REMOTE DELIVERY OF GENOMIC

INFORMATION & GENETIC

COUNSELING:

A NEW DISCIPLINE IN

TELEMEDICINE?SHRIKANT MANE, PHD

DIRECTOR, YALE CENTER FOR GENOME

ANALYSIS

PETROS TSIPOURAS, MD

DEPARTMENT OF GENETICS

YALE UNIVERSITY

GENETIC DIAGNOSIS BY WHOLE

EXOME CAPTURE AND MASSIVELY

PARALLEL DNA SEQUENCING:

CHOI ET AL. PNAS: 2009

• DNA samples were collected and prepared for sequencing

• Identified homozygous missense D652N mutation at a position in

SLC26A3 gene that is known to be associated with congenital chloride

diarrheas.

STAS Cl/HCO3

exchanger

First report on making a clinical diagnosis using, whole exome capture and next-generation high throughput DNA sequencing

• 5 month child

presented with failure

to thrive & dehydration

• Treatments for kidney

disease failed

YALE CENTER FOR GENOME ANALYSIS

3

Established in January 2010

11 Illumina HiSeqs, Pacific Biosciences, PGM and Ion Proton

Dell Cluster with 200 nodes/2500 cores and 3 Petabytes storage

25 Full time staff ( 7 PhDs, 2 MDs, 5 with MS degrees)

Select publications resulting from Next-Generation Sequencing at

YCGA

Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Bilguvar and

Gunel

Nature, v467, 2010

A Novel miRNA Processing Pathway Independent of Dicer Requires Argonaute2 Catalytic Activity. Cifuentes

and Giraldez

Science, v328, 2010

Mitotic recombination in patients with ichthyosis causes reversion of dominant mutations in KRT10. Choate K Science, v330, 2010

Transcriptomic analysis of avian digits reveals conserved and derived digit identities in birds. Wang et al Nature, v477, 2011

Transposom-mediated rewiring of gene regulatory networks contributed to the evolution of pregnancy in

mammals. Lynch and Wagner

Nature, Genet. v43, 2011

K+

channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Choi M Science, v331, 2011

Recessive LAMC3 mutations cause malformations of occipital cortical development. Barak and Gunel. Nat Genet., V43, 2011

Spatio-temporal transcriptome of the human brain. Kang and Sestan Nature, v478, 2011

Langerhans cells facilitate epithelial DNA damage and squamous cell carcinoma. Modi and Girardi Science, v335, 2012

Mutations in kelch-like 3 and cullin 3 causes hypertension and electrolyte abnormalities. Boyden et al Nature, v482, 2012

De novo point mutations, revealed by whole-exome sequencing, are strongly associated with Autism Spectrum

Disorders. Sanders and State

Nature, v485, 2012

Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Krauthammer Nat Genet., V44, 2012

Genomic Analysis of Non-NF2 Meningiomas Reveals Mutations in TRAF7, KLF4, AKT1, and SMO. Clark and

Gunel

Science, v339, 2013

De novo mutations in histone-modifying genes in congenital heart disease. Zaidi and Lifton Nature, v498, 2013

Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Lemaire and Lifton Nat Genet., V45, 2013

Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary

aldosteronism. Scholl and Lifton

Nat Genet., V45, 2013

The evolution of lineage-specific regulatory activities in the human embryonic limb. Cotney and Noonan Cell, v154, 2013

Mutations in DSTYK and dominant urinary tract malformations. Sanna-Cherchi and Gharavi N Eng J Med., 2013

Nanog, Pou5f1 and SoxB1 activate zygotic gene expression during the maternal-to-zygotic transition. Lee and

Giraldez

Nature, 2013

Co-expression networks implicate human mid-fetal deep cortical projection neurons in the pathogenesis of

autism. Willsey and State

Cell, 2013 (In press)

CLINICAL USES OF GENOME

SEQUENCING

Cancer: sequence tumors to guide initial Rx and Rx of recurrent disease

Inherited susceptibilities

Solve clinical mysteries

Newborn screening?

Genome sequencing at birth?

YCGA is carrying out clinical diagnostic work in collaboration with Dr. Allen Bale

Over 700 exomes are analyzed for various disorders

2014 marks the first time when demand for genetic counselors outstripped supply in the

United States. The quick spread of genetic testing is accelerating this need and creating

pressure for scalable solutions.

GENETIC TESTING: COUNSELORS

WIDELY NEEDED

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WHAT IS GENETIC COUNSELING?

“Genetic counseling is the process of helping people

understand and adapt to the medical, psychological,

and familial implications of genetic contribution to

disease. This process integrates the following:

Interpretation of family and medical histories to assess

the chance of disease occurrence or recurrence.

Education about inheritance, testing, management,

prevention, resources and research. Counseling to

promote informed choices and adaptation to the risk or

condition.”

National Society of Genetic Counselors’ Definition Task Force

J. Genet Couns 2006,15, 77-83

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Phone counseling sessions

CURRENT EXAMPLES OF REMOTE GENETIC

COUNSELING

8

Strand remote counseling and sample collection room

at the Mazumdar Shaw Medical Center

Video counseling sessions

BUILDING A SCALABLE SOLUTION

Research on the use of an interactive computer program prior to genetic counseling showed the combination to be more effective than

standard genetic counseling for increasing knowledge of genetic testing

Resulted in significantly shorter counseling sessions

Shifted the focus of counseling session away from basic education toward personal risk and decision-making

9

Green, M. J., Peterson, S. K., Baker, M. W., Harper, G. R., Friedman, L. C., Rubinstein, W.S., & Mauger, D.

T. (2004). Effect of a computer-based decision aid on knowledge, perceptions, and intentions about genetic

testing for breast cancer susceptibility. Journal of the American Medical Association, 292(4), 442-452.

ENHANCING COUNSELING EFFICIENCY

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Counseling Session

Consenting

Family History

Communicating Next Steps

Interpreting Results

Setting Expectations

Prime areas for

technological

disruption short-

term

Future automation

goal

BUILDING A COMPREHENSIVE

SOLUTION

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Physician refers

patient to platform

and authorizes

lab to process sample

Patient gains

access to tracking

information, educational materials

and counseling

tools

Lab processes

sample and updates its progress to

all stakeholder

s

Genetic Report is generated and sent to physician,

who engages counselor for patient

Genetic Counselor can access

patient information and focus session on dynamic decision-making process

Physician

Links patient medical information

Refers the patient into portal

Can connect directly to lab and counselors

Receives genetic report

Can access continuing education materials

BUILDING A ROBUST SOLUTION

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BUILDING A ROBUST SOLUTION

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Patient

Creates personal profile and family history

Can access personalized educational materials

Makes expectations explicit and signs consents

Access to scheduling tools

Connects with a genetic counselor

BUILDING A ROBUST SOLUTION

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Genetic Counselor

Reviews patient information, family history and lab report

Works with physician on patient plan

Engages patient on what the information means

Provides guidance on appropriate next steps

Share and access database of best practices

DEVELOPMENT PLAN

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Technology Infrastructure

Content Development

Logistics Management

User Testing

PLATFORM BENEFITS

Technology can be licensed and used by multiple

stakeholders

Library of content forms basis of sustainable competitive

advantage

Network effects create incentives for continued use by

physicians and patients

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THE FUTURE

Complete automation through an intelligent system

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Physician refers

patient to platform

and authorizes

lab to process sample

Patient gains

access to tracking

information, educational materials

and counseling

tools

Lab processes

sample and updates its progress to

all stakeholder

s

Genetic Report is generated and sent to physician,

who releases

information to patients in online system

Sophisticated and robust

algorithms guide the patients through

results and actionable next steps

PARTNERS/COLLABORATORS

Krishnan Ganapathy, MD

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Petros Tsipouras, MD

Shrikant Mane, PhD

Michael Krauthammer, MD, PhD

Paddaiah Gangisetti, PhD

Elissa Levin, MS

Eric Schadt, PhD

Priscila Bala, MBA

Vijay Chandru, PhD