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Genomics	
  for	
  Rare	
  
Diseases
Dr.	
  Anna	
  Lehman
Provincial	
  Medical	
  Genetics	
  Program
Adult	
  Metabolic	
  Diseases	
  Clinic
Department	
  of	
  Medical	
  Genetics
BC	
  Children’s	
  Hospital	
  Research	
  Institute
Definitions
• Rare	
  Disease:	
  affecting	
  fewer	
  than	
  1	
  in	
  2000	
  people
• Mendelian	
  disease:	
  simple,	
  predictable	
  genetics
Not	
  all	
  Mendelian	
  diseases	
  are	
  Rare
• Familial	
  Hypercholesterolemia	
  (1	
  in	
  500)	
  Austin,	
  Am	
  J	
  Epidemiol	
  2004;160:407–420
• Familial	
  Cardiomyopathies	
  (Hypertrophic: 1	
  in	
  500;	
  Dilated: 1	
  in	
  500)	
  Gene	
  Reviews
• Hereditary	
  Cancer	
  (HBOC:	
  1	
  in	
  400;	
  Lynch	
  1	
  in	
  440)	
  Gene	
  Reviews,	
  2017
• Nonsyndromic Intellectual	
  Disability	
  (~	
  1	
  in	
  100)	
  my	
  estimate
Not	
  all	
  rare	
  diseases	
  are	
  Mendelian
• Polymyositis	
  (prevalence	
  1	
  in	
  14,000)
• Childhood	
  leukemia	
  (incidence	
  1	
  in	
  20,000)
• Congenital	
  diaphragmatic	
  hernia	
  (incidence	
  1	
  in	
  2500)
Rare	
  Diseases	
  are	
  Common
• 1	
  in	
  3	
  children	
  admitted	
  to	
  BCCH	
  
have	
  a	
  rare	
  genetic	
  disease.
• More	
  than	
  1,500	
  rare	
  diseases	
  do	
  not	
  have	
  a	
  known	
  cause.
• Too	
  often,	
  children	
  and	
  families	
  affected	
  by	
  rare	
  diseases	
  must	
  
undertake	
  a	
  frustrating,	
  time-­‐consuming,	
  expensive	
  and	
  painful	
  journey	
  
in	
  search	
  for	
  a	
  diagnosis	
  – the	
  “diagnostic	
  odyssey”.
Rare	
  Diseases	
  Kill
January	
  7th,	
  2017 4,919confirmed	
  genetic	
  disorders
(phenotype	
  and	
  known	
  gene)
Heterogeneic disorders	
  are	
  broken	
  down	
  into	
  subtypes	
  for	
  each	
  different	
  gene
Growing	
  focus	
  on	
  genetic	
  subtypes,	
  because	
  many	
  new	
  therapies	
  are	
  gene-­‐specific,	
  
or	
  even	
  mutation	
  specific
Retinitis	
  Pigmentosa
An	
  endpoint	
  disease	
  resulting	
  from	
  many	
  different	
  molecular	
  mechanisms
National	
  Eye	
  Institute
67	
  genes	
  responsible	
  and	
  counting
(RetNet)
1	
  in	
  3500	
  prevalence
Genetic	
  diagnostic	
  rate	
  2010:	
  50%
(Berger	
  et	
  al	
  2010)
Genetic	
  diagnostic	
  rate	
  2015:	
  65%
Source:	
  RetNet
Test SNVs Indels CNVs Structural	
  rearrangement
Sanger	
   ✔ ✔ ✗ ✗
MLPA ✗ ✗ ✔ ✗
Next	
  Gen	
  panel ✔ ✔ ✗ ✗
Array ✗ ✗ ✔ ✗
Whole	
  genome	
  
sequencing
✔ ✔ ✔ ✔
Genetic	
  Testing:	
  Faster,	
  Cheaper,	
  Better
First	
  medical	
  exome
• Wisconsin
• Late	
  2009
• $100,000
• Life-­‐saving	
  diagnosis
11
Panel	
  or	
  Exome?
• Previously,	
  panels	
  had	
  a	
  major	
  advantage	
  of	
  allowing	
  virtually	
  
complete	
  sequencing	
  coverage	
  of	
  all	
  exons	
  (usually).
• Now,	
  a	
  high-­‐end	
  exome	
  can	
  provide	
  similar	
  coverage.	
  
• So	
  main	
  reason	
  to	
  rely	
  on	
  panels	
  as	
  much	
  as	
  possible	
  is	
  cost.	
  
• A	
  panel	
  $1	
  – 3K	
  and	
  a	
  trio	
  exome	
  is	
  $6K	
  – 11K
• Second	
  reason	
  to	
  use	
  panel	
  is	
  to	
  avoid	
  VUS	
  and	
  IFs
When	
  to	
  order	
  an	
  exome
• Very	
  broad	
  differential	
  (eg.,	
  
intellectual	
  disability	
  /	
  
developmental	
  delay)
• “Weird”	
  presentation	
  (maybe	
  
more	
  than	
  one	
  diagnosis)
• You	
  need	
  a	
  1	
  week	
  turn	
  around	
  
time
• You	
  won’t	
  be	
  satisfied	
  by	
  a	
  
negative	
  result-­‐-­‐-­‐you	
  want	
  to	
  
discover	
  novel	
  genes	
  in	
  the	
  
sequence	
  data	
  yourself
• Disease	
  discovery	
  pace	
  is	
  so	
  fast	
  
right	
  now,	
  your	
  disease	
  panel	
  
will	
  be	
  outdated	
  in	
  a	
  year.
14
What’s	
  Next?	
  Resolving	
  uncertainty
Am	
  J	
  Hum	
  Genet.	
  2016	
  Jun 2;	
  98(6):	
  1067–1076.
651 kids	
  considered	
  for	
  
exome	
  sequencing
401 approved	
  (total	
  will	
  be	
  500)
107 exomes	
  complete
56 diagnoses	
  made	
  (52%)
28 have	
  mutations	
  in	
  
new	
  candidate	
  genes	
  
• Fewer	
  invasive	
  tests
• More	
  effective	
  therapy
• Anticipatory	
  screening
51	
  kids	
  remain	
  undiagnosed
CAUSES	
  Clinic
as	
  of	
  September	
  2016
• Two	
  siblings	
  not	
  growing	
  well	
  &	
  behind	
  in	
  development
• Both	
  had	
  abnormal	
  urine	
  biochemical	
  profile	
  with	
  results	
  
suggestive	
  of	
  beta	
  ureidopropionase deficiency	
  – but	
  
sequencing	
  of	
  UPB1	
  gene	
  – negative	
  – del/dup	
  negative
• MRI	
  – nonspecific	
  ventriculomegaly
• Chromosomal	
  microarray	
  normal
16
Sibling
wt: 74
v:       45
TKT
(transketolase)
NM_001135055.2:c.1690_1692delTAT
NP_001128527.1:p.Tyr564del
autosomal recessive =  compound heterozygous
Child
wt:      73
v: 43
Mother
wt: 52
v:          62
SHORT STATURE,  
DEVELOPMENTAL DELAY,  AND  
CONGENITAL HEART DEFECTS
• developmental delay
• global  developmental  delay
• microcephaly
Child’s  phenotypeDisease  phenotype
Father
wt: 120
v:       0
Functional  impact
• PROVEAN Genome  Variants  
Result  (human37_66)  prediction  
is  deleterious
• This  variant  results  in  a  single  
amino  acid  deletion  564  of  623  
in  exon  13  of  15.
Population  frequency
• 0 in-­house
• In  ExAC
• 6/121,242  alleles
• 0  homozygous
• African >MAF=9.612e-­05
• Not  in  DECIPHER or LOVD
Sibling
wt: 84
v:       70
TKT
(transketolase)
NM_001135055:exon9:c.1202G>A:p.R401H
autosomal recessive =  compound heterozygous
Child
wt:      82
v: 55
Mother
wt: 126
v:              0
SHORT STATURE,  
DEVELOPMENTAL DELAY,  AND  
CONGENITAL HEART DEFECTS
• developmental delay
• global  developmental  delay
• microcephaly
Child’s  phenotypeDisease  phenotype
Father
wt: 61
v:       66 Functional  impact
• 4/4  in  silico programs  predict  an  
impact
• CADD=35
Population  frequency
• 0 in-­house
• Not  in  dbSNP,  EVS,  or  ExAC
• Not  in  DECIPHER or LOVD
19
20
How	
  much	
  evidence	
  is	
  needed	
  for	
  a	
  gene	
  to	
  be	
  
included	
  in	
  the	
  clinome?
• One	
  published	
  patient?
• Ten	
  patients	
  in	
  a	
  database?
• A	
  mouse?
• A	
  Western	
  blot?
• A	
  luciferase	
  assay?
• An	
  odds	
  ratio?
21
What	
  if	
  it	
  is	
  only	
  a	
  susceptibility	
  gene?
The	
  Deciphering	
  Developmental	
  Disorders	
  Study
• 1,133	
  children	
  with	
  severe,	
  undiagnosed	
  developmental	
  
disorders,	
  and	
  their	
  parents,	
  underwent	
  a	
  combination	
  of	
  
exome	
  sequencing and	
  microarray
• As	
  of	
  December	
  2014,	
  a	
  genetic	
  cause	
  had	
  been	
  found	
  for	
  31%
• The	
  study	
  went	
  on	
  to	
  recruit	
  14,000	
  probands
Nature 519, 223–228,	
  2015
23
DDD	
  findings
April	
  2016	
  
Analysis	
  of	
  >4000	
  probands
RDD Conf Day 1: Genomics for Rare Diseases Dr. Anna Lehman
RDD Conf Day 1: Genomics for Rare Diseases Dr. Anna Lehman
RDD Conf Day 1: Genomics for Rare Diseases Dr. Anna Lehman
RDD Conf Day 1: Genomics for Rare Diseases Dr. Anna Lehman
RDD Conf Day 1: Genomics for Rare Diseases Dr. Anna Lehman
RDD Conf Day 1: Genomics for Rare Diseases Dr. Anna Lehman
RDD Conf Day 1: Genomics for Rare Diseases Dr. Anna Lehman
RDD Conf Day 1: Genomics for Rare Diseases Dr. Anna Lehman
$6ooo
What’s	
  Next?	
  Better	
  variant	
  calling
What’s	
  Next?	
  	
  	
  	
  	
  Genome	
  Diversity
RDD Conf Day 1: Genomics for Rare Diseases Dr. Anna Lehman
RDD Conf Day 1: Genomics for Rare Diseases Dr. Anna Lehman
Or,	
  alt.	
  title:	
  “75	
  million	
  new	
  dbSNP entries,	
  and	
  time	
  for	
  an	
  Hg	
  update”
RDD Conf Day 1: Genomics for Rare Diseases Dr. Anna Lehman
Resolving	
  a	
  VUS
1. Decide	
  if	
  segregation	
  studies	
  in	
  your	
  family	
  will	
  be	
  
meaningfully	
  helpful.	
  Of	
  course,	
  for	
  many	
  conditions	
  with	
  
incomplete	
  penetrance,	
  you’re	
  really	
  only	
  wanting	
  to	
  test	
  
clearly	
  affecteds.	
  
2. Consider	
  doing	
  parents	
  (determine	
  if	
  cis or	
  trans	
  for	
  AR;	
  de	
  
novo	
  for	
  AD)
3. Consider	
  functional	
  studies
4. Wait	
  and	
  re-­‐visit	
  the	
  literature

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RDD Conf Day 1: Genomics for Rare Diseases Dr. Anna Lehman

  • 1. Genomics  for  Rare   Diseases Dr.  Anna  Lehman Provincial  Medical  Genetics  Program Adult  Metabolic  Diseases  Clinic Department  of  Medical  Genetics BC  Children’s  Hospital  Research  Institute
  • 2. Definitions • Rare  Disease:  affecting  fewer  than  1  in  2000  people • Mendelian  disease:  simple,  predictable  genetics
  • 3. Not  all  Mendelian  diseases  are  Rare • Familial  Hypercholesterolemia  (1  in  500)  Austin,  Am  J  Epidemiol  2004;160:407–420 • Familial  Cardiomyopathies  (Hypertrophic: 1  in  500;  Dilated: 1  in  500)  Gene  Reviews • Hereditary  Cancer  (HBOC:  1  in  400;  Lynch  1  in  440)  Gene  Reviews,  2017 • Nonsyndromic Intellectual  Disability  (~  1  in  100)  my  estimate
  • 4. Not  all  rare  diseases  are  Mendelian • Polymyositis  (prevalence  1  in  14,000) • Childhood  leukemia  (incidence  1  in  20,000) • Congenital  diaphragmatic  hernia  (incidence  1  in  2500)
  • 5. Rare  Diseases  are  Common • 1  in  3  children  admitted  to  BCCH   have  a  rare  genetic  disease. • More  than  1,500  rare  diseases  do  not  have  a  known  cause. • Too  often,  children  and  families  affected  by  rare  diseases  must   undertake  a  frustrating,  time-­‐consuming,  expensive  and  painful  journey   in  search  for  a  diagnosis  – the  “diagnostic  odyssey”.
  • 7. January  7th,  2017 4,919confirmed  genetic  disorders (phenotype  and  known  gene) Heterogeneic disorders  are  broken  down  into  subtypes  for  each  different  gene Growing  focus  on  genetic  subtypes,  because  many  new  therapies  are  gene-­‐specific,   or  even  mutation  specific
  • 8. Retinitis  Pigmentosa An  endpoint  disease  resulting  from  many  different  molecular  mechanisms National  Eye  Institute 67  genes  responsible  and  counting (RetNet) 1  in  3500  prevalence Genetic  diagnostic  rate  2010:  50% (Berger  et  al  2010) Genetic  diagnostic  rate  2015:  65%
  • 10. Test SNVs Indels CNVs Structural  rearrangement Sanger   ✔ ✔ ✗ ✗ MLPA ✗ ✗ ✔ ✗ Next  Gen  panel ✔ ✔ ✗ ✗ Array ✗ ✗ ✔ ✗ Whole  genome   sequencing ✔ ✔ ✔ ✔ Genetic  Testing:  Faster,  Cheaper,  Better
  • 11. First  medical  exome • Wisconsin • Late  2009 • $100,000 • Life-­‐saving  diagnosis 11
  • 12. Panel  or  Exome? • Previously,  panels  had  a  major  advantage  of  allowing  virtually   complete  sequencing  coverage  of  all  exons  (usually). • Now,  a  high-­‐end  exome  can  provide  similar  coverage.   • So  main  reason  to  rely  on  panels  as  much  as  possible  is  cost.   • A  panel  $1  – 3K  and  a  trio  exome  is  $6K  – 11K • Second  reason  to  use  panel  is  to  avoid  VUS  and  IFs
  • 13. When  to  order  an  exome • Very  broad  differential  (eg.,   intellectual  disability  /   developmental  delay) • “Weird”  presentation  (maybe   more  than  one  diagnosis) • You  need  a  1  week  turn  around   time • You  won’t  be  satisfied  by  a   negative  result-­‐-­‐-­‐you  want  to   discover  novel  genes  in  the   sequence  data  yourself • Disease  discovery  pace  is  so  fast   right  now,  your  disease  panel   will  be  outdated  in  a  year.
  • 14. 14 What’s  Next?  Resolving  uncertainty Am  J  Hum  Genet.  2016  Jun 2;  98(6):  1067–1076.
  • 15. 651 kids  considered  for   exome  sequencing 401 approved  (total  will  be  500) 107 exomes  complete 56 diagnoses  made  (52%) 28 have  mutations  in   new  candidate  genes   • Fewer  invasive  tests • More  effective  therapy • Anticipatory  screening 51  kids  remain  undiagnosed CAUSES  Clinic as  of  September  2016
  • 16. • Two  siblings  not  growing  well  &  behind  in  development • Both  had  abnormal  urine  biochemical  profile  with  results   suggestive  of  beta  ureidopropionase deficiency  – but   sequencing  of  UPB1  gene  – negative  – del/dup  negative • MRI  – nonspecific  ventriculomegaly • Chromosomal  microarray  normal 16
  • 17. Sibling wt: 74 v:       45 TKT (transketolase) NM_001135055.2:c.1690_1692delTAT NP_001128527.1:p.Tyr564del autosomal recessive =  compound heterozygous Child wt:      73 v: 43 Mother wt: 52 v:          62 SHORT STATURE,   DEVELOPMENTAL DELAY,  AND   CONGENITAL HEART DEFECTS • developmental delay • global  developmental  delay • microcephaly Child’s  phenotypeDisease  phenotype Father wt: 120 v:       0 Functional  impact • PROVEAN Genome  Variants   Result  (human37_66)  prediction   is  deleterious • This  variant  results  in  a  single   amino  acid  deletion  564  of  623   in  exon  13  of  15. Population  frequency • 0 in-­house • In  ExAC • 6/121,242  alleles • 0  homozygous • African >MAF=9.612e-­05 • Not  in  DECIPHER or LOVD
  • 18. Sibling wt: 84 v:       70 TKT (transketolase) NM_001135055:exon9:c.1202G>A:p.R401H autosomal recessive =  compound heterozygous Child wt:      82 v: 55 Mother wt: 126 v:              0 SHORT STATURE,   DEVELOPMENTAL DELAY,  AND   CONGENITAL HEART DEFECTS • developmental delay • global  developmental  delay • microcephaly Child’s  phenotypeDisease  phenotype Father wt: 61 v:       66 Functional  impact • 4/4  in  silico programs  predict  an   impact • CADD=35 Population  frequency • 0 in-­house • Not  in  dbSNP,  EVS,  or  ExAC • Not  in  DECIPHER or LOVD
  • 19. 19
  • 20. 20
  • 21. How  much  evidence  is  needed  for  a  gene  to  be   included  in  the  clinome? • One  published  patient? • Ten  patients  in  a  database? • A  mouse? • A  Western  blot? • A  luciferase  assay? • An  odds  ratio? 21 What  if  it  is  only  a  susceptibility  gene?
  • 22. The  Deciphering  Developmental  Disorders  Study • 1,133  children  with  severe,  undiagnosed  developmental   disorders,  and  their  parents,  underwent  a  combination  of   exome  sequencing and  microarray • As  of  December  2014,  a  genetic  cause  had  been  found  for  31% • The  study  went  on  to  recruit  14,000  probands Nature 519, 223–228,  2015
  • 23. 23
  • 25. April  2016   Analysis  of  >4000  probands
  • 34. $6ooo What’s  Next?  Better  variant  calling
  • 35. What’s  Next?          Genome  Diversity
  • 38. Or,  alt.  title:  “75  million  new  dbSNP entries,  and  time  for  an  Hg  update”
  • 40. Resolving  a  VUS 1. Decide  if  segregation  studies  in  your  family  will  be   meaningfully  helpful.  Of  course,  for  many  conditions  with   incomplete  penetrance,  you’re  really  only  wanting  to  test   clearly  affecteds.   2. Consider  doing  parents  (determine  if  cis or  trans  for  AR;  de   novo  for  AD) 3. Consider  functional  studies 4. Wait  and  re-­‐visit  the  literature