Genetics of Chiari Type 1 Malformation Christina Markunas Ph.D. Candidate Center for Human Genetics...
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Transcript of Genetics of Chiari Type 1 Malformation Christina Markunas Ph.D. Candidate Center for Human Genetics...
Genetics of Chiari Type 1 Malformation
Christina Markunas
Ph.D. CandidateCenter for Human Genetics
Duke University Medical Center
Outline
• Brief genetics review
• Why study the genetics of a disease?
• Why do we think CM1/S has a genetic component?
• What genetic approaches can we take?
• Discuss previous and current genetic studies of CM1
Outline
• Brief genetics review
• Why study the genetics of a disease?
• Why do we think CM1/S has a genetic component?
• What genetic approaches can we take?
• Discuss previous and current genetic studies of CM1
Genes
• Humans have >20,000 genes
• Instructions or blueprints for our body
• Receive ½ our genes from mom and ½ our genes from dad
• Genes produce proteins that help determine how we grow and develop
Why study the genetics of a disease?
• Development of genetic tests– More accurate and quicker diagnoses– Testing for at-risk family members
• Better understanding of disease mechanism
• Potential new therapies/treatments
Why do we think CM1 has a genetic component?
• Familial Clustering• Twin Studies• Co-segregation with known genetic syndromes• Heritability estimates of posterior fossa
measurements• Preliminary evidence from a linkage screen
Why do we think CM1 has a genetic component?
• Familial Clustering• Twin Studies• Co-segregation with known genetic syndromes• Heritability estimates of posterior fossa
measurements• Preliminary evidence from a linkage screen
Does the disorder run in families?
• We have 23 pairs of chromosomes– Receive ½ from mom
and ½ from dad• We have > 20,000 genes
Does the disorder run in families?
• We have 23 pairs of chromosomes– Receive ½ from mom
and ½ from dad• We have > 20,000 genes
Does the disorder run in families?
• We have 23 pairs of chromosomes– Receive ½ from mom
and ½ from dad• We have > 20,000 genes
Does the disorder run in families?
• We have 23 pairs of chromosomes– Receive ½ from mom
and ½ from dad• We have > 20,000 genes
Does the disorder run in families?
• We have 23 pairs of chromosomes– Receive ½ from mom
and ½ from dad• We have > 20,000 genes
Does the disorder run in families?
• We have 23 pairs of chromosomes– Receive ½ from mom
and ½ from dad• We have > 20,000 genes
Does the disorder run in families?
• We have 23 pairs of chromosomes– Receive ½ from mom
and ½ from dad• We have > 20,000 genes
Does the disorder run in families?
• We have 23 pairs of chromosomes– Receive ½ from mom
and ½ from dad• We have > 20,000 genes
CM1/S in Families
• Milhorat, et al. Neurosurgery 1999– 43/364 symptomatic patients (12%) reported that they
had ≥ 1 close relative with CM1/S
– An additional 72 patients (20%) reported that they had ≥ 1 close relative with symptoms similar to their own
• Additional studies– Speer, et al. Neurosurgical Focus 2000
– Szewka, et al. Pediatr.Neurol. 2006
– Boyles, et al. Am J Med Genet A 2006
• We have collected >100 CM1/S multiplex families
Why do we think CM1 has a genetic component?
• Familial Clustering• Twin Studies• Co-segregation with known genetic syndromes• Heritability estimates of posterior fossa
measurements• Preliminary evidence from a linkage screen
Twin Studies
• Same environment• Share all genes
• Same environment• Share ½ genes
Identical Fraternal
CM1 Twin Studies
• Higher concordance between 3 sets of identical twins compared to 3 sets of fraternal twins– Speer, et al. Journal of Genetic Counseling. 2003
• Concordance between identical twins and triplets– Atkinson, et al. Neurosurgery. 1998– Stovner, et al. Ann Neurol. 1992– Szewka, et al. Pediatr.Neurol. 2006– Cavendar, et al. J.Neurosurg. 1995
Why do we think CM1 has a genetic component?
• Familial Clustering• Twin Studies• Co-segregation with known genetic syndromes• Heritability estimates of posterior fossa
measurements• Preliminary evidence from a linkage screen
Co-segregation with known genetic syndromes
• Achondroplasia• Craniosynostosis• Paget’s Disease• Ehlers Danlos Syndrome• Marfan Syndrome• X-linked Aqueductal
Stenosis• Carpenter’s Syndrome• Cleidocranial Dysplasia• Empty Sella Turcica• Familial Osteosclerosis• Hajdu-Cheney Syndrome
• Hypophosphatemic Rickets• Klippel Feil• Marshall Smith Syndrome• Noonan Syndrome• Primary Basilar
Impression/Invagination• Renal-coloboma Syndrome• Spondylo-epiphyseal
Dysplasia Tarda• Williams-Beuren Syndrome
• Albright Hereditary Osteodystrophy (pseudohypoparathyroidism)
Speer, et al. Journal of Genetic Counseling 2003; Milhorat, et al. J.Neurosurg.Spine 2007.
Why do we think CM1 has a genetic component?
• Familial Clustering• Twin Studies• Co-segregation with known genetic syndromes• Heritability estimates of posterior fossa
measurements• Preliminary evidence from a linkage screen
Outline
• Brief genetics review
• Why study the genetics of a disease?
• Why do we think CM1/S has a genetic component?
• What genetic approaches can we take?
• Discuss previous and current genetic studies of CM1
Genome Screens• Finding a gene is similar
to searching the US for a house without an address
• Must search genome by increments
• Enables geneticists to localize a gene to a small region on a single chromosome
Genetic Approach to a Disease
Define the phenotype
CM1/S
*Small Posterior Fossa*
1) Affected/Unaffected
2) PF Measures
Genetic Approach to a Disease
Define the phenotype
Look for evidence of a
genetic component
Perform Initial Analysis
CM1/S
*Small Posterior Fossa*
1) Affected/Unaffected
2) PF Measures
-Familial clustering
-Twin Studies
-Co-segregation with Genetic Syndromes
Linkage Analysis
Genetic Approach to a Disease
Define the phenotype
CM1/S
*Small Posterior Fossa*
1) Affected/Unaffected
2) PF Measures
Genetic Approach to a Disease
Define the phenotype
Look for evidence of a
genetic component
CM1/S
*Small Posterior Fossa*
1) Affected/Unaffected
2) PF Measures
Genetic Approach to a Disease
Define the phenotype
Look for evidence of a
genetic component
CM1/S
*Small Posterior Fossa*
1) Affected/Unaffected
2) PF Measures
-Familial clustering
-Twin Studies
-Co-segregation with Genetic Syndromes
Genetic Approach to a Disease
Define the phenotype
Look for evidence of a
genetic component
Design Study
CM1/S
*Small Posterior Fossa*
1) Affected/Unaffected
2) PF Measures
-Familial clustering
-Twin Studies
-Co-segregation with Genetic Syndromes
Genetic Approach to a Disease
Define the phenotype
Look for evidence of a
genetic component
Design Experiment
CM1/S
*Small Posterior Fossa*
1) Affected/Unaffected
2) PF Measures
-Familial clustering
-Twin Studies
-Co-segregation with Genetic Syndromes
-Family-based Study
-Genome Screen
Genetic Approach to a Disease
Define the phenotype
Look for evidence of a
genetic component
Design Experiment
Genotype population
CM1/S
*Small Posterior Fossa*
1) Affected/Unaffected
2) PF Measures
-Familial clustering
-Twin Studies
-Co-segregation with Genetic Syndromes
-Family-based Study
-Genome Screen
Genetic Approach to a Disease
Define the phenotype
Look for evidence of a
genetic component
Design Experiment
Genotype population
CM1/S
*Small Posterior Fossa*
1) Affected/Unaffected
2) PF Measures
-Familial clustering
-Twin Studies
-Co-segregation with Genetic Syndromes
-Family-based Study
-Genome Screen
Genotype using Illumina’s 610 chip
Genetic Approach to a Disease
Define the phenotype
Look for evidence of a
genetic component
Design Experiment
Genotype population
Perform Initial Analysis
CM1/S
*Small Posterior Fossa*
1) Affected/Unaffected
2) PF Measures
-Familial clustering
-Twin Studies
-Co-segregation with Genetic Syndromes
-Family-based Study
-Genome Screen
Genotype using Illumina’s 610 chip
Genetic Approach to a Disease
Define the phenotype
Look for evidence of a
genetic component
Design Experiment
Genotype population
Perform Initial Analysis
CM1/S
*Small Posterior Fossa*
1) Affected/Unaffected
2) PF Measures
-Familial clustering
-Twin Studies
-Co-segregation with Genetic Syndromes
-Family-based Study
-Genome Screen
Genotype using Illumina’s 610 chipLinkage Analysis
Genetic Approach to a Disease
Define the phenotype
Look for evidence of a
genetic component
Design Experiment
Genotype population
Perform Initial Analysis
Follow-up genomic
regions / genes
CM1/S
*Small Posterior Fossa*
1) Affected/Unaffected
2) PF Measures
-Familial clustering
-Twin Studies
-Co-segregation with Genetic Syndromes
-Family-based Study
-Genome Screen
Genotype using Illumina’s 610 chipLinkage Analysis
Genetic Approach to a Disease
Define the phenotype
Look for evidence of a
genetic component
Design Experiment
Genotype population
Perform Initial Analysis
Follow-up genomic
regions / genes
CM1/S
*Small Posterior Fossa*
1) Affected/Unaffected
2) PF Measures
-Familial clustering
-Twin Studies
-Co-segregation with Genetic Syndromes
-Family-based Study
-Genome Screen
Genotype using Illumina’s 610 chipLinkage Analysis-Fine-Mapping
-Sequencing
Genetic Approach to a Disease
Define the phenotype
Look for evidence of a
genetic component
Design Experiment
Replication
Genotype population
Perform Initial Analysis
Follow-up genomic
regions / genes
CM1/S
*Small Posterior Fossa*
1) Affected/Unaffected
2) PF Measures
-Familial clustering
-Twin Studies
-Co-segregation with Genetic Syndromes
-Family-based Study
-Genome Screen
Genotype using Illumina’s 610 chipLinkage Analysis-Fine-Mapping
-Sequencing
Genome Screen - Linkage
• We have 23 pairs of chromosomes– Receive ½ from mom
and ½ from dad• We have > 20,000 genes
Genome Screen - Linkage
• We have 23 pairs of chromosomes– Receive ½ from mom
and ½ from dad• We have > 20,000 genes
Follow-up
Outline
• Brief genetics review
• Why study the genetics of a disease?
• Why do we think CM1/S has a genetic component?
• What genetic approaches can we take?
• Discuss previous and current genetic studies of CM1
Previous Linkage Screen – 23 families
A.L. Boyles, et al. Am J Med Genet A, Dec 15, 2006
Image from U.S. Department of Energy Genome Programs(http://genomics.energy.gov)
Heritability of PF Measures
Measurement h2 p-value
Left Herniation 0 0.5
Right Herniation 0 0.5
Max Herniation 0 0.5
Foramen Magnum 0.19 0.27
Tentorium 0.11 0.31
Supraoccipital 0.28 0.07
Tentorial Angle 0.10 0.39
Clivus 0.39 0.05
Basal Angle 0.51 0.01
PF Volume 0.96 0.0035
Cranial Volume 0.11 0.32
A.L. Boyles, et al. Am J Med Genet A , Dec 15, 2006
Current Ascertainment• Continued enrollment of CM1/S multiplex families (>100
families ascertained thus far)• Collecting:
– Medical records– Family history– Pre-surgical MRIs– Questionnaire
• Symptoms• Associated conditions• Disease onset• Pregnancy History
Current Genome Screen
• Phase I– 234 individuals from 40 CM1/S families– Genotyping and Quality Control: Complete– Analysis: In progress
• Phase II– Genotype another 240 individuals– Goal is to complete in the fall…
Posterior Fossa Measurements
• Collection of Pre-surgical MRIs– Collected > 200 so far– Measurements are in progress
• Goals:– Re-estimate heritability– Use as a phenotype– Identification of subtypes
Interested?
• Please pick up a study brochure after the session
• Feel free to contact the study coordinator with any questions:– Phone: 1-877-385-2626– Email: [email protected]
Acknowledgements
• Principal Investigator: Allison Ashley-Koch, Ph.D. • Principal Investigator: Simon Gregory, Ph.D.• Herbert Fuchs, M.D., Ph.D.• Gerald Grant, M.D.• David Enterline, M.D.• Heidi Cope, M.S., C.G.C.• Karen Soldano• Shonda Evans• Kaiti Dunlap
Funding provided by:
• National Institutes of Health (NINDS)
• Conquer Chiari