A Rare International Dialogue (Friday, May 10, 2019) Using Genomics to Match Rare Disease Patients to Therapies - Jan Friedman, University of British Columbia

1. Jan M. Friedman, MD, PhD
University of British Columbia
Vancouver, Canada

2. Phenotype
Genotype
The First Era

3. The First Era

4. The Second Era
Genotype
Phenotype
Phenotype
Genotype

5. The Second Era

6. 8326
CAM 126
5566
Zahir F, et al. J Med Genet 44:556, 2007
35 kb
Critical Region
The Second Era
Ch14

7. The Second Era
Zahir F, et al. J Med Genet 44:556, 2007

8. Phenotype Genotype?
Genotype Phenotype?
Genotype
Phenotype
The Third Era

9. Child
wt: 87
v: 95
Mother
wt: 100
v: 0
Father
wt: 151
v: 0
The Third Era

10. • Genome-wide sequencing
- Exome sequencing: looking
at all ~20,000 protein-
coding genes at once
- Whole genome sequencing:
looking at all 6,000,000,000
bp of DNA in the cells at
once
The Third Era

11. • Male infant admitted to NICU on
day 22 with intractable seizures
since day 5
• Product of an uncomplicated 36
week pregnancy and C-section
delivery for fetal distress
• Normal birth weight, length and
head circumference, normal
examination, no malformations
Patient R06

12. • Extensive investigations and
multiple specialist consultations
uninformative
• Exome sequencing undertaken
on day 32, returned on day 44:
pathogenic de novo mutation of
KCNT1, compatible with
malignant migrating partial
seizures of infancy (MMPSI)
Patient R06

13. • MMPSI extremely rare
• Severe form of epilepsy with
onset of frequent seizures within
a few weeks of birth
• Seizures usually do not respond
to conventional therapy
• Developmental progress stalls
with intractable seizures
Patient R06

14. • World experts in MMPSI
consulted, suggested treatment
with KBr (used as anticonvulsant
and sedative in late 19th and
early 20th centuries; not used in
past 40 years)
• Seizure frequency and duration
greatly reduced by treatment
Patient R06

15. • Female infant admitted to NICU
immediately after delivery
• Prenatal U/S diagnosis: bilateral
cataracts and enlarged heart
• Healthy term pregnancy and
repeat C-section delivery
• Normal birth weight, length and
head circumference; cataracts,
enlarged heart and liver, cyanosis
Patient R01

16. • Persistent metabolic acidosis,
and cardiac failure, suspected
mitochondrial disorder
• Poor response to ventilation,
metabolic cocktail, etc.
• Diagnosis of Sengers syndrome
suggested on basis of cataracts,
cardiomyopathy, and metabolic
acidosis
Patient R01

17. • Sengers syndrome: extremely
rare autsomal recessive disorder
with dismal prognosis
• Exome sequencing undertaken
on day 2, returned on day 9: two
pathogenic variants of AGK, one
maternal, one paternal;
compatible with Sengers
syndrome in child
Patient R01

18. • Parents, in consultation with
medical staff, requested
comfort care
• Child died on day 17
• Parents became pregnant again,
prenatal diagnosis showed
unaffected fetus, healthy
daughter born the following year
Patient R01

19. Genome-wide
sequencing is the key
to diagnosing rare
genetic diseases.

20. Genotype
Phenotype