Selecting the right genes to report in newborn genomic sequencing: The BabySeq Project

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1 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

2 Genomic sequencing in newborns Opportunities Challenges

3 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?

4 Project Overview Pre-Enrollment Genetic Counseling, Consent, Blood Draw, Family History with Genetic Counselor 240 Healthy Newborns at BWH and Parents Standard NBS Family History Randomization Standard NBS Family History Genome Report 240 Newborns in NICU at BCH and Parents Standard NBS Family History Randomization 10-month Follow-up Consultation and Exam with Study Physician and Genetic Counselor Standard NBS Family History Genome Report Optional: Indication-Based Analysis 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. Outcomes collected. Study Physicians and GCs available for questions from parents, NICU MDs and outside MDs Medical Record Review

5 Two reporting strategies Genomic Newborn Sequencing Report Well newborn nursery NICU Risk for childhood-onset disease Carrier status for childhood-onset disease Pharmacogenomic (relevant to pediatrics) Blood type Indication Based Analysis Genes associated with the infant s clinical features Option to query PGx variants related to the infant s care

6 Criteria for including a variant in a BabySeq report Pathogenic Likely pathogenic Uncertain significance Likely benign Benign Genomic Newborn Sequencing Report Indication Based Analysis

7 Criteria for including a gene in a BabySeq report GNSR IBA Specific disease suspected Strong Moderate Limited Gene-disease evidence level High Moderate Low Penetrance Childhood Adulthood Age of onset

8 MedSeq Genome Filtering Approach Applied to BabySeq Initial Filters Curated Exclusion Datasets >5 million variants HGMD ClinVar >5% Novel LOF Medical exome >1% ~ variants <60 A B variants C variants Gene exclusions 10% in WGS Cases Variant exclusions 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 Data Set C - Variant Exclusions Benign interpretation LOF but LOF not disease mechanism GWAS or PGx association only Heidi Rehm Being addressed for BabySeq before launch

9 Identifying genes to be reported on GNSR GNSR criteria: High evidence to cause highly penetrant childhood-onset disease ~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

10 ClinGen Clinical Validity Classifications Evidence level for a causal role in disease DEFINITIVE STRONG MODERATE LIMITED NO EVIDENCE DISPUTED EVIDENCE AGAINST Criteria Role of gene in disease repeatedly demonstrated for multiple pathogenic variants AND Upheld 3 years Multiple families with pathogenic variants AND Supporting functional data AND 2 independent reports 3 families with reasonably pathogenic variants reported AND Supporting functional data <3 families with reasonably pathogenic variants reported OR Multiple variants without sufficient evidence for pathogenicity No reported evidence for a causal role in disease Valid evidence refuting a role in disease equivalent or stronger than evidence supporting this role Evidence refuting role in disease significantly outweighs evidence supporting this

11 Curating age of onset, penetrance and actionability Age of onset: Has the disease / gene / variant ever been reported in childhood? 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 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?

12 1,566 gene-disease associations curated so far 22% 0.1% 10% 34% 4% 5% 10% 13% 3% 0.3% 33% 81% 84% Evidence level for causal role in disease Earliest reported age of onset Penetrance 906 genes meet GNSR reporting criteria

13 Should they be reported in GNSR? Childhood-onset Strong evidence High penetrance Moderate evidence/penetrance but clinically actionable in childhood Carriers at risk for adult-onset disease Mixed presentation Adult-onset Limited evidence Low penetrance Will be reported Need to discuss! Will not be reported

14 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

15 Indication Based Analysis OMIM Literature HGMD KEGG database Indication-based gene list Phenomizer GeneReviews Expert review GeneTests

16 Common NICU indications with potential genetic basis Clinical presentation Number of genes in indicationbased 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 Bowel hypomotility / obstruction Seizures Hyperbilirubinemia Hypoglycemia Hypothyroidism Hearing loss Anemia Thrombocytopenia Inborn errors of metabolism Neonatal respiratory distress Hypotonia Renal dysplasia Neonatal diabetes mellitus Skeletal dysplasia Dermatological disorders Thrombophilia Multiple anomalies N/A All indications with gene panels prepared in advance Total 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

17 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

18 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

19 Thank you!