review
KEGG database Phenomizer
Common NICU indications with potential genetic basis
Clinical presentation Number of genes in indication-based panel
Number of cases
% Cases in the NICU (Total)
% Cases in the NICU with potential genetic basis
Most common indications with potential genetic basis at BCH NICU*
CHD / cardiomyopathy / arrhythmias 306 60 9.4 21.1 Bowel hypomotility / obstruction 112 35 5.5 12.3
Seizures 667 25 3.9 8.8 Hyperbilirubinemia 103 21 3.3 7.4
Hypoglycemia 70 14 2.2 4.9 Hypothyroidism 56 13 2 4.6
Hearing loss 91 12 1.9 4.2 Anemia 208 10 1.6 3.5
Thrombocytopenia 208 10 1.6 3.5 Inborn errors of metabolism 290 7 1.1 2.5 Neonatal respiratory distress 529 5 0.8 1.8
Hypotonia 699 3 0.5 1.1 Renal dysplasia 238 3 0.5 1.1
Neonatal diabetes mellitus 75 1 0.2 0.4 Skeletal dysplasia 204 1 0.2 0.4
Dermatological disorders 283 1 0.2 0.4 Thrombophilia 37 1 0.2 0.4
Multiple anomalies N/A 60 9.4 21.1
All indications with gene panels prepared in advance 222 35.1 78.4
Total 282 44.5
Additional common NICU indications with potential genetic basis
Cleft lip-palate / Robin sequence 259 Congenital liver disease 379 Pulmonary hypertension 55
*Based on BCH NICU admissions in 2011
Lessons learned during gene curation for BabySeq…
Evidence level for a causal role in disease is difficult to quantify with same
set of rules for every gene
Expert opinion is important
Phenotypes associated with diseases that have variable expressivity need
to be curated together
Assigned evidence levels only apply to causal role in disease
It is extremely challenging to determine penetrance from the literature
Many attributes need to be reviewed at the variant level
Classifications need to be updated as new information becomes available
BabySeq Project Team Leadership Alan H. Beggs, PhD (joint PI) Robert C. Green, MD, MPH (joint PI) Heidi L. Rehm, PhD Peter J. Park, PhD Tim Yu, MD, PhD Pankaj B. Agrawal, MD, MMSC Richard B. Parad, MD, MPH Ingrid A. Holm, MD, MPH Amy L. McGuire, JD, PhD Project Managers Caroline Weipert, MS Meghan Towne, MS, CGC Co-Investigators Ozge Ceyhan-Birsoy, PhD Kurt Christensen, PhD Leslie Frankel, PhD Anne Hansen, MD, MPH Lise Johnson, MD Joel Krier, MD
Co-Investigators, continued Harvey Levy, MD Philip Lupo, PhD David Miller, MD, PhD Patrice Milos, PhD Ann Poduri, MD Steve Ringer, MD, PhD Amy Roberts, MD Jason Vassy, MD, MPH Susan Waisbren, PhD Louise Wilkins-Haug, MD, PhD Matt Lebo, PhD Consultants George Church, PhD Lisa Diller, MD Dmitry Dukhovny, MD, MPH Steve Joffe, MD, MPH Peter Kraft, PhD Michelle Lewis, MD, JD David Margulies, MD, PhD Neela Sahai, MD
Advisory Board Bruce Korf, MD, PhD (Chair) Les Biesecker, MD Steve Cederbaum, MD Alex Kemper, MD, MPH Zak Kohane, MD, PhD Lou Kunkel, PhD Jim Lupski, MD, PhD Sharon Terry, MA Chris Walsh, MD, PhD Staff Lindsay Feuerman Christina Liu Ali Noorbaksh Jill Robinson, MA
Thank you!