SLDB

Speech/Language Disorders Database

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Gene / phenotype associations for CNTNAP2

  • Click column headers to sort. Click to expand any row to see more details about the particular assertion of an association between variants of CNTNAP2 and a particular phenotypic variable.
  • Click the Pubmed IDs in the last column to link out to the primary research article. Click the links in the last column to download the full Genotype-Phenotype record as JSON or XML formatted text.
Entrez Id Symbol Location Disorder Brief Phenotype Reference Year Download
26047 CNTNAP2 7q35 SLI Nonword repetition Vernes et al 2008 JSON | XML

Additional Phenotype Details: 
Standardized tests for nonword repetition (NWR) include the Children's Test of Nonword Repetition (CNRep, Gathercole et al 1994), the nonword repetition test (NRT, Dollaghan & Campbell 1998), and the Nonword Repetition subtest of the Comprehensive Test of Phonological Processing (Wagner et al. 1999).

References

Gathercole SE, Willis CS, Baddeley AD, Emslie H. The Children’s Test of Nonword Repetition: a test of phonological working memory. Memory 1994;2:103-27.

Dollaghan, C., & Campbell, T. F. (1998). Nonword repetition and child language impairment. Journal of Speech, Language, and Hearing Research, 41, 1136–1146

Wagner, R. K., Torgesen, J. K., & Rashotte, C. A. (1999). Comprehensive test of phonological processing. Austin, TX: PRO-ED.

Basic Study Type:  Association study

Study Cohort: 
Summary:

847 individuals from 184 families.

Details:

"The study subjects were members of epidemiologically and clinically ascertained families identified by the Specific Language Impairment Consortium [20,21]. These families were recruited from four sites in the United Kingdom: the Newcomen Centre at Guy’s Hospital [20,21], the Cambridge Language and Speech Project [22], the Child Life and Health Department at Edinburgh University [23], and the Manchester Language Study [24]. Families were selected through a proband with specific language impairment [see "Other" for diagnostic criteria]. . .We excluded any children with a nonverbal IQ of less than 80, a clinical diagnosis of an autistic-spectrum disorder, or another known medical or developmental condition that can impair language, such as hearing loss, cleft lip, or cleft palate. Moreover, for clinically ascertained samples, children were comprehensively assessed on scales evaluating language, IQ, and behavior, and those with overt pragmatic difficulties, behavioral characteristics associated with autism, or a family history indicative of autism were also excluded.

"We collected quantitative phenotypic data from probands and all available siblings. We then determined composite CELF-R scores for expressive and receptive language abilities. We also used a measure of the ability to repeat nonsense words, the Children’s Test of Nonword Repetition [26], which has been established as a robust endophenotype of specific language impairment. [12] (Scores on the scale range from 46 to 141, with a mean of 100 and a standard deviation of 15 in the general population. Lower scores indicate poorer performance.) . . .Additional information on the consortium families has been reported previously [20,21] and is available in Table S2 in the Supplementary Appendix, which shows means, standard deviations, and intertrait correlations for language measures used in this study."

Genotyping Methods: 
"To directly test the hypothesis that variants of the identified FOXP2 target (the CNTNAP2 gene) may increase susceptibility to common language impairments, we genotyped single-nucleotide polymorphisms (SNPs) in consortium families, followed by quantitative association analyses of measures of expressive and receptive language abilities and nonsense-word repetition. We genotyped and validated 38 SNPs from the CNTNAP2 locus on chromosome 7q35 in samples from 847 members of 184 consortium families, using Golden Gate assays on the Illumina platform (for details, see the Methods section and Table S3 in the Supplementary Appendix)."

Analysis Methods: 
"We used a quantitative transmission disequilibrium test (QTDT), adopting an orthogonal association model that considers only the within-family variance and is robust to population stratification. After identifying significant single SNP associations, we used the Merlin package to generate haplotypes for the cluster of nine associated SNPs, which were similarly analyzed with QTDT. Finally, we investigated the possibility of an effect of sex or imprinting within QTDT, using these nine SNP-tag haplotypes."

Other Details: Diagnostic criteria for SLI:

"Language skills [of] 1.5 SD or more below the normative mean for the child’s age on the Clinical Evaluation of Language Fundamentals–Revised (CELF-R) scale [25]. . .(Scores on the scale range from 50 to 150, with a mean of 100 and a standard deviation of 15 in the general population. Lower scores indicate poorer performance.)"

Associated Markers:
rs17236239  (P = 0.00005)  - Survives multiple comparisons correction (P = 0.002)


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26047 CNTNAP2 7q35 Dyslexia Orthographic coding Newbury et al 2011 JSON | XML

Additional Phenotype Details: May be assessed by a forced word choice test as in Olson et al 1994, requiring "(identification of a correctly spelt word from two phonologically equivalent options, e.g. rane vs rain" (Newbury et al 2011).

Basic Study Type:  Association study

Study Cohort: 
Summary: SLI cohort consists of 780 individuals from 181 families. Dyslexia cohort consists of 634 probands and siblings from 264 families. For case-control analysis, also had 331 unrelated dyslexic individuals.


SLI cohort

"The SLI families used in this study were provided by the SLI Consortium (SLIC) cohort which has previously been described in detail (SLIC 2002, 2004; Falcaro et al. 2008). This family-based sample included 780 individuals from 181 2-generation families and had a child male:female ratio of 1.6:1. . . The samples were assessed by one of five separate centres across the UK and were derived from both clinical and epidemiological studies. The Newcomen Centre at Guy’s Hospital, London, the Cambridge Language and Speech Project (CLASP—(Burden et al. 1996)), the Child Life and Health Department at the University of Edinburgh (Clark et al. 2007), the Department of Child Health at the University of Aberdeen and the Manchester Language Study (Conti-Ramsden and Botting 1999; Conti-Ramsden et al. 1997)."

Dyslexia cohort

"The collection of families used for quantitative trait association has been extensively described previously (Francks et al. 2004). Briefly, all probands and siblings from our complete Oxford set of 264 unrelated nuclear families (a total of 634 siblings with a male:female ratio of 1.5:1), were identified from the dyslexia clinic at the Royal Berkshire Hospital (Reading, U.K)."

For case-control analyses only: "In addition to the dyslexia family-based sample, we analysed a collection of 331 UK unrelated cases which have not been investigated in previous studies for any of the loci under study here. These samples were recruited through the Dyslexia Research Centre clinics in Oxford and Reading, and the Aston Dyslexia and Development clinic in Birmingham. The cases are between 8 and 18.5 years of age, have a BAS2 single-word reading score B100 (at chronological age) and >1.5 SDs below that predicted by their IQ scores. Since these individuals were collected as a case cohort, we did not investigate quantitative measures for them."

Genotyping Methods: 
"In total 31 SNPs were genotyped. These included four SNPs from MRPL19/C2ORF3, four SNPs from DCDC2, six SNPs from KIAA0319, two SNPs from DYX1C1, five SNPs from CNTNAP2, five SNPs from CMIP and five SNPs from ATP2C2 (Table 1). SLI and dyslexia individuals were genotyped in separate experiments, therefore the SNP data quality varied between these cohorts. In addition, control data were not available for all SNPs, therefore case–control analyses were not performed for all 31 SNPs. SNPs were genotyped using the Sequenom iPLEX assay. Genotypes in the form of marker clusters were checked manually in the MassArray TyperAnalyser software. Any SNP with a success rate of <80% or any SNP that showed consistent bad inheritances (>10 errors after data clean-up) within each independent cohort were removed from the association analyses. Probabilities of Hardy–Weinberg Equilibrium (HWE) were calculated for all SNPs within PEDSTATS (Wigginton and Abecasis 2005) and any SNP with a HWE-P of <0.0001 was excluded."

Analysis Methods: 
- QTDT (Quantitative Transmission Disequilibrium Test) performed independently within SLI and dyslexia families; IBD (Identity By Descent) calculated in MERLIN

- Also conducted case-control analyses (allelic association test, within PLINK)

Other Details: 
SLI cohort, diagnostic criteria:

"All families were ascertained on the basis of a single proband with receptive and/or expressive language skills, either currently or in the past, more than 1.5 SD below the normative mean for their chronological age."

SLI cohort, other inclusion criteria

"Any child reported to have a nonverbal IQ of below 80 was excluded from the study. Other exclusion criteria included monozygotic twinning, chronic illness requiring multiple hospital visits or admissions, deafness, a clinical diagnosis of autism, English being a second language, children with known neurological disorders and children under local authority care."

SLI cohort, phenotypic measures:

"Language abilities of all available SLIC children (regardless of language ability) were assessed using the expressive (ELS, n = 392) and receptive (RLS, n = 392) scales of the Clinical Evaluation of Language Fundamentals (CELF-R) battery (Semel et al. 1992) and a 28-item nonword repetition (NWR, n = 451) test (Gathercole et al. 1994). Reading aptitude was measured using the single word reading (Read, n = 312), single-word spelling (Spell, n = 310) and reading comprehension (Comp, n = 276) tests from the Wechsler Objective Reading Dimensions (WORD) (Rust et al. 1993). Verbal and non-verbal IQ were examined, primarily for exclusion purposes, using the Wechsler Intelligence Scales for Children (WISC-III) (Wechsler 1992). Due to the age constraints of standardised tests, all phenotypic data were collected for children only. All scores were normalised for age effects. Due to logistical constraints, the reading tests were only performed for a subset of SLI individuals."

Dyslexia cohort, diagnostic criteria:

"Families were ascertained if the proband had a British Abilities Scales (BAS) single-word reading score >2 SDs below that predicted by their intelligence quotient (IQ) and if at least one other sibling had a history of reading problems. These criteria identified some probands with high IQ scores and BAS reading scores within the ‘normal’ range. Therefore, after collecting 173 UK families the ascertainment conditions were changed such that the only required criterion was that the probands’ difference in their BAS single-word reading score had to be >=1 SD below the population mean for their age (and not IQ), along with an IQ >= 90."


Dyslexia cohort, other inclusion criteria
"Probands were excluded if they had been diagnosed with co-occuring developmental disorders such as SLI, autism or attention deficit-hyperactivity disorder (ADHD)."

Dyslexia cohort, phenotypic measures

"We administered a battery of psychometric tests to all probands and siblings in each family, and we age-adjusted and standardized their scores against a normative control data set, as described elsewhere (Marlow et al. 2001; Fisher et al. 2002). These included measures of single-word reading ability (READ; n = 634) and spelling ability (SPELL; n = 603) from the British Ability Scales (BAS) (Elliot et al. 1983) or Wide Range Achievement Test (WRAT-R) for children older than 14.5 (Jastak and Wilkson 1984), phonological decoding ability (PD; n = 629) (use of letter to sound relationship rules to read pseudowords) (Castles and Coltheart 1993), phonemic awareness (PA; n = 591) (awareness of the phonemic structure of language; test which required the individuals to orally move phonemes either within the same word or between words, also known as ‘‘spoonerism’’) (Gallagher and Frederickson 1995), orthographic coding (OC-irreg; n = 625) (the ability to read real words that do not follow conventional spelling to sound rules e.g. yacht) (Castles and Coltheart 1993) and orthographic coding assessed by a forced word choice test (OC-choice; n = 548) (identification of a correctly spelt word from two phonologically equivalent options, e.g. rane vs rain) between (Olson et al. 1994). Tests of verbal and non-verbal reasoning were assessed using the BAS similarities (SIM; n = 620) or BAS matrices (MAT; n = 588) tests respectively (Elliot et al. 1983). The Similarities sub-scale of the Wechsler Adult Intelligence Scales (WAIS), which is analogous to the BAS similarities test, was used when age was >17.5 years (Wechsler 1981). Note that the measures of reading and spelling were derived from different tests of the same constructs to those utilized in the SLI cohort."

Associated Markers:
rs7794745  (P = 0.0425)


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26047 CNTNAP2 7q35 SLI Nonword repetition Newbury et al 2011 JSON | XML

Additional Phenotype Details: 
Standardized tests for nonword repetition (NWR) include the Children's Test of Nonword Repetition (CNRep, Gathercole et al 1994), the nonword repetition test (NRT, Dollaghan & Campbell 1998), and the Nonword Repetition subtest of the Comprehensive Test of Phonological Processing (Wagner et al. 1999).

References

Gathercole SE, Willis CS, Baddeley AD, Emslie H. The Children’s Test of Nonword Repetition: a test of phonological working memory. Memory 1994;2:103-27.

Dollaghan, C., & Campbell, T. F. (1998). Nonword repetition and child language impairment. Journal of Speech, Language, and Hearing Research, 41, 1136–1146

Wagner, R. K., Torgesen, J. K., & Rashotte, C. A. (1999). Comprehensive test of phonological processing. Austin, TX: PRO-ED.

Basic Study Type:  Association study

Study Cohort: 
Summary: SLI cohort consists of 780 individuals from 181 families. Dyslexia cohort consists of 634 probands and siblings from 264 families. For case-control analysis, also had 331 unrelated dyslexic individuals.


SLI cohort

"The SLI families used in this study were provided by the SLI Consortium (SLIC) cohort which has previously been described in detail (SLIC 2002, 2004; Falcaro et al. 2008). This family-based sample included 780 individuals from 181 2-generation families and had a child male:female ratio of 1.6:1. . . The samples were assessed by one of five separate centres across the UK and were derived from both clinical and epidemiological studies. The Newcomen Centre at Guy’s Hospital, London, the Cambridge Language and Speech Project (CLASP—(Burden et al. 1996)), the Child Life and Health Department at the University of Edinburgh (Clark et al. 2007), the Department of Child Health at the University of Aberdeen and the Manchester Language Study (Conti-Ramsden and Botting 1999; Conti-Ramsden et al. 1997)."

Dyslexia cohort

"The collection of families used for quantitative trait association has been extensively described previously (Francks et al. 2004). Briefly, all probands and siblings from our complete Oxford set of 264 unrelated nuclear families (a total of 634 siblings with a male:female ratio of 1.5:1), were identified from the dyslexia clinic at the Royal Berkshire Hospital (Reading, U.K)."

For case-control analyses only: "In addition to the dyslexia family-based sample, we analysed a collection of 331 UK unrelated cases which have not been investigated in previous studies for any of the loci under study here. These samples were recruited through the Dyslexia Research Centre clinics in Oxford and Reading, and the Aston Dyslexia and Development clinic in Birmingham. The cases are between 8 and 18.5 years of age, have a BAS2 single-word reading score B100 (at chronological age) and >1.5 SDs below that predicted by their IQ scores. Since these individuals were collected as a case cohort, we did not investigate quantitative measures for them."

Genotyping Methods: 
"In total 31 SNPs were genotyped. These included four SNPs from MRPL19/C2ORF3, four SNPs from DCDC2, six SNPs from KIAA0319, two SNPs from DYX1C1, five SNPs from CNTNAP2, five SNPs from CMIP and five SNPs from ATP2C2 (Table 1). SLI and dyslexia individuals were genotyped in separate experiments, therefore the SNP data quality varied between these cohorts. In addition, control data were not available for all SNPs, therefore case–control analyses were not performed for all 31 SNPs. SNPs were genotyped using the Sequenom iPLEX assay. Genotypes in the form of marker clusters were checked manually in the MassArray TyperAnalyser software. Any SNP with a success rate of <80% or any SNP that showed consistent bad inheritances (>10 errors after data clean-up) within each independent cohort were removed from the association analyses. Probabilities of Hardy–Weinberg Equilibrium (HWE) were calculated for all SNPs within PEDSTATS (Wigginton and Abecasis 2005) and any SNP with a HWE-P of <0.0001 was excluded."

Analysis Methods: 
- QTDT (Quantitative Transmission Disequilibrium Test) performed independently within SLI and dyslexia families; IBD (Identity By Descent) calculated in MERLIN

- Also conducted case-control analyses (allelic association test, within PLINK)

Other Details: 
SLI cohort, diagnostic criteria:

"All families were ascertained on the basis of a single proband with receptive and/or expressive language skills, either currently or in the past, more than 1.5 SD below the normative mean for their chronological age."

SLI cohort, other inclusion criteria

"Any child reported to have a nonverbal IQ of below 80 was excluded from the study. Other exclusion criteria included monozygotic twinning, chronic illness requiring multiple hospital visits or admissions, deafness, a clinical diagnosis of autism, English being a second language, children with known neurological disorders and children under local authority care."

SLI cohort, phenotypic measures:

"Language abilities of all available SLIC children (regardless of language ability) were assessed using the expressive (ELS, n = 392) and receptive (RLS, n = 392) scales of the Clinical Evaluation of Language Fundamentals (CELF-R) battery (Semel et al. 1992) and a 28-item nonword repetition (NWR, n = 451) test (Gathercole et al. 1994). Reading aptitude was measured using the single word reading (Read, n = 312), single-word spelling (Spell, n = 310) and reading comprehension (Comp, n = 276) tests from the Wechsler Objective Reading Dimensions (WORD) (Rust et al. 1993). Verbal and non-verbal IQ were examined, primarily for exclusion purposes, using the Wechsler Intelligence Scales for Children (WISC-III) (Wechsler 1992). Due to the age constraints of standardised tests, all phenotypic data were collected for children only. All scores were normalised for age effects. Due to logistical constraints, the reading tests were only performed for a subset of SLI individuals."

Dyslexia cohort, diagnostic criteria:

"Families were ascertained if the proband had a British Abilities Scales (BAS) single-word reading score >2 SDs below that predicted by their intelligence quotient (IQ) and if at least one other sibling had a history of reading problems. These criteria identified some probands with high IQ scores and BAS reading scores within the ‘normal’ range. Therefore, after collecting 173 UK families the ascertainment conditions were changed such that the only required criterion was that the probands’ difference in their BAS single-word reading score had to be >=1 SD below the population mean for their age (and not IQ), along with an IQ >= 90."


Dyslexia cohort, other inclusion criteria
"Probands were excluded if they had been diagnosed with co-occuring developmental disorders such as SLI, autism or attention deficit-hyperactivity disorder (ADHD)."

Dyslexia cohort, phenotypic measures

"We administered a battery of psychometric tests to all probands and siblings in each family, and we age-adjusted and standardized their scores against a normative control data set, as described elsewhere (Marlow et al. 2001; Fisher et al. 2002). These included measures of single-word reading ability (READ; n = 634) and spelling ability (SPELL; n = 603) from the British Ability Scales (BAS) (Elliot et al. 1983) or Wide Range Achievement Test (WRAT-R) for children older than 14.5 (Jastak and Wilkson 1984), phonological decoding ability (PD; n = 629) (use of letter to sound relationship rules to read pseudowords) (Castles and Coltheart 1993), phonemic awareness (PA; n = 591) (awareness of the phonemic structure of language; test which required the individuals to orally move phonemes either within the same word or between words, also known as ‘‘spoonerism’’) (Gallagher and Frederickson 1995), orthographic coding (OC-irreg; n = 625) (the ability to read real words that do not follow conventional spelling to sound rules e.g. yacht) (Castles and Coltheart 1993) and orthographic coding assessed by a forced word choice test (OC-choice; n = 548) (identification of a correctly spelt word from two phonologically equivalent options, e.g. rane vs rain) between (Olson et al. 1994). Tests of verbal and non-verbal reasoning were assessed using the BAS similarities (SIM; n = 620) or BAS matrices (MAT; n = 588) tests respectively (Elliot et al. 1983). The Similarities sub-scale of the Wechsler Adult Intelligence Scales (WAIS), which is analogous to the BAS similarities test, was used when age was >17.5 years (Wechsler 1981). Note that the measures of reading and spelling were derived from different tests of the same constructs to those utilized in the SLI cohort."

Associated Markers:
rs17236239  (P = 8 x 10^5)
rs10246256  (P = 0.0008)
rs2710102  (P = 0.0005)
rs2710117  (P = 0.0010)


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26047 CNTNAP2 7q35 SLI Receptive language skills Newbury et al 2011 JSON | XML

Additional Phenotype Details: May be assessed using the receptive language scale of the Clinical Evaluation of Language Fundamentals (CELF-R) battery (Semel et al. 1992).

Reference

Semel EM, Wiig EH, Secord W (1992) Clinical evaluation of language fundamentals—revised. Phychological Corporation, San Antonio.

Basic Study Type:  Association study

Study Cohort: 
Summary: SLI cohort consists of 780 individuals from 181 families. Dyslexia cohort consists of 634 probands and siblings from 264 families. For case-control analysis, also had 331 unrelated dyslexic individuals.


SLI cohort

"The SLI families used in this study were provided by the SLI Consortium (SLIC) cohort which has previously been described in detail (SLIC 2002, 2004; Falcaro et al. 2008). This family-based sample included 780 individuals from 181 2-generation families and had a child male:female ratio of 1.6:1. . . The samples were assessed by one of five separate centres across the UK and were derived from both clinical and epidemiological studies. The Newcomen Centre at Guy’s Hospital, London, the Cambridge Language and Speech Project (CLASP—(Burden et al. 1996)), the Child Life and Health Department at the University of Edinburgh (Clark et al. 2007), the Department of Child Health at the University of Aberdeen and the Manchester Language Study (Conti-Ramsden and Botting 1999; Conti-Ramsden et al. 1997)."

Dyslexia cohort

"The collection of families used for quantitative trait association has been extensively described previously (Francks et al. 2004). Briefly, all probands and siblings from our complete Oxford set of 264 unrelated nuclear families (a total of 634 siblings with a male:female ratio of 1.5:1), were identified from the dyslexia clinic at the Royal Berkshire Hospital (Reading, U.K)."

For case-control analyses only: "In addition to the dyslexia family-based sample, we analysed a collection of 331 UK unrelated cases which have not been investigated in previous studies for any of the loci under study here. These samples were recruited through the Dyslexia Research Centre clinics in Oxford and Reading, and the Aston Dyslexia and Development clinic in Birmingham. The cases are between 8 and 18.5 years of age, have a BAS2 single-word reading score B100 (at chronological age) and >1.5 SDs below that predicted by their IQ scores. Since these individuals were collected as a case cohort, we did not investigate quantitative measures for them."

Genotyping Methods: 
"In total 31 SNPs were genotyped. These included four SNPs from MRPL19/C2ORF3, four SNPs from DCDC2, six SNPs from KIAA0319, two SNPs from DYX1C1, five SNPs from CNTNAP2, five SNPs from CMIP and five SNPs from ATP2C2 (Table 1). SLI and dyslexia individuals were genotyped in separate experiments, therefore the SNP data quality varied between these cohorts. In addition, control data were not available for all SNPs, therefore case–control analyses were not performed for all 31 SNPs. SNPs were genotyped using the Sequenom iPLEX assay. Genotypes in the form of marker clusters were checked manually in the MassArray TyperAnalyser software. Any SNP with a success rate of <80% or any SNP that showed consistent bad inheritances (>10 errors after data clean-up) within each independent cohort were removed from the association analyses. Probabilities of Hardy–Weinberg Equilibrium (HWE) were calculated for all SNPs within PEDSTATS (Wigginton and Abecasis 2005) and any SNP with a HWE-P of <0.0001 was excluded."

Analysis Methods: 
- QTDT (Quantitative Transmission Disequilibrium Test) performed independently within SLI and dyslexia families; IBD (Identity By Descent) calculated in MERLIN

- Also conducted case-control analyses (allelic association test, within PLINK)

Other Details: 
SLI cohort, diagnostic criteria:

"All families were ascertained on the basis of a single proband with receptive and/or expressive language skills, either currently or in the past, more than 1.5 SD below the normative mean for their chronological age."

SLI cohort, other inclusion criteria

"Any child reported to have a nonverbal IQ of below 80 was excluded from the study. Other exclusion criteria included monozygotic twinning, chronic illness requiring multiple hospital visits or admissions, deafness, a clinical diagnosis of autism, English being a second language, children with known neurological disorders and children under local authority care."

SLI cohort, phenotypic measures:

"Language abilities of all available SLIC children (regardless of language ability) were assessed using the expressive (ELS, n = 392) and receptive (RLS, n = 392) scales of the Clinical Evaluation of Language Fundamentals (CELF-R) battery (Semel et al. 1992) and a 28-item nonword repetition (NWR, n = 451) test (Gathercole et al. 1994). Reading aptitude was measured using the single word reading (Read, n = 312), single-word spelling (Spell, n = 310) and reading comprehension (Comp, n = 276) tests from the Wechsler Objective Reading Dimensions (WORD) (Rust et al. 1993). Verbal and non-verbal IQ were examined, primarily for exclusion purposes, using the Wechsler Intelligence Scales for Children (WISC-III) (Wechsler 1992). Due to the age constraints of standardised tests, all phenotypic data were collected for children only. All scores were normalised for age effects. Due to logistical constraints, the reading tests were only performed for a subset of SLI individuals."

Dyslexia cohort, diagnostic criteria:

"Families were ascertained if the proband had a British Abilities Scales (BAS) single-word reading score >2 SDs below that predicted by their intelligence quotient (IQ) and if at least one other sibling had a history of reading problems. These criteria identified some probands with high IQ scores and BAS reading scores within the ‘normal’ range. Therefore, after collecting 173 UK families the ascertainment conditions were changed such that the only required criterion was that the probands’ difference in their BAS single-word reading score had to be >=1 SD below the population mean for their age (and not IQ), along with an IQ >= 90."


Dyslexia cohort, other inclusion criteria
"Probands were excluded if they had been diagnosed with co-occuring developmental disorders such as SLI, autism or attention deficit-hyperactivity disorder (ADHD)."

Dyslexia cohort, phenotypic measures

"We administered a battery of psychometric tests to all probands and siblings in each family, and we age-adjusted and standardized their scores against a normative control data set, as described elsewhere (Marlow et al. 2001; Fisher et al. 2002). These included measures of single-word reading ability (READ; n = 634) and spelling ability (SPELL; n = 603) from the British Ability Scales (BAS) (Elliot et al. 1983) or Wide Range Achievement Test (WRAT-R) for children older than 14.5 (Jastak and Wilkson 1984), phonological decoding ability (PD; n = 629) (use of letter to sound relationship rules to read pseudowords) (Castles and Coltheart 1993), phonemic awareness (PA; n = 591) (awareness of the phonemic structure of language; test which required the individuals to orally move phonemes either within the same word or between words, also known as ‘‘spoonerism’’) (Gallagher and Frederickson 1995), orthographic coding (OC-irreg; n = 625) (the ability to read real words that do not follow conventional spelling to sound rules e.g. yacht) (Castles and Coltheart 1993) and orthographic coding assessed by a forced word choice test (OC-choice; n = 548) (identification of a correctly spelt word from two phonologically equivalent options, e.g. rane vs rain) between (Olson et al. 1994). Tests of verbal and non-verbal reasoning were assessed using the BAS similarities (SIM; n = 620) or BAS matrices (MAT; n = 588) tests respectively (Elliot et al. 1983). The Similarities sub-scale of the Wechsler Adult Intelligence Scales (WAIS), which is analogous to the BAS similarities test, was used when age was >17.5 years (Wechsler 1981). Note that the measures of reading and spelling were derived from different tests of the same constructs to those utilized in the SLI cohort."

Associated Markers:
rs17236239  (P = 0.0336)
rs10246256  (P = 0.0032)
rs2710102  (P = 0.0312)
rs2710117  (P = 0.0056)


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26047 CNTNAP2 7q35 SLI Expressive language skills Newbury et al 2011 JSON | XML

Additional Phenotype Details: May be assessed using the expressive language scale of the Clinical Evaluation of Language Fundamentals (CELF-R) battery (Semel et al. 1992).

Reference

Semel EM, Wiig EH, Secord W (1992) Clinical evaluation of language fundamentals—revised. Phychological Corporation, San Antonio.

Basic Study Type:  Association study

Study Cohort: 
Summary: SLI cohort consists of 780 individuals from 181 families. Dyslexia cohort consists of 634 probands and siblings from 264 families. For case-control analysis, also had 331 unrelated dyslexic individuals.


SLI cohort

"The SLI families used in this study were provided by the SLI Consortium (SLIC) cohort which has previously been described in detail (SLIC 2002, 2004; Falcaro et al. 2008). This family-based sample included 780 individuals from 181 2-generation families and had a child male:female ratio of 1.6:1. . . The samples were assessed by one of five separate centres across the UK and were derived from both clinical and epidemiological studies. The Newcomen Centre at Guy’s Hospital, London, the Cambridge Language and Speech Project (CLASP—(Burden et al. 1996)), the Child Life and Health Department at the University of Edinburgh (Clark et al. 2007), the Department of Child Health at the University of Aberdeen and the Manchester Language Study (Conti-Ramsden and Botting 1999; Conti-Ramsden et al. 1997)."

Dyslexia cohort

"The collection of families used for quantitative trait association has been extensively described previously (Francks et al. 2004). Briefly, all probands and siblings from our complete Oxford set of 264 unrelated nuclear families (a total of 634 siblings with a male:female ratio of 1.5:1), were identified from the dyslexia clinic at the Royal Berkshire Hospital (Reading, U.K)."

For case-control analyses only: "In addition to the dyslexia family-based sample, we analysed a collection of 331 UK unrelated cases which have not been investigated in previous studies for any of the loci under study here. These samples were recruited through the Dyslexia Research Centre clinics in Oxford and Reading, and the Aston Dyslexia and Development clinic in Birmingham. The cases are between 8 and 18.5 years of age, have a BAS2 single-word reading score B100 (at chronological age) and >1.5 SDs below that predicted by their IQ scores. Since these individuals were collected as a case cohort, we did not investigate quantitative measures for them."

Genotyping Methods: 
"In total 31 SNPs were genotyped. These included four SNPs from MRPL19/C2ORF3, four SNPs from DCDC2, six SNPs from KIAA0319, two SNPs from DYX1C1, five SNPs from CNTNAP2, five SNPs from CMIP and five SNPs from ATP2C2 (Table 1). SLI and dyslexia individuals were genotyped in separate experiments, therefore the SNP data quality varied between these cohorts. In addition, control data were not available for all SNPs, therefore case–control analyses were not performed for all 31 SNPs. SNPs were genotyped using the Sequenom iPLEX assay. Genotypes in the form of marker clusters were checked manually in the MassArray TyperAnalyser software. Any SNP with a success rate of <80% or any SNP that showed consistent bad inheritances (>10 errors after data clean-up) within each independent cohort were removed from the association analyses. Probabilities of Hardy–Weinberg Equilibrium (HWE) were calculated for all SNPs within PEDSTATS (Wigginton and Abecasis 2005) and any SNP with a HWE-P of <0.0001 was excluded."

Analysis Methods: 
- QTDT (Quantitative Transmission Disequilibrium Test) performed independently within SLI and dyslexia families; IBD (Identity By Descent) calculated in MERLIN

- Also conducted case-control analyses (allelic association test, within PLINK)

Other Details: 
SLI cohort, diagnostic criteria:

"All families were ascertained on the basis of a single proband with receptive and/or expressive language skills, either currently or in the past, more than 1.5 SD below the normative mean for their chronological age."

SLI cohort, other inclusion criteria

"Any child reported to have a nonverbal IQ of below 80 was excluded from the study. Other exclusion criteria included monozygotic twinning, chronic illness requiring multiple hospital visits or admissions, deafness, a clinical diagnosis of autism, English being a second language, children with known neurological disorders and children under local authority care."

SLI cohort, phenotypic measures:

"Language abilities of all available SLIC children (regardless of language ability) were assessed using the expressive (ELS, n = 392) and receptive (RLS, n = 392) scales of the Clinical Evaluation of Language Fundamentals (CELF-R) battery (Semel et al. 1992) and a 28-item nonword repetition (NWR, n = 451) test (Gathercole et al. 1994). Reading aptitude was measured using the single word reading (Read, n = 312), single-word spelling (Spell, n = 310) and reading comprehension (Comp, n = 276) tests from the Wechsler Objective Reading Dimensions (WORD) (Rust et al. 1993). Verbal and non-verbal IQ were examined, primarily for exclusion purposes, using the Wechsler Intelligence Scales for Children (WISC-III) (Wechsler 1992). Due to the age constraints of standardised tests, all phenotypic data were collected for children only. All scores were normalised for age effects. Due to logistical constraints, the reading tests were only performed for a subset of SLI individuals."

Dyslexia cohort, diagnostic criteria:

"Families were ascertained if the proband had a British Abilities Scales (BAS) single-word reading score >2 SDs below that predicted by their intelligence quotient (IQ) and if at least one other sibling had a history of reading problems. These criteria identified some probands with high IQ scores and BAS reading scores within the ‘normal’ range. Therefore, after collecting 173 UK families the ascertainment conditions were changed such that the only required criterion was that the probands’ difference in their BAS single-word reading score had to be >=1 SD below the population mean for their age (and not IQ), along with an IQ >= 90."


Dyslexia cohort, other inclusion criteria
"Probands were excluded if they had been diagnosed with co-occuring developmental disorders such as SLI, autism or attention deficit-hyperactivity disorder (ADHD)."

Dyslexia cohort, phenotypic measures

"We administered a battery of psychometric tests to all probands and siblings in each family, and we age-adjusted and standardized their scores against a normative control data set, as described elsewhere (Marlow et al. 2001; Fisher et al. 2002). These included measures of single-word reading ability (READ; n = 634) and spelling ability (SPELL; n = 603) from the British Ability Scales (BAS) (Elliot et al. 1983) or Wide Range Achievement Test (WRAT-R) for children older than 14.5 (Jastak and Wilkson 1984), phonological decoding ability (PD; n = 629) (use of letter to sound relationship rules to read pseudowords) (Castles and Coltheart 1993), phonemic awareness (PA; n = 591) (awareness of the phonemic structure of language; test which required the individuals to orally move phonemes either within the same word or between words, also known as ‘‘spoonerism’’) (Gallagher and Frederickson 1995), orthographic coding (OC-irreg; n = 625) (the ability to read real words that do not follow conventional spelling to sound rules e.g. yacht) (Castles and Coltheart 1993) and orthographic coding assessed by a forced word choice test (OC-choice; n = 548) (identification of a correctly spelt word from two phonologically equivalent options, e.g. rane vs rain) between (Olson et al. 1994). Tests of verbal and non-verbal reasoning were assessed using the BAS similarities (SIM; n = 620) or BAS matrices (MAT; n = 588) tests respectively (Elliot et al. 1983). The Similarities sub-scale of the Wechsler Adult Intelligence Scales (WAIS), which is analogous to the BAS similarities test, was used when age was >17.5 years (Wechsler 1981). Note that the measures of reading and spelling were derived from different tests of the same constructs to those utilized in the SLI cohort."

Associated Markers:
rs17236239  (P = 0.0071)
rs10246256  (P = 0.0062)
rs2710102  (P = 0.0200)
rs2710117  (P = 0.0189)


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26047 CNTNAP2 7q35 SLI Spelling ability Newbury et al 2011 JSON | XML

Additional Phenotype Details: Possible measures include the spelling subtests of any of a number of intelligence and literacy tests, e.g.:

Peabody Individual Achievement Test (PIAT)
Western Australian Literacy and Numeracy Assessment (WALNA)
Wide Range Achievement Test (WRAT)

Basic Study Type:  Association study

Study Cohort: 
Summary: SLI cohort consists of 780 individuals from 181 families. Dyslexia cohort consists of 634 probands and siblings from 264 families. For case-control analysis, also had 331 unrelated dyslexic individuals.


SLI cohort

"The SLI families used in this study were provided by the SLI Consortium (SLIC) cohort which has previously been described in detail (SLIC 2002, 2004; Falcaro et al. 2008). This family-based sample included 780 individuals from 181 2-generation families and had a child male:female ratio of 1.6:1. . . The samples were assessed by one of five separate centres across the UK and were derived from both clinical and epidemiological studies. The Newcomen Centre at Guy’s Hospital, London, the Cambridge Language and Speech Project (CLASP—(Burden et al. 1996)), the Child Life and Health Department at the University of Edinburgh (Clark et al. 2007), the Department of Child Health at the University of Aberdeen and the Manchester Language Study (Conti-Ramsden and Botting 1999; Conti-Ramsden et al. 1997)."

Dyslexia cohort

"The collection of families used for quantitative trait association has been extensively described previously (Francks et al. 2004). Briefly, all probands and siblings from our complete Oxford set of 264 unrelated nuclear families (a total of 634 siblings with a male:female ratio of 1.5:1), were identified from the dyslexia clinic at the Royal Berkshire Hospital (Reading, U.K)."

For case-control analyses only: "In addition to the dyslexia family-based sample, we analysed a collection of 331 UK unrelated cases which have not been investigated in previous studies for any of the loci under study here. These samples were recruited through the Dyslexia Research Centre clinics in Oxford and Reading, and the Aston Dyslexia and Development clinic in Birmingham. The cases are between 8 and 18.5 years of age, have a BAS2 single-word reading score B100 (at chronological age) and >1.5 SDs below that predicted by their IQ scores. Since these individuals were collected as a case cohort, we did not investigate quantitative measures for them."

Genotyping Methods: 
"In total 31 SNPs were genotyped. These included four SNPs from MRPL19/C2ORF3, four SNPs from DCDC2, six SNPs from KIAA0319, two SNPs from DYX1C1, five SNPs from CNTNAP2, five SNPs from CMIP and five SNPs from ATP2C2 (Table 1). SLI and dyslexia individuals were genotyped in separate experiments, therefore the SNP data quality varied between these cohorts. In addition, control data were not available for all SNPs, therefore case–control analyses were not performed for all 31 SNPs. SNPs were genotyped using the Sequenom iPLEX assay. Genotypes in the form of marker clusters were checked manually in the MassArray TyperAnalyser software. Any SNP with a success rate of <80% or any SNP that showed consistent bad inheritances (>10 errors after data clean-up) within each independent cohort were removed from the association analyses. Probabilities of Hardy–Weinberg Equilibrium (HWE) were calculated for all SNPs within PEDSTATS (Wigginton and Abecasis 2005) and any SNP with a HWE-P of <0.0001 was excluded."

Analysis Methods: 
- QTDT (Quantitative Transmission Disequilibrium Test) performed independently within SLI and dyslexia families; IBD (Identity By Descent) calculated in MERLIN

- Also conducted case-control analyses (allelic association test, within PLINK)

Other Details: 
SLI cohort, diagnostic criteria:

"All families were ascertained on the basis of a single proband with receptive and/or expressive language skills, either currently or in the past, more than 1.5 SD below the normative mean for their chronological age."

SLI cohort, other inclusion criteria

"Any child reported to have a nonverbal IQ of below 80 was excluded from the study. Other exclusion criteria included monozygotic twinning, chronic illness requiring multiple hospital visits or admissions, deafness, a clinical diagnosis of autism, English being a second language, children with known neurological disorders and children under local authority care."

SLI cohort, phenotypic measures:

"Language abilities of all available SLIC children (regardless of language ability) were assessed using the expressive (ELS, n = 392) and receptive (RLS, n = 392) scales of the Clinical Evaluation of Language Fundamentals (CELF-R) battery (Semel et al. 1992) and a 28-item nonword repetition (NWR, n = 451) test (Gathercole et al. 1994). Reading aptitude was measured using the single word reading (Read, n = 312), single-word spelling (Spell, n = 310) and reading comprehension (Comp, n = 276) tests from the Wechsler Objective Reading Dimensions (WORD) (Rust et al. 1993). Verbal and non-verbal IQ were examined, primarily for exclusion purposes, using the Wechsler Intelligence Scales for Children (WISC-III) (Wechsler 1992). Due to the age constraints of standardised tests, all phenotypic data were collected for children only. All scores were normalised for age effects. Due to logistical constraints, the reading tests were only performed for a subset of SLI individuals."

Dyslexia cohort, diagnostic criteria:

"Families were ascertained if the proband had a British Abilities Scales (BAS) single-word reading score >2 SDs below that predicted by their intelligence quotient (IQ) and if at least one other sibling had a history of reading problems. These criteria identified some probands with high IQ scores and BAS reading scores within the ‘normal’ range. Therefore, after collecting 173 UK families the ascertainment conditions were changed such that the only required criterion was that the probands’ difference in their BAS single-word reading score had to be >=1 SD below the population mean for their age (and not IQ), along with an IQ >= 90."


Dyslexia cohort, other inclusion criteria
"Probands were excluded if they had been diagnosed with co-occuring developmental disorders such as SLI, autism or attention deficit-hyperactivity disorder (ADHD)."

Dyslexia cohort, phenotypic measures

"We administered a battery of psychometric tests to all probands and siblings in each family, and we age-adjusted and standardized their scores against a normative control data set, as described elsewhere (Marlow et al. 2001; Fisher et al. 2002). These included measures of single-word reading ability (READ; n = 634) and spelling ability (SPELL; n = 603) from the British Ability Scales (BAS) (Elliot et al. 1983) or Wide Range Achievement Test (WRAT-R) for children older than 14.5 (Jastak and Wilkson 1984), phonological decoding ability (PD; n = 629) (use of letter to sound relationship rules to read pseudowords) (Castles and Coltheart 1993), phonemic awareness (PA; n = 591) (awareness of the phonemic structure of language; test which required the individuals to orally move phonemes either within the same word or between words, also known as ‘‘spoonerism’’) (Gallagher and Frederickson 1995), orthographic coding (OC-irreg; n = 625) (the ability to read real words that do not follow conventional spelling to sound rules e.g. yacht) (Castles and Coltheart 1993) and orthographic coding assessed by a forced word choice test (OC-choice; n = 548) (identification of a correctly spelt word from two phonologically equivalent options, e.g. rane vs rain) between (Olson et al. 1994). Tests of verbal and non-verbal reasoning were assessed using the BAS similarities (SIM; n = 620) or BAS matrices (MAT; n = 588) tests respectively (Elliot et al. 1983). The Similarities sub-scale of the Wechsler Adult Intelligence Scales (WAIS), which is analogous to the BAS similarities test, was used when age was >17.5 years (Wechsler 1981). Note that the measures of reading and spelling were derived from different tests of the same constructs to those utilized in the SLI cohort."

Associated Markers:
rs17236239  (P = 0.0086)
rs10246256  (P = 0.0002)
rs2710102  (P = 0.0089)
rs2710117  (P = 0.0051)


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26047 CNTNAP2 7q35 SLI Reading comprehension Newbury et al 2011 JSON | XML

Additional Phenotype Details: May be assessed with the reading comprehension test from the Wechsler Objective Reading Dimensions (WORD) (Rust et al. 1993).

Basic Study Type:  Association study

Study Cohort: 
Summary: SLI cohort consists of 780 individuals from 181 families. Dyslexia cohort consists of 634 probands and siblings from 264 families. For case-control analysis, also had 331 unrelated dyslexic individuals.


SLI cohort

"The SLI families used in this study were provided by the SLI Consortium (SLIC) cohort which has previously been described in detail (SLIC 2002, 2004; Falcaro et al. 2008). This family-based sample included 780 individuals from 181 2-generation families and had a child male:female ratio of 1.6:1. . . The samples were assessed by one of five separate centres across the UK and were derived from both clinical and epidemiological studies. The Newcomen Centre at Guy’s Hospital, London, the Cambridge Language and Speech Project (CLASP—(Burden et al. 1996)), the Child Life and Health Department at the University of Edinburgh (Clark et al. 2007), the Department of Child Health at the University of Aberdeen and the Manchester Language Study (Conti-Ramsden and Botting 1999; Conti-Ramsden et al. 1997)."

Dyslexia cohort

"The collection of families used for quantitative trait association has been extensively described previously (Francks et al. 2004). Briefly, all probands and siblings from our complete Oxford set of 264 unrelated nuclear families (a total of 634 siblings with a male:female ratio of 1.5:1), were identified from the dyslexia clinic at the Royal Berkshire Hospital (Reading, U.K)."

For case-control analyses only: "In addition to the dyslexia family-based sample, we analysed a collection of 331 UK unrelated cases which have not been investigated in previous studies for any of the loci under study here. These samples were recruited through the Dyslexia Research Centre clinics in Oxford and Reading, and the Aston Dyslexia and Development clinic in Birmingham. The cases are between 8 and 18.5 years of age, have a BAS2 single-word reading score B100 (at chronological age) and >1.5 SDs below that predicted by their IQ scores. Since these individuals were collected as a case cohort, we did not investigate quantitative measures for them."

Genotyping Methods: 
"In total 31 SNPs were genotyped. These included four SNPs from MRPL19/C2ORF3, four SNPs from DCDC2, six SNPs from KIAA0319, two SNPs from DYX1C1, five SNPs from CNTNAP2, five SNPs from CMIP and five SNPs from ATP2C2 (Table 1). SLI and dyslexia individuals were genotyped in separate experiments, therefore the SNP data quality varied between these cohorts. In addition, control data were not available for all SNPs, therefore case–control analyses were not performed for all 31 SNPs. SNPs were genotyped using the Sequenom iPLEX assay. Genotypes in the form of marker clusters were checked manually in the MassArray TyperAnalyser software. Any SNP with a success rate of <80% or any SNP that showed consistent bad inheritances (>10 errors after data clean-up) within each independent cohort were removed from the association analyses. Probabilities of Hardy–Weinberg Equilibrium (HWE) were calculated for all SNPs within PEDSTATS (Wigginton and Abecasis 2005) and any SNP with a HWE-P of <0.0001 was excluded."

Analysis Methods: 
- QTDT (Quantitative Transmission Disequilibrium Test) performed independently within SLI and dyslexia families; IBD (Identity By Descent) calculated in MERLIN

- Also conducted case-control analyses (allelic association test, within PLINK)

Other Details: 
SLI cohort, diagnostic criteria:

"All families were ascertained on the basis of a single proband with receptive and/or expressive language skills, either currently or in the past, more than 1.5 SD below the normative mean for their chronological age."

SLI cohort, other inclusion criteria

"Any child reported to have a nonverbal IQ of below 80 was excluded from the study. Other exclusion criteria included monozygotic twinning, chronic illness requiring multiple hospital visits or admissions, deafness, a clinical diagnosis of autism, English being a second language, children with known neurological disorders and children under local authority care."

SLI cohort, phenotypic measures:

"Language abilities of all available SLIC children (regardless of language ability) were assessed using the expressive (ELS, n = 392) and receptive (RLS, n = 392) scales of the Clinical Evaluation of Language Fundamentals (CELF-R) battery (Semel et al. 1992) and a 28-item nonword repetition (NWR, n = 451) test (Gathercole et al. 1994). Reading aptitude was measured using the single word reading (Read, n = 312), single-word spelling (Spell, n = 310) and reading comprehension (Comp, n = 276) tests from the Wechsler Objective Reading Dimensions (WORD) (Rust et al. 1993). Verbal and non-verbal IQ were examined, primarily for exclusion purposes, using the Wechsler Intelligence Scales for Children (WISC-III) (Wechsler 1992). Due to the age constraints of standardised tests, all phenotypic data were collected for children only. All scores were normalised for age effects. Due to logistical constraints, the reading tests were only performed for a subset of SLI individuals."

Dyslexia cohort, diagnostic criteria:

"Families were ascertained if the proband had a British Abilities Scales (BAS) single-word reading score >2 SDs below that predicted by their intelligence quotient (IQ) and if at least one other sibling had a history of reading problems. These criteria identified some probands with high IQ scores and BAS reading scores within the ‘normal’ range. Therefore, after collecting 173 UK families the ascertainment conditions were changed such that the only required criterion was that the probands’ difference in their BAS single-word reading score had to be >=1 SD below the population mean for their age (and not IQ), along with an IQ >= 90."


Dyslexia cohort, other inclusion criteria
"Probands were excluded if they had been diagnosed with co-occuring developmental disorders such as SLI, autism or attention deficit-hyperactivity disorder (ADHD)."

Dyslexia cohort, phenotypic measures

"We administered a battery of psychometric tests to all probands and siblings in each family, and we age-adjusted and standardized their scores against a normative control data set, as described elsewhere (Marlow et al. 2001; Fisher et al. 2002). These included measures of single-word reading ability (READ; n = 634) and spelling ability (SPELL; n = 603) from the British Ability Scales (BAS) (Elliot et al. 1983) or Wide Range Achievement Test (WRAT-R) for children older than 14.5 (Jastak and Wilkson 1984), phonological decoding ability (PD; n = 629) (use of letter to sound relationship rules to read pseudowords) (Castles and Coltheart 1993), phonemic awareness (PA; n = 591) (awareness of the phonemic structure of language; test which required the individuals to orally move phonemes either within the same word or between words, also known as ‘‘spoonerism’’) (Gallagher and Frederickson 1995), orthographic coding (OC-irreg; n = 625) (the ability to read real words that do not follow conventional spelling to sound rules e.g. yacht) (Castles and Coltheart 1993) and orthographic coding assessed by a forced word choice test (OC-choice; n = 548) (identification of a correctly spelt word from two phonologically equivalent options, e.g. rane vs rain) between (Olson et al. 1994). Tests of verbal and non-verbal reasoning were assessed using the BAS similarities (SIM; n = 620) or BAS matrices (MAT; n = 588) tests respectively (Elliot et al. 1983). The Similarities sub-scale of the Wechsler Adult Intelligence Scales (WAIS), which is analogous to the BAS similarities test, was used when age was >17.5 years (Wechsler 1981). Note that the measures of reading and spelling were derived from different tests of the same constructs to those utilized in the SLI cohort."

Associated Markers:
rs10246256  (P = 0.0016)
rs2710117  (P = 0.0067)


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26047 CNTNAP2 7q35 SLI Single-word reading Newbury et al 2011 JSON | XML

Additional Phenotype Details: Possible measures include the single-word reading subtest of Wechsler Objective Reading Dimensions
(WORD), and the British Ability Scales (BAS) test of single-word reading.


References

Elliot CD, Murray DJ, Pearson LS (1979) The British ability scales. NFER, Slough, UK

Rust J, Golombok S, Trickey G (1993) Wechsler objective reading dimensions. Psychological Corporation, Sidcup.

Basic Study Type:  Association study

Study Cohort: 
Summary: SLI cohort consists of 780 individuals from 181 families. Dyslexia cohort consists of 634 probands and siblings from 264 families. For case-control analysis, also had 331 unrelated dyslexic individuals.


SLI cohort

"The SLI families used in this study were provided by the SLI Consortium (SLIC) cohort which has previously been described in detail (SLIC 2002, 2004; Falcaro et al. 2008). This family-based sample included 780 individuals from 181 2-generation families and had a child male:female ratio of 1.6:1. . . The samples were assessed by one of five separate centres across the UK and were derived from both clinical and epidemiological studies. The Newcomen Centre at Guy’s Hospital, London, the Cambridge Language and Speech Project (CLASP—(Burden et al. 1996)), the Child Life and Health Department at the University of Edinburgh (Clark et al. 2007), the Department of Child Health at the University of Aberdeen and the Manchester Language Study (Conti-Ramsden and Botting 1999; Conti-Ramsden et al. 1997)."

Dyslexia cohort

"The collection of families used for quantitative trait association has been extensively described previously (Francks et al. 2004). Briefly, all probands and siblings from our complete Oxford set of 264 unrelated nuclear families (a total of 634 siblings with a male:female ratio of 1.5:1), were identified from the dyslexia clinic at the Royal Berkshire Hospital (Reading, U.K)."

For case-control analyses only: "In addition to the dyslexia family-based sample, we analysed a collection of 331 UK unrelated cases which have not been investigated in previous studies for any of the loci under study here. These samples were recruited through the Dyslexia Research Centre clinics in Oxford and Reading, and the Aston Dyslexia and Development clinic in Birmingham. The cases are between 8 and 18.5 years of age, have a BAS2 single-word reading score B100 (at chronological age) and >1.5 SDs below that predicted by their IQ scores. Since these individuals were collected as a case cohort, we did not investigate quantitative measures for them."

Genotyping Methods: 
"In total 31 SNPs were genotyped. These included four SNPs from MRPL19/C2ORF3, four SNPs from DCDC2, six SNPs from KIAA0319, two SNPs from DYX1C1, five SNPs from CNTNAP2, five SNPs from CMIP and five SNPs from ATP2C2 (Table 1). SLI and dyslexia individuals were genotyped in separate experiments, therefore the SNP data quality varied between these cohorts. In addition, control data were not available for all SNPs, therefore case–control analyses were not performed for all 31 SNPs. SNPs were genotyped using the Sequenom iPLEX assay. Genotypes in the form of marker clusters were checked manually in the MassArray TyperAnalyser software. Any SNP with a success rate of <80% or any SNP that showed consistent bad inheritances (>10 errors after data clean-up) within each independent cohort were removed from the association analyses. Probabilities of Hardy–Weinberg Equilibrium (HWE) were calculated for all SNPs within PEDSTATS (Wigginton and Abecasis 2005) and any SNP with a HWE-P of <0.0001 was excluded."

Analysis Methods: 
- QTDT (Quantitative Transmission Disequilibrium Test) performed independently within SLI and dyslexia families; IBD (Identity By Descent) calculated in MERLIN

- Also conducted case-control analyses (allelic association test, within PLINK)

Other Details: 
SLI cohort, diagnostic criteria:

"All families were ascertained on the basis of a single proband with receptive and/or expressive language skills, either currently or in the past, more than 1.5 SD below the normative mean for their chronological age."

SLI cohort, other inclusion criteria

"Any child reported to have a nonverbal IQ of below 80 was excluded from the study. Other exclusion criteria included monozygotic twinning, chronic illness requiring multiple hospital visits or admissions, deafness, a clinical diagnosis of autism, English being a second language, children with known neurological disorders and children under local authority care."

SLI cohort, phenotypic measures:

"Language abilities of all available SLIC children (regardless of language ability) were assessed using the expressive (ELS, n = 392) and receptive (RLS, n = 392) scales of the Clinical Evaluation of Language Fundamentals (CELF-R) battery (Semel et al. 1992) and a 28-item nonword repetition (NWR, n = 451) test (Gathercole et al. 1994). Reading aptitude was measured using the single word reading (Read, n = 312), single-word spelling (Spell, n = 310) and reading comprehension (Comp, n = 276) tests from the Wechsler Objective Reading Dimensions (WORD) (Rust et al. 1993). Verbal and non-verbal IQ were examined, primarily for exclusion purposes, using the Wechsler Intelligence Scales for Children (WISC-III) (Wechsler 1992). Due to the age constraints of standardised tests, all phenotypic data were collected for children only. All scores were normalised for age effects. Due to logistical constraints, the reading tests were only performed for a subset of SLI individuals."

Dyslexia cohort, diagnostic criteria:

"Families were ascertained if the proband had a British Abilities Scales (BAS) single-word reading score >2 SDs below that predicted by their intelligence quotient (IQ) and if at least one other sibling had a history of reading problems. These criteria identified some probands with high IQ scores and BAS reading scores within the ‘normal’ range. Therefore, after collecting 173 UK families the ascertainment conditions were changed such that the only required criterion was that the probands’ difference in their BAS single-word reading score had to be >=1 SD below the population mean for their age (and not IQ), along with an IQ >= 90."


Dyslexia cohort, other inclusion criteria
"Probands were excluded if they had been diagnosed with co-occuring developmental disorders such as SLI, autism or attention deficit-hyperactivity disorder (ADHD)."

Dyslexia cohort, phenotypic measures

"We administered a battery of psychometric tests to all probands and siblings in each family, and we age-adjusted and standardized their scores against a normative control data set, as described elsewhere (Marlow et al. 2001; Fisher et al. 2002). These included measures of single-word reading ability (READ; n = 634) and spelling ability (SPELL; n = 603) from the British Ability Scales (BAS) (Elliot et al. 1983) or Wide Range Achievement Test (WRAT-R) for children older than 14.5 (Jastak and Wilkson 1984), phonological decoding ability (PD; n = 629) (use of letter to sound relationship rules to read pseudowords) (Castles and Coltheart 1993), phonemic awareness (PA; n = 591) (awareness of the phonemic structure of language; test which required the individuals to orally move phonemes either within the same word or between words, also known as ‘‘spoonerism’’) (Gallagher and Frederickson 1995), orthographic coding (OC-irreg; n = 625) (the ability to read real words that do not follow conventional spelling to sound rules e.g. yacht) (Castles and Coltheart 1993) and orthographic coding assessed by a forced word choice test (OC-choice; n = 548) (identification of a correctly spelt word from two phonologically equivalent options, e.g. rane vs rain) between (Olson et al. 1994). Tests of verbal and non-verbal reasoning were assessed using the BAS similarities (SIM; n = 620) or BAS matrices (MAT; n = 588) tests respectively (Elliot et al. 1983). The Similarities sub-scale of the Wechsler Adult Intelligence Scales (WAIS), which is analogous to the BAS similarities test, was used when age was >17.5 years (Wechsler 1981). Note that the measures of reading and spelling were derived from different tests of the same constructs to those utilized in the SLI cohort."

Associated Markers:
rs17236239  (P = 0.0272)
rs10246256  (P = 0.0003)
rs2710102  (P = 0.0354)
rs2710117  (P = 0.0205)


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26047 CNTNAP2 7q35 Dyslexia Nonword repetition Peter et al 2011 JSON | XML

Additional Phenotype Details: 
May be assessed using the Nonword Repetition subtest from the Comprehensive Test of Phonological Processing (Wagner et al. 1999).

Basic Study Type:  Association study

Study Cohort: 
Summary:

188 family trios (predominantly Caucasion, also Asian, African American, Native American, Hispanic, and other/unknown), each with proband with dyslexia identified between 1st and 9th grade.

Detail:

"Data for this study were collected by the University of Washington Learning Disabilities Center (UWLDC). . .The participant recruitment process and the phenotyping and genotyping procedures have been described in detail elsewhere (Berninger et al. 2006; Raskind et al. 2000). . .
"For the present study, 188 family trios from separate families of predominantly Caucasian ethnic background were selected. Per parent report, the probands were of the following ethnic backgrounds: 92.0% Caucasian, 2.1% Asian, 1.1% African American, 1.1% Native American, .5% Hispanic, and 3.2% other or unknown. These trios were the same as those reported in a previous study on associations of dyslexia to the DYX1 locus and DYX1 candidate genes (Brkanac et al. 2007)."

Genotyping Methods: 
FOXP2 SNPs analyzed:

rs2035980
rs923875
rs12533005
rs10230558
rs7782412
rs936146

CNTNAP2 SNPs analyzed:

rs851715
rs2710102
rs17236239
rs4431523


"Following the TaqMan Genotyping Master Mix Protocol for a 10-µL reaction, PCR amplification and allele identification were carried out with an ABI 7500 Real-Time PCR system and ABI Sequence Detection Software Version 1.31. The reaction mixture contained 5 µL of TaqMan Genotyping Mix, 2.5 µL of water, 0.5 µL of an AB Validated TaqMan SNP Genotyping Assay probe mixture, and 10 ng of DNA. Enzyme activation occurred at 95°C for 10 min, followed by 40 cycles of denaturation at 95°C for 15 s, and annealing and extension at 60°C for 1 min."

Analysis Methods: 
- Pairwise correlations between the selected traits (separately in parents and probands), with Bonferroni correction

- PEDSTATS (Wigginton and Abecasis 2005) to check for errors and Hardy-Weinberg equilibrium

- "Family-based QTDT as implemented in MERLIN (Abecasis et al. 2002), selecting the Abecasis orthogonal model."

- "Associations were evaluated using PLINK version 1.06"

- Linear association modeling (LAM)

- "All empirical p values in the QTDT and association testing were based on 100,000 permutations."

Other Details: 
Diagnostic criteria and proband means

"Each participating family was identified through a proband child in grades 1 through 9 who met dual criteria of discrepancy from the Verbal Comprehension Index (prorated verbal IQ, VIQ) and low achievement (below the population mean and typically well below) for dyslexia in accuracy or rate of orally reading pseudowords, real words, or passages, or spelling and/or for dysgraphia in automatic alphabet letter writing or spelling. . .The probands’ average word reading and decoding skills on nationally normed measures were more than .67 SD below the population mean and ranged from 1.5 to 1.8 SD below their VIQ. On average, probands met inclusionary criteria on 6.0 of 10 measures of reading and spelling and on 4.1 of 6 measures of writing (Berninger et al. 2006)."

Criteria for inclusion

"To participate in the study, the proband was required to have a VIQ of at least 90 on the Wechsler Intelligence Scale for Children-3rd Edition (Wechsler 2008), to exclude children with a higher probability of having an undiagnosed neurologic or developmental disorder. Children with neurological
or psychiatric disorders or other medical conditions, or preschool history of significant difficulty in learning language or other developmental milestones, which could have impaired their reading or writing for reasons other than dyslexia or dysgraphia were excluded, except for attention deficit/hyperactivity disorder. The protocol for the UWLDC study included measures of verbal reasoning/comprehension, reading and writing and phenotypes known to be associated with dyslexia or dysgraphia organized in a working memory architecture (Berninger et al. 2006)."

Phenotypic measures

- NWR (nonword repetition)
Nonword Repetition subtest from the Comprehensive Test of Phonological Processing (Wagner et al. 1999)

- SR (sentence repetition)
Sentence Memory subtest from the Stanford-Binet Intelligence Scale (Thorndike et al. 1986)

- RWRE (real word reading efficiency)
Tested using "a subtest of the prepublication version of the Test of Word Reading Efficiency (TOWRE) (Torgesen et al. 1999). . .The published version of this subtest is titled Sight Word Efficiency."

- Nonword reading (referred to in text as WATT)
Word Attack subtest (WATT) of the Woodcock Reading Mastery Test–Revised (Woodcock 1987)

- RAPA (rapid alternating place of articulation)
". . .a motor speech task requiring rapid repetition of the syllable sequence “pataka” ten times (Fletcher 1978)."

- FS-D (finger succession-dominant hand)
Timed "repetitions of sequential finger to thumb touches with index to middle finger to ring finger, and then pinky." (Berninger and Rutberg 1992)

Associated Markers:
rs2710102  (P = 0.0174)


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26047 CNTNAP2 7q35 Early communicative behavior Whitehouse et al 2011 JSON | XML

Additional Phenotype Details: Measured at 2 years of age

"Parent-completed checklist containing seven items assessing early communicative behavior, such as protoimperative actions (e.g. looking or pointing at an item to request it), the following of simple commands (e.g. ‘come here’, ‘sit down’), and the use of two- or three-word strings (e.g. ‘go, car’,
‘shut door’). Parents indicate whether their child shows this behavior always (2 points), sometimes (1 point) or never (zero points), yielding an overall score ranging from 0 to 14. The validity and reliability of
the IMQ range from 0.85 to 0.9 (Bricker et al . 1988)."

Associated Markers:
rs2710102  (P = 0.0239)  - C/T
rs1603450  (P = 0.0426)  - G/A
rs759178  (P = 0.0248)  - G/T
rs2710102-rs759178-rs17236239-rs2538976  (P = 0.0488; 0.0014)  - TTAA and CGAG haplotypes, respectively


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26047 CNTNAP2 7q35 Delayed speech Al-Murrani et al 2012 JSON | XML

Basic Study Type:  Candidate gene sequencing

Study Cohort: 
Summary: 3 year old boy with delayed speech, his 5 year old brother, and their parents.

"The proband is a 3-year-old boy who was referred to the genetic service for an opinion regarding an abnormal molecular karyotype result. He is the second child born to a nonconsanguineous European couple with normal language development. The proband’s perinatal history was uneventful and he was born at term. He exhibited mild motor delay in that he walked at around 18–20 months of age, and his speech was late to develop. At 2.5 years of age he was able to pronounce six words. At 3 years of age, he was using up to 3 words in sentences but his speech was difficult to understand. His speech therapist noted the presence of reduced tone of his orofacial musculature with associated tendency to dribble. The communication difficulties have resulted in behavioural problems. He was a nondysmorphic child with normal growth. Audiology assessment revealed normal hearing.
"His 5-year-old brother exhibits normal language development for his age but he has been noted by his kindergarten teachers to have difficulties in comprehension and following instructions.
"The proband’s mother was not affected by any learning or speech difficulties."

Genotyping Methods: 
"0.1 micrograms of genomic DNA was labelled using the Affymetrix Cytogenetics Reagent Kit and labelled DNA was applied to an Affymetrix Cytogenetics Array (2.7 million probes) according to the manufacturer’s instructions (Affymetrix Inc, CA, USA). The array was scanned and the data analysed using the Affymetrix Chromosome Analysis Suite (ChAS; version 1.0.1) and interpreted with the aid of the UCSC genome browser (http://genome.ucsc.edu/; hg18 assembly)."

Analysis Methods: 
"The proband’s molecular karyotype revealed a 451 kb interstitial deletion on chromosome 7q35 (145,944,468-146,395,611); Figure 1. A similar deletion was identified in the proband’s mother and brother; Figure 2. We considered that validation by quantitative real-time PCR, fluorescence in situ hybridization, or junctional fragment sequencing was not warranted given the array probe density over this region of chromosome 7 and the detection of this novel deletion with approximately the same coordinates in first degree relatives of the proband." The proband's brother and mother had similar deletions.


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26047 CNTNAP2 7q35 N400 event related potential Kos et al 2012 JSON | XML

Additional Phenotype Details: N400 is a negative potential measured around 400 ms after the beginning of the word for semantically incongruent words, and is considered to be an index of semantic processing

Associated Markers:
rs7794745   - "While in both genotype groups the agreement violations elicited a P600 effect, only carriers of the T-allele exhibited an anterior negativity preceding the P600 effect. In addition, the P600 effect of the T-carriers seemed to have a later onset compared to the AA-group."


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