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The Genetics of Developmental Learning
Disabilities
Minding your ps and qs
A tale of alphabets, chromosomes, and alleles
Wendy Raskind, M.D., Ph.D.
University of Washington
IDA 10/29/08
Examples of Complex Developmental
Disorders
 Dyslexia (RD)
 Specific language impairment (SLI)
 Speech Sound disorder (SSD)
 Autism and autistic spectrum disorders (ASD)
Disclaimer!!! Too many groups, too many disorders.
Therefore, no specific citations.
Topics
 Evidence for a genetic basis
 Population variation
 Gene search strategies and current status
 “Next gen” approaches
Population variation
Evidence that a trait is genetic:
Clustering
Observation
Aggregation
Twin studies
Patterns of transmission
Segregation
Linkage
Genes
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
Clustering
Observation
Hinshelwood: more than one person in family with “congenital
word blindness”, 1917
Aggregation
Parents and offspring share exactly 50% of alleles
Siblings share on average 50% of alleles
Unless consanguinous, parents don’t share alleles by descent
Twin Studies
MZ twins share all alleles; DZ twins share on avg 50% of alleles
Can 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
If heritability is high (variation is mostly due to genes) MZ twins
will resemble each other in the trait more than DZ twins
Heritability of 1 implies that the variation is all genetic
Heritability of 0 implies it is all environmental
A non zero heritability tells nothing about the number of
genes
Segregation analysis
Determines the pattern of inheritance of a trait
Heritability of dyslexia phenotypes
Twin studies and segregation analyses
• Composite of word recognition, reading
•
•
comprehension, and spelling
Word recognition (single word reading)
Phonological decoding (read pronounceable
.58
.45
nonwords)
.61
homophone)
.58
of phonemes)
.56
• Orthographic coding (choice of real word from
• Phonological awareness (transposition or deletion
Molecular Genetics
Linkage studies
Types of differences used to trace a trait in a
family 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
Chromosomes
Short tandem repeat polymorphism
(STRP)
Tetranucleotide …ATTGATTGATTG…ATTG(n)
One repeat unit
homozygous
heterozygous
Single nucleotide polymorphism (SNP)
electropherogram
A and G
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
The ps and qs of dyslexia
DYX8
DYX3
DYX5
p34-36
p15-16
q22.3
p13-q13
DYX2
DYX7
p21.3-22
p15.5
q13-16.2
DYX4
DYX1
q12
DYX6
q21
p11.2
DYX9
q27.3
UWLDC finding
Study 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. DYX1C1
Gene disrupted by t(2;15) in a family with dyslexia is
a putative transcription factor
Studied SNPs in the gene in subjects and controls
Dyslexia subjects
Controls
Some positive SNP
associations:
-3GA and 124GT
Not confirmed by all
Inconsistent risk alleles
Dyslexia
SNP 1
SNP 2
= SNP 1
= SNP 2
“Real” risk allele not known
DYX2 locus: 2. KIAA0319 and 3. DCDC2
DCDC2
KIAA0319
Targeted association studies
Ann Rev Genomics Human Genet 8:57-79, 2008
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. ROBO1
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
However……
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
Functional Studies
All four candidate genes are expressed in brain
RNAi studies show DYX1C1, KIAA0319 and DCDC2 affect
neuronal migration
Ann Rev Genomics Human Genet 8:57-79, 2008
ROBO1 affects extension of axons
But 50% of genes are expressed in brain
No clearly pathogenic mutations yet identified
Speech Sound Disorder (SSD):
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
Language problems of SSD are shared with other syndromes
Prader-Willi Syndrome
15q11-13
Autism
15q11-13
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)
Severe vocal dyspraxia
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
Rare mutations found in others with severe vocal dyspraxia
but not in “usual” SSD
No mutations in dyslexia or autism found
Function of FOXP2
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.
Specific Language Impairment (SLI)
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
 No linkage to FOXP2 and no mutations in FOXP2
Comorbidity of RD, SLI, SSD:
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
 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
 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 Defects
Fragile X Syndrome (FRAX, FMR1)
 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”
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
 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, Xp22.2p22.3)
Pathways in Autistic Spectrum Disorders
Some genes affect
synapse function:
neuroligins,
neurexins, Shank3
Others may interact
or have similar
function
Garber Science 317:190-191, 2007
Etiologies of Autism: II. Duplication/Deletion
Syndromes
Cytogenetic 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)
22q del syndrome
 broad bulbous nose
 square tip of nose
 schizophrenia
 short philtrum
 autism
 hypertelorism; telecanthus
 learning disabilities
 small head
 low set ears
 long slender hands and fingers
 palatal abnormalities
 cardiac abnormalities
 immune and autoimmune defects
Copy 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
Complex Disorders: Competing Hypotheses
 Common disease/common variant hypothesis
(CDCV): much of the genetic variation is due to
relatively few common variants
low penetrance, perhaps combination of alleles
consider the putative modest effect of DCDC2 and
KIAA0319 on dyslexia
 Rare disease/rare variant hypothesis: multiple
different disorders, each caused by rare alleles
genetic heterogeneity, high penetrance
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
Next-Generation Sequencing
1953 James Watson and Francis Crick describe double helix
2003 Human Genome Project whole sequence assembly
2007 Resequencing James Watson’s genome
$300,000,000
$1,000,000
beginning of 2008
$60,000
end of 2008
$10,000
projected for 2012
$100