Alison  M.  Elliott,  PhD,  MS,  CGCClinical  Associate  Professor,  Dept  of  Medical  GeneticsUniversity  of  British  ColumbiaProject  Lead  – CAUSESCORD  – March  31,  2017

CAUSES  Genomic  sequencing  initiative  at  BC  Children’s  Hospital  Vancouver,  BC

Current  state  in  BC  wrt  GWS� Exome  Sequencing  (ES)  is  not  routinely  available  in  British  Columbia.  Physicians  submit  an  application  to  the  Medical  Services  Plan  (MSP)  and  funding  is  granted  in  restricted  situations.  

A  translational  research  program  at  BC  Children’s  Hospital  to  obtain  the  

evidence  needed  to  establish  genome-­‐wide sequencing  as  a  provincially-­‐funded  standard  of  care  for  children  

who  need  it.

What  is  the  CAUSES  Clinic?

CAUSES  Goals• N=500  families  over  3  years• Function  as  a  clinical  program• Study known  disease  genes• Research  to  generate  the  evidence  to  

determine  the  need,  utility,  efficiency  of  GWS  in  clinical  setting

• With  appropriate  evidence  -­‐ convince  Medical  Services  Plan  to  fund  as  a  clinical  test

• Improve  health  outcomes  of  BC  children

CAUSES  Patients  

Pediatric  patients  who  are  most  likely  to  benefit  from  receiving  a  specific  genetic  diagnosis  receive  priority  for  testing,  and  those  for  whom  DNA  is  available  for  both  parents.

Referral sent with relevant clinical information

Alternate Advice for testing

Consult letter sent to referring MD

Research VisitGenetic Counselling

Physical Examination

Sequencing & bioinfomatics

Clinical Interpretation with CAUSES team and referring

MD

Sanger validation –

clinical report

Revisit genomic data

Eligible for other research

Follow-up with familyGenetic CounsellingNo Diagnosis

Genomic Consultation

CAUSES - TREATING OUR FAMILIES

DiagnosisFollow-up with familyGenetic Counselling

New management plan

The  CAUSES  Team

Extended  Team�Referring  physicians  –representatives  from  each  discipline

�Molecular  genetics  laboratory  specialists  and  technicians

�Bioinformatics  specialists�Health  economics,  health  services,  and  genetic  counselling  researchers

Families  Seen  in  Clinic

�Opened  our  doors  in  June  2015�Over  240  families  have  been  seen  for  pre-­‐test  genetic  counselling

�183  families  have  been  sequenced�An  additional  50  families  recently  sent  for  sequencing

CAUSES:  First  100  Families�During  the  first  year,  130  families  were  seen  for  pre-­‐test  genetic  counselling  

�Began  returning  results  back  to  families  in  December  2015

�By  the  time  the  100th family  was  sent  for  genome-­‐wide  sequencing,  407  genomic  consultations  were  received  and  processed  

Telehealth  (TH)� Involves  the  use  of  information  and  communication  technology  to  deliver  health  services  to  patients  over  distance

�Time  and  cost  of  travel  can  constitute  a  barrier  for  some  families  to  access  healthcare

�Although  TH  has  been  well  utilized  in  more  traditional  GC  encounters  (breast  cancer,  previously  advanced  maternal  age),  its  use  in  genomic  medicine  not  well  documented

http://diversitymd.com/telehealth-­‐increasingly-­‐used-­‐for-­‐mental-­‐health-­‐care/

Telehealth

Age  Distribution

Syndromic  ID  74%,  Isolated  ID  10%,  MCA  11%,  Organ  Dysfunction  5%

CAUSES:  Results  of  first  100  FamiliesClassification  – Research  results  (distinct  from  lab):�Definite�Probable  �Uncertain�Negative

Diagnostic  Hit  Rate�Definite/probable  diagnosis:  in  46%  �Patients  have  already  had  extensive  work  up  – most  CMA

�High  diagnostic  yield  compared  to  other  studies

�Contribution  of  Genomic  Consultation  Service  – enriches  pool  suitable  for  ES

�NonClinome  important

�Severe  intellectual  disability,  global  developmental  delay,  feeding  difficulties,  dysmorphic  features

https://www.bcchf.ca/stories/miracle-­‐stories/collyns-­‐doran/

Research�Health  Economics�Health  Implementation�Clinical  Utility�Genetic  Counselling

Benefits-­‐Research• Economic  and  health  services  studies  that  improve  care

• Genetic  counselling  research• Promotion  of  clinical  and  discovery  research  – Rare  Disease  Hub  – Dr.  Anna  Lehman  -­‐ BCCHRI

• International  collaboration  and  leadership

Benefits-­‐Families• Change  management  -­‐ Optimize  care• Anticipatory  guidance• Increase  understanding  – family  and  healthcare  

providers• Eliminate  need  for  additional  diagnostic  

testing/procedures,  visits  to  physicians• Improved  genetic  counselling  – recurrence  risk• Improved  access  to  support  services

Benefits-­‐Education/Training  • Physicians  and  other  practicing  health  professionals

• Medical  residents  and  speciality  fellows

• Genetic  counselling  students• Other  graduate  students  and  postdoctoral  fellows

GoalsTimeline

Referral sent to CAUSES with relevant clinical information

Advice for testinge.g. gene panel

Consult letter sent to referring MD with genomic guidance

If (-) investigationsWGS Route:

Clinical encounterGenetic counselling

Sequencing & bioinfomatics

Interpretation by CAUSES medical team, laboratory representative, pediatric

subspecialist & referring MD(s)

Diagnosis

Research

Follow-up with family with genetic counsellor

and referring MD(s)

New management plan implemented by referring care

team

No Diagnosis

Version Jan 15, 2015

Genomics Consult by CAUSES medical team

Research(reported

Timeline

Results(reported,(improvements(in(care

2015 2016 2017 2018

Clinic(Organization,(Protocols,(Approvals

Patients(evaluated(and(tested

Translational(research

Research(Planning,(Protocols,(Approvals

MSP(Approval

Project(Cost:(~$6,100,000

Mining(for(Miracles:(($3,000,000(

Funding(Partners:

Department of Pediatrics

Project  Funding

Mining  for  Miracles

Other  Funding  Partners:

� Global  developmental  delay,  growth  retardation,  multiple  café-­‐au-­‐lait  spots,  feeding  difficulties,  joint  hypermobility,  synophrys,  bilateral  ptosis

https://www.bcchf.ca/stories/miracle-­‐stories/griffin-­‐wilson/

Phenotype Gene DiagnosisSevere  intellectual  disability, global  

developmental  delay,  feeding  difficulties,  dysmorphic  features

ASXL3Bainbridge-­‐Ropers  syndrome

Autosomal  dominant

Siblings  with  congenital  cataracts,  erythematous  and  telangiectatic  skin  

changes,  short  statureRECQL2

Werner  syndromeAutosomal  recessive

46,  XY  complete  gonadal dysgenesisSRY  positive SRY/NR5A1 Gonadal dysgenesis

Y-­‐linked/Autosomal  Dominant

MicrocephalyGlobal developmental  delay CAMK2G

Intellectual DisabilityAutosomal  dominant

Developmental delay,  hypotonia,  congenital  heart  defect,  dysmorphic  

facial  features ARID1BSyndromic and  Non  syndromic  ID  gene  (overlap  with  Coffin-­‐Siris  

syndrome)Autosomal  Dominant

Congenital  arthrogryposis,  truncal  hypotonia  and  peripheral  hypertonia,acquired  microcephaly,  intellectual  

disability

NALCNCLIFHAHDD  syndrome  (congenital    contractures  of  the  limbs  and  face,  

hypotonia,  and  developmental  delay)Autosomal  Dominant

Global  developmental  delay, growth  retardation,  multiple  café-­‐au-­‐lait  spots,  feeding  difficulties,  joint  hypermobility,  

synophrys,  bilateral  ptosisCBL

Noonan  syndrome-­‐like  disorder  with  or  without  juvenile  

myelomonocytic leukaemiaAutosomal dominant

Common  Themes/Genes

Phenotype Diagnosis

Moderate  intellectual  disability, small  stature,  

microcephaly,  dysmorphic  features

Global  developmental  delay,  Tetralogy  of  Fallot,  

dysmorphic  features

Autism,  mild intellectual  disability, sensorineural  hearing  loss,  decreased  

growth

Phenotype Diagnosis

Moderate  intellectual  disability, small  stature,  

microcephaly,  dysmorphic  features

EP300Rubinstein–Taybi  syndrome  (RTS)  -­‐2

Autosomal  dominant

Global  developmental  delay,  Tetralogy  of  Fallot,  

dysmorphic  features

Autism,  mild intellectual  disability, sensorineural  hearing  loss,  decreased  

growth

Phenotype Diagnosis

Mild  intellectual  disability, mild  joint  

hypermobility,  pulmonary  stenosis,  scoliosis,  hypotonia,  mild  dysmorphic  

features

Developmental  delay,  increased tone,  

nonspecific  white  matter  changes

Phenotype Diagnosis

Mild  intellectual  disability, mild  joint  

hypermobility,  pulmonary  stenosis,  scoliosis,  hypotonia,  mild  dysmorphic  

featuresDDX3XMental  

retardation,  X-­‐linked102

Developmental  delay,  increased tone,  

nonspecific  white  matter  changes

�GDD  and  hypotonia  in  both�Dysmorphic  features  in  both

�GDD  and  hypotonia  in  both�Dysmorphic  features  in  both

ARID1B

Inheritance�>70%  of  causal/likely  causal  variants  are  de  novo  (both  autosomal  dominant  and  X-­‐linked)

�Reinforces  importance  of  starting  with  trios

�Issue  of  Incidental  Findings

The  importance  of  genetic  counselling

Consent  for  GWS  (Burke  and  Clarke,  Arch  Dis  Child  2016)

�Family  history  – consider  potential  known  or  likely  genetic  disease

�Describe  method  being  used�Broad  description  of  categories  of  results  – pathogenic,  benign,  incidental  findings,  variants  of  unknown  significance

Consent  for  GWS  (Burke  and  Clarke,  Arch  Dis  Child  2016)

�Potential  need  for  biological  parental  samples  to  understand  implication  of  variant

�Potential  future  recontact  as  genetic  knowledge  and  understanding  improves

�Use  of  structured  consent  forms  and  information  leaflets  and  resources  to  support  information  sharing  and  decision-­‐making

Challenges�Consent  forms  should  be  patient  friendly�When  does  consent  become  uninformed  –length  of  consent  form

�Protocols  differ  from  centre  to  centre�Our  consent  form  is  currently  14  pages  –different  form  for  each  parent  and  proband

�Time  with  patient  – send  consents  ahead  of  appt

Incidental  Findings� Findings  (variants)  unrelated  to  primary  diagnosis

�Pathogenic  variants  that  could  alert  patients  and  providers  to  important  medical  conditions  not  previously  suspected  in  the  individual

CCMG  guidelines� “until  the  benefits  of  reporting  incidental  findings  are  established,  we  do  not  endorse  the  intentional  clinical  analysis  of  disease-­‐associated  genes  other  than  those  linked  to  the  primary  diagnosis”  (CCMG  position  statement,  Boycott  et  al.,  2015)

� CAUSES  -­‐ not  specifically  screening  for  incidental  findings,  parents  DNA  used  to  assist  in  the  analysis  of  child’s  test

So  how  do  we  handle  them?  �CAUSES  – pediatric  onset  medically  actionable  will  be  reported

�Adult  – adult-­‐onset  medically  actionable  – opt  in  or  opt  out

� “Actionable”  indicates  the  availability  of  a  therapy  that  credible  scientific  evidence  indicates  can  significantly  reduce  the  mortality  or  morbidity  of  disease

The  consenting  process� Families  will  be  counselled  that  we  are  not  specifically  screening  for  incidental  findings  in  the  child  and  that  the  parents’  DNA  will  be  used  to  assist  in  analysis  of  the  child’s  test  and  not  to  screen  for  other  disease-­‐related  variants.  

�Non-­‐paternity  will  not  be  disclosed.  

� Regarding  children  (and  incompetent  adults),  the  parents  /  guardian  will  be  informed  that  pathogenic  incidental  findings  will  be  reported  back  for  actionable  disorders  that  may  have  childhood  onset  of  symptoms.    Examples  include  disorders  such  as:  Neurofibromatosis  Type  1,  Beckwith-­‐Weidemann,  Long  QT  syndrome.  

�The  parents/guardian  will  be  informed  that  we  will  not  disclose  the  status  of  exclusively  adult-­‐onset  risk  alleles  in  children.  

�Adult  participants  will  be  given  the  option  for  receipt  of  pathogenic  incidental  findings  related  to  medically  actionable  conditions.  “Actionable”  for  our  purposes  indicates  the  availability  of  a  therapy  that  credible  scientific  evidence  indicates  can  significantly  reduce  the  mortality  of  morbidity  of  a  disease.  

What  about  carrier  status?�One  possible  special  scenario  is  the  finding  of  an  X-­‐linked  recessive  mutation  in  a  carrier  mother.  Actionability  in  this  scenario  would  relate  to  a  25%  risk  of  a  pregnancy  being  affected,  which  may  meaningfully  alter  pregnancy  planning.  

Carriers  and  IFs�In  contrast,  finding  that  only  one  parent  is  a  carrier  of  an  autosomal  recessive  condition  would  not  dramatically  increase  risk  of  having  an  affected  child,  and  this  would  not  be  reported  back  as  an  actionable  incidental  finding.  

CAUSES  Clinic  Consenting�1) The  primary  goal  of  this  study  to  identify  the  variants  in  a  patient’s  DNA  that  cause  the  genetic  disorder.  This  goal  will  be  accomplished  by  using  GWS.

�2) The  second  goal  is  to  study  the  healthcare  costs  associated  with  having  a  suspected  genetic  disorder.  This  goal  will  be  accomplished  by  performing  a  comprehensive  healthcare  economic  analysis  that  will  involve  reviewing    healthcare  records  and  related  data  resources.

�3) We  will  also  be  studying  the  effectiveness  of  an  online  educational  tool  to  assist  in  the  families’  decision  making  process.  

�4)  For  a  subset  of  patients,  we  will  compare  different  bioinformatic  approaches  to  analyzing  the  genomic  data  in  order  to  identify  the  most  effective  pipeline  for  identifying  disease-­‐causing  gene  changes  (also  known  as  causative  variants).

Options�Photography�Incidental  findings  (parent)�Future  Research�Biobanking  (proband)�DECIPHER

Results  -­‐ What  gets  reported  out?

�Analytical  validity  – Sanger  post  GWS�Clinical  Significance  – clinical  correlate� Importance  of  having  everyone  at  the  table  at  time  of  variant  discussion:

Referring/treating  physician,  bioinformatician,  molecular  geneticists,  clinical  research  team  –geneticists,  subspecialists  and  genetic  counsellors

•Follow  up  with  family  •CAUSES  Genetic counsellor  contacts  family•Revisit genomic  data  in  six  months

•And  this  is  effective!

When  there  is  no  variant  to  Sanger:

RAPIDOMICS:  Rapid  Genome-­‐wide  Sequencing  in  the  Neonatal  Intensive  Care  Unit

The  Need�Genetic  disorders  are  the  leading  cause  of  infant  mortality  and  are  highly  represented  in  neonatal  intensive  care  units  (NICUs)

�Lack  of  a  causal  genetic  diagnosis  problematic  with  respect  to  patient  management  and  outcome

�Ascertainment  of  genetic  disease  in  the  NICU    challenging  

�Full  clinical  phenotype  may  not  be  apparent,  

�Atypical  presentation  �Genetic  heterogeneity  is  common  for  known  conditions  and  serial  testing  of  individual  candidate  genes  or  gene  panels  may  be  unavailable  or  too  time  consuming  to  influence  treatment

�Kingsmore’s  group  performed  rapid  GWS  in  35  critically  ill  neonates  (Willig  et  al.,  Lancet  Respir  Med  2015)

�Results  available  as  early  as  5  days�57%  diagnosed  with  a  genetic  disease  through  GWS    versus  9%  by  conventional  genetic  testing

Current  State�Rapid  GWS  not  routinely  available  clinically  in  BC

�Performed  in  US  for  a  number  of  babies  recently  after  special  appeal  to  BC  Medical  Services  Plan�>CA$12,000  per  patient�Actionable  results  obtained  within  3-­‐7  days  for  all  babies

Goal�Gather  evidence  to  make  rapid  GWS  a  standard  of  care  in  BC  for  sick  newborn  infants  who  need  it

Rapidomics

�Pilot  project  to  sequence  25  trios  (neonate  plus  both  parents)

�Research  sequencing  through  collaboration  with  experienced  UBC  lab  (Dr.  Matthew  Farrer)

�Patient  identification:  Consultation  between  neonatologist  and  geneticist  –other  paediatric  subspecialists  involved  as  necessary

�Biochemical  Diseases�Genetics  – Dr.  Anna  Lehman�Genetic  counsellor  – Christele  du  Souich�Transfusions  – blood  in  EDTA  tube  prior�Coincide  with  MSP  funded  Exomes  for  some

Sequencing�By  end  of  week  one  – annotated  variant  list  to  be  discussed  by  RAPIDOMICS  and  NICU  team

�Causal  variant(s)  will  be  confirmed  by  clinical  Sanger  sequencing  (report  within  one  week)    

�N=12  families  enrolled

R# Presenting  Phenotype Exome  Results

R01Bilateral  cataracts,  cardiomyopathy,  non dysmorphic

Positive:  compound  heterozygous  variants in  AGK,  

Sengers  syndrome

R02IUGR,  microcephaly,  right  sided  hydronephrosis,  

hepatosplenomagaly,  persistent  thrombocytopenia,  transient  hypotension,  PDA  (resolved),  transient  hypoglycemia

Negative  

R03enlarged  cystic  kidneys,  low  set  ears,  postaxial  polydactyly  of all  

four  extremities

Positive:  2  pathogenic  variants  in  BBS4  gene,  Bardet-­‐Biedl  

syndrome

R05

postnatally:  enlarged  liver;  large  anterior  fontanelle;  wide  internipple  distance; dysmorphic  features:  downslanting  

palpebral  fissures; low  set,  small  ears;  large  nuchal  fold;  right  ventricular  hypertrophy; jittery;  short  

Positive:  pathogenic  de  novo  variant  in  RAF1,  Noonan  

syndrome

R06intractable  seizures,  non  dysmorphic

Positive:  KCNT1    pathogenic  variant,  Early  Infantile  Epileptic  

Encephalopathy

R07 multiple  pterygia,  vertebral  anomalies,  diaphragmatic  hernia,  macrocephaly,  hypertelorism,  low  set  ears,  webbed  neck,  

arthrogryposis,  scoliosis

Negative

R# Presenting  Phenotype Exome  Results

R08

intestinal  atresias  throughout  GI  tract,  ventricular  septal  heart  defect,  ectopic  kidney,  bilateral  renal  cystic  dysplasia,  non  dysmorphic,  severe

combined  immune  deficiency  *abnormal  CMA  result  (deletion  including  TTC7A  exons  12-­‐14,  13kb)  that  explains  SCID  and  GI  findings,  does  not  account  for  cardiac  and  

renal  findings

Negative

R09

multiple  congenital  anomalies:  heart  defect  with  dextrocardia  and  situs  inversus  totalis,  intra-­‐abdominal  heterotaxy,  midline  liver,  

bilateral  cleft  lip  and  palate

Negative

R10

multiple  congenital  anomalies:  single  right  kidney,  atrial  septal  defect,  simple,  abnormal  ears,  absent  septum  pellucidum,  choanal  atresia,  

coloboma,  triphalangeal  thumbs

Positive:  CHD7 pathogenic  de  novo  variant;  CHARGE

R11 central  hypotonia,  peripheral  hypertonia,  contractures,  hydrocephalus,  relative  macrocephaly,  dysplastic  undescended  right  

testis

Positive,  Sanger  validation  -­‐pending

So  far…� 6/11  – (54.5%)  diagnostic  rate� 4 -­‐ de  novo  autosomal  dominant,  2  – autosomal  recessive

� Trios  – important  – especially  when  considering  management  implications  and  turn  around  time

Research  – CAUSES  and  RAPIDOMICS� In  addition  to  cost  of  caring,  knowledge  and  modes  of  genetic  counselling

�Comparing  parental  attitudes  and  motivations  to  pursue  sequencing  in  pediatric  versus  NICU  populations  (GC  Student,  Emma  Smith)

�Comparing  uptake  of  sequencing�Comparing  uptake  of  IFs� Societal  GBC  grant  re.  parents  who  decline  GWS  in  NICU

� Wasserman  lab  – Dr.  Wyeth  Wasserman,  Allison  Mathews,  Phillip  Richmond  and  David  Arenillas

� CFRI  -­‐ IT  – Elodie  Portalas-­‐Casamar  and  Gurm  Dhugga� MGL – Michelle  Zhou  PHSA – Dr.  Sema  Aydede  � UBC – Dr.  Larry  Lynd

Inheritance

70%  of  variants  – de  novo,  17%  X-­‐linked,  5%  autosomal  recessive

�Acute  clinical  usefulness  noted  in  65%  of  patients  with  a  genomic  diagnosis� 20%  obtained  a  diagnosis  with  strongly  favourable  effects  on  management

� 30%    started  on  palliative  care