Screening for Possible
KIAA0319 Gene Variants
Associated with Dyslexia
By: Bethany Blank
Mentor: Dr. Caporale
Background
• Dyslexia
▫ Learning Disorder
▫ Neurodevelopmental Disorder
▫ Developmental vs. Acquired
• Prevalence
▫ 5-17%
Common Signs and Symptoms
• Difficulties
▫
▫
▫
▫
▫
▫
Learning to read/write/spell
Carrying out a sequence of directions
Conveying thoughts in logical sequence
Phonology
Learning foreign languages
Understanding jokes/idioms
• Often family history
• Immune problems
• Associated with other disorders (ADHD)
What It Can Look Like:
Diagnostic Methods
• Categorical diagnosis (affected/unaffected)
• Standardized Tests
▫ Given by certified school psychologists or
neuropsychologist
• Developing brain imaging diagnosis
• No genetic testing available
Genetic Background
• Complex
▫ Polygenetic
▫ Heterogeneity
▫ Environmental Component
• Variety of Studies
▫ Twin Studies
▫ Family Cohorts
▫ Unrelated Diagnosed Individuals
• Heritability 0.4-0.8
Genetic Background
• 9 Candidate Regions (DYX1-DYX9)
▫ 14 candidate genes
• Chromosome 6
▫ Region DYX2
▫ Genes KIAA0319 and DCDC2
▫ More well replicated
Genetic Background
• KIAA0319 (6p22.3)
▫ Large gene ~102,000 bp, 22 exons
▫ Involved in early brain development
 Cerebral cortex
▫ Neuron migration
▫ Underexpression=incomplete migration
Objectives
• Identify a gene variant marker associated with
dyslexia
▫ Potentially to be used as a diagnostic tool
• Sequence exons in KIAA0319
▫ Cohorts:
 Clinically diagnosed dyslexic individuals
 Control group (no signs of learning disabilities)
• Look for significant variants unique to dyslexic
cohort
• Compare results to previous studies
Methods
Received IRB
Approval
Recruit
Participants
DNA Collection
Days
(Consent Form,
Survey, and DNA
Collection)
Methods
Isolate
DNA
PCR and
Purification of
Products
Gel
Electrophoresis
Methods
Cycle Sequence
and Purification of
Products
Sanger
Sequencing
Analyze and
Compare
Sequences
Sequences
Variation
Homozygous wild type
Homozygous variant (found in
longest repeat sequences)
Heterozygous
Variation
Allele Type
Dyslexia
Control
1
1
1
2
1
0
3
0
1
4
0
1
5
0
2
6
0
2
• 3 allele types Dyslexia Group
only
7
1
1
8
1
4
9
1
0
• Based on one allele
10
4
6
11
2
1
• In 5’ Untranslated Region
12
0
1
13
1
0
14
1
4
• Based on GT Repeat Region
and additional SNPs
• 5 allele types Control Group
only
5’ UTR Significance
• GT Repeat (Microsat) correlated with regulation
of transcription
▫ Wide variation due to rapid gene evolution and
changing environmental conditions
• Microsats:
▫
▫
▫
▫
Relieve DNA supercoiling
Alter nucleosome placement
Bridges promoter and regulatory elements
With G/T (purine/pyrimidine) alternating, DNA
becomes left-handed Z-form
• Microsat + SNPs collectively play role in
regulation
Conclusions
• Variation was found in exon 1
• 5’ UTR located in exon 1 plays a role in
regulating transcriptional and translational
activity of gene
• 2 Allele types for GT repeat in individuals
• KIAA0319 gene alone does not cause dyslexia
(variants in additional regions in conjunction)
Moving Forward
• Increase sample size
▫ (specifically those clinically diagnosed)
• Explore other exons of KIAA0319
• Further explore 2 alleles of GT repeat
• Remain up to date on other research of
this gene
▫ Much is still unknown/poorly replicated
 Function
 Protein structure
 SNPs
Thank you!
• Dr. Caporale
• URSCA
• Friends and Family
• My sister
Literature Cited
• Carrion-Castillo, A., Franke, B. and Fisher, S. E. (2013), Molecular Genetics of
Dyslexia: An Overview. Dyslexia, 19: 214–240. doi: 10.1002/dys.1464
• Eicher J, Powers N, et al. . 2014. Characterization of the DXY2 locus on chromosome
6p22 with reading disability, language impairment, and IQ. Human Genetics [Internet].
[cited 2014 Sep 15] 133(7): 869–881. Available from:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053598/#__ffn_sectitle.
• National Center for Learning Disabilities [Internet]. National Center for Learning
Disabilities Inc; [modified 2014; cited 2014 Sep 15]. Available from:
http://www.ncld.org.
• Nopola-Hemmi, J., Taipale, M., Haltia, T., Lehesjoki, A. E., Voutilainen, A., & Kere, J.
(2000). Two translocations of chromosome 15q associated with dyslexia. Journal of
Medical Genetics, 37(10), 771-775.
• Poelmans, G., Buitelaar, J. K., Pauls, D. L., & Franke, B. (2011). A theoretical
molecular network for dyslexia: Integrating available genetic findings. Molecular
Psychiatry, I 6(4), 365-382.
• Schumacher, J., Hoffmann, P., Schmal, C., Schulte-Korne, G., & Nothen, M. M.
(2007). Genetics of dyslexia: The evolving landscape. Journal of Medical Genetics,
44(5), 289-297.
Questions
?