The Genetics of Developmental Learning Disabilities Wendy Raskind, M.D., Ph.D. University of...
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Transcript of The Genetics of Developmental Learning Disabilities Wendy Raskind, M.D., Ph.D. University of...
The Genetics of Developmental Learning Disabilities
Wendy Raskind, M.D., Ph.D.University of Washington IDA 10/29/08
Minding your ps and qsMinding your ps and qsA tale of alphabets, chromosomes, and allelesA tale of alphabets, chromosomes, and alleles
Dyslexia (RD)Dyslexia (RD)
Specific language impairment (SLI)Specific language impairment (SLI)
Speech Sound disorder (SSD)Speech Sound disorder (SSD)
Autism and autistic spectrum disorders (ASD)Autism and autistic spectrum disorders (ASD)
Dyslexia (RD)Dyslexia (RD)
Specific language impairment (SLI)Specific language impairment (SLI)
Speech Sound disorder (SSD)Speech Sound disorder (SSD)
Autism and autistic spectrum disorders (ASD)Autism and autistic spectrum disorders (ASD)
Examples of Complex Developmental Examples of Complex Developmental DisordersDisorders
Disclaimer!!! Too many groups, too many disorders. Disclaimer!!! Too many groups, too many disorders. Therefore, no specific citations.Therefore, no specific citations.
Evidence for a genetic basis
Population variation
Gene search strategies and current status
“Next gen” approaches
TopicsTopics
Evidence that a trait is genetic:Evidence that a trait is genetic:
Clustering
Genes
Observation
Twin studies
Aggregation
Patterns of transmission
Segregation
Linkage
Dyslexia: Dyslexia: Unexpected difficulty in accuracy and rate of word reading, decoding, text reading, and spelling that is neurobiological in
origin (IDA 2003)
Several lines of evidence that dyslexia has a genetic basis
ClusteringClustering
ObservationHinshelwood: more than one person in family with “congenital word blindness”, 1917
AggregationParents and offspring share exactly 50% of allelesSiblings share on average 50% of allelesUnless consanguinous, parents don’t share alleles by descent
Twin StudiesMZ twins share all alleles; DZ twins share on avg 50% of allelesCan estimate heritability by comparing how similar MZ twins are to how similar DZ twins are
Heritability: proportion of the phenotypic variation in a population that is attributable to genetic variation among individuals
Heritability of 1 implies that the variation is all geneticHeritability of 0 implies it is all environmental
A non zero heritability tells nothing about the number of genes
Segregation analysisSegregation analysisDetermines the pattern of inheritance of a trait
If heritability is high (variation is mostly due to genes) MZ twins will resemble each other in the trait more than DZ twins
HeritabilityHeritability
Heritability of dyslexia phenotypesHeritability of dyslexia phenotypes Twin studies and segregation analyses
•Composite of word recognition, reading comprehension, and spelling .58
•Word recognition ((single word reading) .45
•Phonological decoding (read pronounceable nonwords) .61
•Orthographic coding (choice of real word from homophone) .58
•Phonological awareness (transposition or deletion of phonemes) .56
Linkage studiesLinkage studies
Types of differences used to trace a trait in a Types of differences used to trace a trait in a family or populationfamily or population
Protein isoform
Chromosome/karyotype
Short tandem repeat polymorphism (STRP)
Single nucleotide polymorphism (SNP)
Marker: a polymorphic DNA sequence that varies in the population with known frequency
Short tandem repeat polymorphism Short tandem repeat polymorphism (STRP)(STRP)
Tetranucleotide …ATTGATTGATTG…ATTG(n)
One repeat unit
homozygous
heterozygous
How big is the genome?How big is the genome?
~3 billion base pairs in the haploid genome (3,000,000,000)
~25,000 protein coding genes
~1.5% of the genome codes for protein
So if we differ by 1 base per 1000, there are 3 million
differences in the haploid genome
p15-16
DYX3
DYX6p11.2
DYX5
p13-q13
q13-16.2
DYX4
DYX8p34-36
DYX7p15.5
DYX1
DYX2p21.3-22
q21
DYX9
q27.3
The ps and qs of dyslexiaThe ps and qs of dyslexia
UWLDC finding
q22.3
q12
Study designs varyStudy designs vary
Study populations: single family, sib pairs, multigenerational families
Inclusion criteria: discrepancy vs low performance
Phenotypes: global description, single assessment measures, various combinations of measures
Trait: categorical dichotomous or continuous variable
Candidate genes: 1. Candidate genes: 1. DYX1C1DYX1C1
Gene disrupted by t(2;15) in a family with dyslexia is a putative transcription factor
Some positive SNP associations: -3GA and 124GT
Dyslexia subjects Controls
= SNP 1 = SNP 2
SNP 1
SNP 2
Dyslexia
Studied SNPs in the gene in subjects and controls
Not confirmed by all
Inconsistent risk alleles
“Real” risk allele not known
Ann Rev Genomics Human Genet 8:57-79, 2008
Targeted association studies
DCDC2 KIAA0319
DYX2 locus: 2. DYX2 locus: 2. KIAA0319 KIAA0319 and 3. and 3. DCDC2DCDC2
Associations not corroborated by all studies
Evidence is strongest only for severe phenotypes
Opposite allele association in different studies
Good readers also carry the “risk” SNP haplotype
Nonsynonymous SNP in KIAA0319 - rare allele appears to protect
Candidate gene for DYX5: 4. Candidate gene for DYX5: 4. ROBO1ROBO1
Mapped in a single large Finnish family with AD inheritance
Disrupted by t(3;8)(p12;q11) in a family with dyslexia
Rare SNP haplotype associated with dyslexia and with decreased expression
One person with severe dyslexia in the translocation family did not carry t(3;8)
Expression studies done in lymphocytes
Quite variable effects on expression levels
No mutations in general dyslexia populations
However……
Ann Rev Genomics Human Genet 8:57-79, 2008
RNAi studies show DYX1C1, KIAA0319 and DCDC2 affect neuronal migration
All four candidate genes are expressed in brain
ROBO1 affects extension of axons
But 50% of genes are expressed in brain
No clearly pathogenic mutations yet identified
But 50% of genes are expressed in brain
No clearly pathogenic mutations yet identified
Functional StudiesFunctional Studies
Significant difficulties in acquiring expressive and/or receptive language, despite adequate intelligence and opportunity
Common ~3-5%
More common in males than females
High heritability (familial aggregation but complex segregation patterns)
High comorbidity with dyslexia and specific language impairment
Speech Sound Disorder (SSD): Speech Sound Disorder (SSD):
Prader-Willi Syndrome 15q11-13
Autism 15q11-13
Language problems of SSD are shared with other syndromes
SSD confers increased risk for dyslexia
Targeted linkage analyses of SSD: suggestive but not consistent evidence
15q14
15q21 (DYX1)
6p22 (DYX2)
3p12-q13 (DYX5)
1p36 (DYX8)
Incoordination of muscles used in articulation of speech
Mapped to 7q31 in a single large British family with AD inheritance (SPCH1)
de novo t(5;7)(q22;q31.2) and t(2;7)(p23;q31.3) led to identification of FOXP2
Heterozygous missense mutation in FOXP2 in original family
Severe vocal dyspraxiaSevere vocal dyspraxia
No mutations in dyslexia or autism found
Rare mutations found in others with severe vocal dyspraxia but not in “usual” SSD
Transcription factor: regulates production of RNA from DNA. May initiate, enhance, or inhibit the transcription of a gene.
RNAi knockdown impairs ability of songbirds to imitate songs.
Function of FOXP2Function of FOXP2
Characterized by late onset of expressive language and poor receptive language abilities, poor comprehension relative to reading accuracy, poor understanding of syntax and morphology in the absence of explanatory factors (e.g., low non-verbal IQ, hearing impairment, neurologic damage)
Moderate to high heritability
Male predominance (8% of boys and 6% of girls) Linkage studies: SLI1 16q
SLI2 19q
SLI3 13q21
Specific Language Impairment (SLI) Specific Language Impairment (SLI)
No linkage to FOXP2 and no mutations in FOXP2
Comorbidity of RD, SLI, SSD:Comorbidity of RD, SLI, SSD:
Shared Genetic Influences?Shared Genetic Influences?
All are common disorders with high heritability
Male predominance
Share some clinical features
Only soft evidence for overlap of genomic locations
Can’t really know until the genes are found
Same holds for relationship to ADHD
Autism Autism
impaired social interaction
speech perseveration
delayed echolalia
social anxiety
gaze aversion
hand flapping and other stereotyped repetitive actions
self injury
Autism and autistic spectrum disorders Autism and autistic spectrum disorders
High heritability, > 90%
• MZ twin concordance 70-95%
• DZ twin concordance 0-24%
Does not exhibit Mendelian inheritance pattern
• Risk to sibs is ~5-15%
• Rapid fall off in risk to extended family members
• 4-5:1 male predominance; even more skewed for higher IQ subset
Prevalence rising? Narrow definition 1/500, ASD 1/150
Etiologies of Autism: I. Single Gene DefectsEtiologies of Autism: I. Single Gene Defects
most common inherited form of mental retardation
X-linked inheritance
affects 1/3600 males
mild to moderate intellectual impairment
verbal worse than performance IQ
1/4000 females are carriers of the full mutation; may have executive function impairment
accounts for 4-7% of people with a diagnosis of autism
~33% of people with fragile X have an autism diagnosis
many others have “autistic-like behaviors”
Fragile X Syndrome (FRAX, Fragile X Syndrome (FRAX, FMR1)FMR1)
Rett Syndrome Rett Syndrome
X-linked, ~1/15000 (1/8000 girls)
99.5% sporadic
autistic behaviors onset in 1st 3-4 yrs = repetitive hand wringing, slapping, loss of acquired language
distinct from autism – progressive decline, female predominance, microcephaly
MECP2 gene at Xq28 codes for a protein that is critical for maintenance of methylation status
Loss of function leads to gene reactivation
Developmental arrest of brain and autonomic neurologic system
Additional Genetic Heterogeneity Additional Genetic Heterogeneity
Known genes (e.g., FMR1, MECP2, TS, NF1, PTEN, Shank3, NLGN3, NLGN4)
Linkage studies of multiplex families (e.g., 1p, 2q32, 3p25-26, 5q, 6q21, 7q22, 7q31-22, 13q, 15q11-13, 16p13, 17, 19p)
Translocations (e.g., 2q37, 5p15, 11q25, 16q22.3, 17p11.2, 18q21.1, 18q23, 22q11.2, 22q13.3, Xp22.2-p22.3)
Pathways in Autistic Spectrum DisordersPathways in Autistic Spectrum Disorders
Garber Science 317:190-191, 2007
Some genes affect synapse function: neuroligins, neurexins, Shank3
Others may interact or have similar function
Etiologies of Autism: II. Duplication/Deletion Etiologies of Autism: II. Duplication/Deletion SyndromesSyndromes
Cytogenetic SyndromesCytogenetic Syndromes
Idic(15) is the most frequently identified chromosomal abnormality in autism
Maternal isodisomy or loss of the paternal allele leads to PWS
Paternal isodisomy or loss of the maternal allele leads to AS
Velocardiofacial Syndrome (VCFS)Velocardiofacial Syndrome (VCFS)22q del syndrome 22q del syndrome
broad bulbous nose
square tip of nose
short philtrum
hypertelorism; telecanthus
small head
low set ears
long slender hands and fingers
palatal abnormalities
cardiac abnormalities
immune and autoimmune defects
schizophrenia
autism
learning disabilities
Copy Number Variations (CNVs) and AutismCopy Number Variations (CNVs) and Autism
more common in autism (~10%) than controls (~1%)
some regions overlap with linkage signals
sometimes region contains a strong candidate gene
some regions found by more than one group
some identified regions remain controversial
some are apparently benign population polymorphisms
Common disease/common variant hypothesis (CDCV): much of of the genetic variation is due to relatively few common variants
Rare disease/rare variant hypothesis: multiple different disorders, each caused by rare alleles
genetic heterogeneity, high penetrance
low penetrance, perhaps combination of alleles consider the putative modest effect of DCDC2 and KIAA0319 on dyslexia
Complex Disorders: Competing Hypotheses Complex Disorders: Competing Hypotheses
Genome-Wide Association Studies (GWAS)
Relies on common disease/common variant hypothesis Enabled by HapMap Project
Simultaneous genotyping of thousands of SNPs
Requires large numbers of cases and controls
Rarely finds the functional variant
Usually effect size is very small
May suggest a candidate gene for rare variant search