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!