SLDB

Speech/Language Disorders Database

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Gene / phenotype associations for FOXP2

  • Click column headers to sort. Click to expand any row to see more details about the particular assertion of an association between variants of FOXP2 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
93986 FOXP2 7q31 Dyspraxia Impairment in selection and sequencing of fine orofacial movements necessary for articulation Lai et al 2001 JSON | XML

Basic Study Type:  - Targeted sequencing - FISH (fluorescent in situ hybridization) - Brain expression analysis - Mutation search

Study Cohort: 
The KE family. "Affected members have a severe impairment in the selection and sequencing of fine orofacial movements, which are necessary for articulation (referred to as a developmental verbal dyspraxia; MIM 602081)[4,8,9]. The disorder is also characterized by deficits in several facets of language processing (such as the ability to break up words into their constituent phonemes) and grammatical skills (including production and comprehension of word inflections and syntactical structure)[7,8]."

"Although the mean non-verbal IQ of affected members is lower than that of unaffected members [8], there are affected individuals in the family who have non-verbal ability close to the population average, despite having severe speech and language difficulties; therefore, non-verbal deficits cannot be considered as characteristic of the disorder. Functional and structural brain-imaging studies of affected members of the KE family have suggested that the basal ganglia may be a site of bilateral pathology associated with the trait [9]. Although there has been some debate over which feature of the phenotype constitutes the core deficit in this disorder, all the different studies agree that the gene disrupted in the KE family is likely to be important in neural mechanisms mediating the development of speech and language."

Genotyping Methods: 
FOXP2 mRNA sequence and genomic structure

"We used a reverse-transcriptase polymerase chain reaction (RT-PCR)-based approach to confirm the FOXP2 mRNA sequence that had been predicted by bioinformatics. Primers were designed from putative exonic sequence and used to amplify by PCR first-strand complementary DNA from a range of adult tissues, which was obtained from Clontech. Products were sequenced as described [6] and compared with the predicted sequence."


Translocation mapping

"We performed FISH on metaphase spreads of cells from CS, using a series of roughly 10-kb genomic probes obtained from the NH0563O05 BAC clone, as described [6]. In parallel, we ran Southern blot analyses of several restriction fragments spanning the FOXP2 locus, comparing digested DNA from CS with that from unaffected controls, according to standard procedures."

Mutation search

"On the basis of genomic sequence information, we designed primers to flank each FOXP2 exon. These were used for PCR amplification of DNA from affected and unaffected individuals of the KE family, and from hybrid cell lines containing the affected chromosome 7 (ref. 6). We sequenced products as described [6]. The G-to-A transition detected in exon 14 of affected individuals destroys a restriction site for the enzyme MaeII (ACGT). An assay using this restriction enzyme was developed to test for the exon 14 change in 182 unrelated normal controls."

Other Details: 
Expression analyses of FOXP2

"Adult and fetal northern blots were obtained from Clontech and hybridized according to the manufacturers' instructions, using a cDNA probe isolated from exons 8-11 of FOXP2."


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93986 FOXP2 7q31 Dyspraxia Susceptibility to developmental verbal dyspraxia MacDermot et al 2005 JSON | XML

Additional Phenotype Details: Impaired ability to sequence movements for speech.

Basic Study Type:  Mutation screening

Study Cohort: 
Summary:

49 white 4-12yo individuals (except two who were in their 30s) with unexplained speech and language deficits, and their affected siblings

Details:

"After the publication by Lai et al. (2001), our department received many referrals of cases with unexplained speech and language deficits, requesting testing for FOXP2 abnormalities. . .Patients were enrolled sequentially, with no preference given to those with a family history of language disorder. The referring doctors and parents filled in a questionnaire for the study, which contained confirmation of the phenotype and provided results of the karyotype, speech examination report, and family history. DNA samples were collected from 49 probands, of whom 10 had one (or more) affected siblings whose samples were also included in the study. All affected cases were white, were within the 4–12-year-old age group (except for one pair of siblings aged 30 and 33 years), and resided in Europe, Australia, or the United States."

Genotyping Methods: 
"We conducted mutation screening across all FOXP2 exons identified by Lai et al. (2001) via denaturing high-performance liquid chromatography (DHPLC), followed by direct sequencing of fragments showing variant elution patterns, using identical protocols and primers to those described elsewhere by Newbury et al. (2002). We similarly analyzed additional alternatively spliced and 5' UTR exons reported by Bruce and Margolis (2002) (see table A1 for sequences of all primers). All assays spanned entire exons, plus short stretches of flanking intronic sequence."

Other Details: 
Inclusion criteria

"To more closely match the phenotype of the KE family, patients were selected for FOXP2 screening only if they fulfilled the following criteria: presence of speech articulation problems diagnosed by a clinician (e.g., a pediatrician or neurologist), normal karyotype, absence of mental retardation and congenital abnormalities, normal hearing, and no other medical/genetic diagnosis."


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93986 FOXP2 7q31 Dyspraxia Susceptibility to developmental verbal dyspraxia Feuk et al 2006 JSON | XML

Additional Phenotype Details: Impaired ability to sequence movements for speech.

Basic Study Type:  - qRT-PCR (quantitative real-time polymerase chain reaction) to estimate FOXP2 expression

Study Cohort: 
Summary:

- 13 patients with DVD (developmental verbal dyspraxia)
- 9 subjects without DVD (but with deletions or uniparental disomy)

Detail:

"We characterized 22 samples in this study. In this article, we describe 13 individuals with DVD who can be divided into groups on the basis of their genetic characteristics (table 1)—namely, group A, consisting of 5 individuals with 7q31 deletions of FOXP2 on the paternally inherited chromosome; group B, consisting of 1 individual with a 7q31 translocation interrupting FOXP2; and group C, consisting of 7 patients with matUPD7. Table 1 also describes nine individuals without DVD. Group D includes two patients, one with with partial matUPD7 and one with a deletion, with rearrangements starting downstream of FOXP2; group E includes two patients with paternal UPD7 (patUPD7); and group F has five patients with FOXP2 deletions (on the paternally derived chromosome) and a more complex global developmental delay, including speech and language disorder.
"The patients with matUPD7 have also received diagnoses of Silver-Russell Syndrome (SRS [MIM 180860]). . .All individuals described in groups A, B, and C in table 1 had normal hearing. . . All parental karyotypes were normal, indicating that deletions were de novo."
Paper includes further detail.

Genotyping Methods: 
"For qPCR, 2 µg of total RNA was reversely transcribed in a 100-µl reaction with random hexamers, with the use of Taqman Reverse Transcription Reagents kit, and real-time PCR was performed using an ABI7700 sequence-detection system. PCR was performed in 25-µl reactions with 45 cycles of amplification. Each plate contained a water control, a calibrator sample (control 1 cDNA), and serially diluted concentrations of control 3 cDNA (range 62.5–0.5 ng), from which a standard curve was generated for transcript quantification."

Other Details: 


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93986 FOXP2 7q31 Dyspraxia Susceptibility to developmental verbal dyspraxia Lennon et al 2007 JSON | XML

Additional Phenotype Details: Impaired ability to sequence movements for speech.

Basic Study Type:  - aCGH (array comparative genomic hybridization) - FISH (fluorescent in situ hybridization)

Study Cohort: 
Summary: 7 year old boy with developmental verbal dyspraxia, moderate mental retardation, and other developmental issues; his mother and two sisters.

"The propositus (Fig. 1) was born at full-term to a 26-year-old gravida four, para two. The pregnancy was complicated with gestational diabetes controlled by diet. He was delivered by spontaneous vaginal delivery; birth weight was 4025.7 g. He was discharged home at 2 days of life. The family history was significant for a maternal uncle, approximately 35 years of age, with mental retardation that ‘‘looks different’’ by report. He does not speak; however, he can understand a conversation and communicate via nonverbal cues. He has been noted to have similar features to the propositus. No pictures of him were available for review unfortunately, neither was he available for genetic studies. The maternal grandmother had one pregnancy that ended in a first trimester miscarriage. The propositus has two sisters, one 13, the other one 8 years of age, both of them healthy. The mother noticed that her son was not gaining milestones appropriately by age 5 months. It was also noticed that he was not opening his eyes properly. The medical history is significant for global developmental delay, congenital ptosis and plagiocephaly. The plagiocephaly was treated with helmet therapy for 9 months starting at about 6 months of age. The skull asymmetry improved after the helmet therapy was instituted. He had congenital ptosis that required surgical correction at 2 years of age. Developmentally, he rolled at 9 months, sat upright at 16 months, was able to walk well after 26 months of age and run at age 3 years. He could go up and down stairs at 4 years. He developed a pincer grasp at 2 years. In terms of speech/language milestones, he used his first words (single word language) at age 3 years. He has never spoken using phrases or ‘‘word combinations.’’ There is no history of difficulties with feeding. He does have a history of drooling; this has improved with age although it is still noticeable when he is concentrating intently; he also has low oral-motor tone.
"A psychological evaluation was conducted when the patient was seven years, 4 months. The instruments utilized included the Bayley Scales of Infant Development, Third Edition, the Vineland Adaptive Behavior Scales, Interview Edition, and the Autism Diagnostic Observation Schedule, Module One. The results of the evaluation revealed that his overall cognitive abilities were most like those of a child around the age of 42 months. His receptive language skills were at the 32-month-old level; while his expressive language abilities fell at the 21-month-old level. He was observed to drool during the evaluation, and was also noted to have low oral-motor tone. Based on the pattern of his language abilities, and issues with his oral-motor tone, he does meet criteria as having developmental verbal dyspraxia. His mother’s reports of his adaptive behavior revealed mild deficits in the areas of communication, self-help skills, and socialization. Based on his overall cognitive abilities and his mother’s reports of his adaptive behavior, the patient met formal criteria for moderate mental retardation. Although he exhibited delays in both receptive and expressive language, relative to overall cognition, his expressive language skills were significantly more delayed. The patient did not meet ADOS-G criteria for autism. He used a range of nonverbal gestures, his vocalizations were socially directed, he exhibited shared enjoyment in interactions, exhibited excellent pretend-play skills, and used eye contact for the purposes of modulating social interactions. Some hand-wringing and some repetitive play was noted on occasion, but he did not exhibit any unusual sensory interests.
"Physical exam at 7 years of age showed: FOC 54 cm (90th centile), height 123.9 cm (75th centile), weight is 25.3 kg (50–75th centile). He was dysmorphic. There was plagiocephaly over the left aspect of the occiput. There was hypoplasia of the supraorbital ridges. The eyebrows were arched at their outer third. He had long eyelashes. There were scars in the eyebrow regions from ptosis correction surgery. His eyes overall appeared small. There was hypertelorism noted. The nose was bulbous. The ears were normally shaped but anteriorly rotated. Mouth and throat were benign although he had a high arched palate. Inspection of his chest reveals that his nipples were hypoplastic and very low set. Abdomen, genitourinary and skeletal exam was normal.
"Testing to assess the etiology of his problems included: EMG/NCV, chromosomes, fragile X testing, mitochondrial DNA testing, myotonic dystrophy DNA testing, urine organic acids, serum amino acids, lactate, CPK, ammonia, and thyroid function tests; all of them were reported as normal. He also had normal hearing evaluations. A brain MRI at age six and one-half years was normal. A follow-up blood sample was sent for comparative genomic hybridization microarray studies."

Genotyping Methods: 
"Array-Based Comparative Genomic Hybridization. Version 5.0 of our array-CGH, by which our patient was examined, contains 853 BAC and PAC clones designed to cover genomic regions of 75 known genomic disorders and all the clinically relevant subtelomeric regions. Our array also includes pericentric clones for detecting markers with centromeres, and clones broadly spanning chromosomes 13, 18, 21, X, and Y for detection of these most common aneuploidies. This array-CGH is now routinely used in our Cytogenetics Laboratory for chromosome microarray analysis and is built upon a previously published version of the microarray [Cheung et al., 2005]. Clone preparation, hybridization and microarray data analysis were performed as previously described [Yu et al., 2003]. Chemical modification of BAC DNA and attaching it efficiently to an unmodified glass surface to produce arrays was performed as previously described [Cai et al., 2002].
"FISH Analysis. FISH analysis for confirming the clone deletions or duplications on the BAC array-CGH are routinely performed using standard procedures. Briefly, the BAC clone of interest (RP11–12L9) was grown in TB media with 20 ug/ml chloramphenicol. DNA was isolated using a standard alkaline lysis kit (Eppendorf Plasmid Mini Prep; Hamburg, Germany). DNA was labeled using digoxigenin-11-UTP (target) and detected with anti-digoxigenin-rhodamine fragments. Digital FISH images were captured by a Power Macintosh G3 System and MacProbe version 4.4 (Applied Imaging; San Jose, CA).
"The Illumina Sentrix HumanHap300 Genotyping BeadChip. The Illumina HumanHap300 BeadChip enables whole-genome genotyping of over 317,000 tagSingle Nucleotide Polymorphism (tagSNP) markers derived from the International HapMap Project (www.hapmap.org). This BeadChip employs the SBE-based (single base extension) Infinium II assay developed by Illumina. The mean spacing between SNPs is 9 kb providing an effective resolution of ~90 kb using a ten SNP moving average along the genome. In this study, Infinium genotyping was performed according to the Infinium User’s manual, and the Illumina HumanHap300 BeadChip was hybridized, washed and scanned as previously reported [Peiffer et al., 2006]. . While the SNPs allow detection of allelic variation, genomic imbalances can also be detected with the array using statistical techniques [Lai and Zhao, 2005]. High-density coverage of the genome allows for fine mapping of breakpoints when deletions or duplications are detected."

Other Details: 
WNT2 is also deleted in the 7-year-old boy.


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93986 FOXP2 7q31 SLI Speech articulation Rice et al 2009 JSON | XML

Additional Phenotype Details: May be tested using the Goldman Fristoe Test of Articulation (GFTA).

Basic Study Type:  Linkage and association studies

Study Cohort: 
Summary:

322 subjects (86 probands, 134 siblings, 102 parents and other relatives)

Detail:

Participants "were drawn from an ongoing longitudinal study of Specific Language Impairment. . .There were 86 probands, mean ages 6;1 to 8;10 across variables, ascertained from school speech pathology caseloads followed by assessment to meet the requirements of the study. There were a total of 134 siblings: 77 males, mean age 8;6; 57 females, mean age 8;5. Previous studies report longitudinal outcomes for part of this sample, documenting that the children’s language impairments persist into adolescence [13, 69–72]."

Genotyping Methods: 
For linkage study:

"Several extended families were included, and some phenotypes were available for relatives besides siblings. The pair counts for each phenotype by the type of relative are shown in Table 3, and these data were included in the linkage analyses. . .Well-characterized microsatellite markers in the critical regions of linkage were identified through the NCBI UNISTS website, with intermarker centimorgan distances taken from the Rutgers Combined Linkage-Physical map v2 [89]. Markers were selected to be about 2 cM apart, particularly targeting the candidate genes. The positions and heterogeneity of each marker are shown in Table 4.

"Fluorescent labeled primers for the selected markers were obtained from Applied Biosystems (Foster City, CA) or IDT (Coralville, IA) and genotyping was done on an AB 3730 DNA Analyzer (Applied Biosystems, Foster City, CA). Allele calls were reviewed by two experienced technologists and were checked for inheritance and recombination errors using the programs GAS [90] and MERLIN [91]. Any markers with unresolvable genotypes were re-run and re-evaluated or eliminated from the analysis."

For association study:

"We genotyped 53 SNPs covering the candidate genes DCDC2 and KIAA0319 on chromosome 6p22 and the FOXP2 region of chromosome 7. SNPs were selected which tag regions of linkage disequilibrium using the Tagger function on HapMap (URL), along with SNPs selected to replicate previously reported associations and haplotypes with RD. In all, 36 SNPs were genotyped on chromosome six spanning the genes DCDC2, KIAA0319, and TTRAP. On chromosome 7, we genotyped 17 SNPs spanning FOXP2, including the region upstream of the gene. . .Genotyping was done on a Sequenom MassArray iPlex system."

Analysis Methods: 
Linkage analysis:

The authors performed linkage analysis with both quantitative and categorical measures, using MERLIN and verifying the results by running the same quantitative analysis using the DeFries-Fulker Augmented analysis.

Association analysis:

"Only quantitative traits were used in this analysis, and analysis was again done by two methods: QTDT and FBAT. The same quantitative measures were used as in the linkage analyses. "

Other Details: 
Inclusion criteria:

"Probands met four entrance screening criteria. The first was nonverbal intelligence above 85. For children ages 3;6 to 6;11 it was measured with the Columbia Mental Maturity Scales [73] and for children ages 7–17, the performance IQ scales from the Wechsler Intelligence Test for Children [74] were utilized. Parents and children ages 17 years and older were evaluated with the performance scales for the Wechsler Intelligence Test for Adults [75]. Probands met exclusionary criteria for nonverbal intelligence; this requirement was not met for parents and siblings whose intellectual status was an outcome of the study. The second criterion for the probands was normal hearing acuity. The third was no history of neurological disorders or diagnosis of autism. The fourth was intelligible speech sufficient for language transcription and production of target phonemes used in word final morphology, as in “goes” and “talks.” Probands were identified as SLI based on language performance one standard deviation or more below the mean on an age appropriate language test. All probands were screened for articulation to ensure they could produce the phonemes needed for morphological measurement and sufficient intelligibility for reliable spontaneous language transcription. Family members received age appropriate speech, language, and reading assessments. Siblings were recruited from age 2 years to adulthood. Within age levels, all participants received the same assessments. The probands and siblings received multiple times of measurement as part of the longitudinal study. For the phenotyping in this study, the lowest value of each variable of interest was selected. This is in keeping with the methods used in the SLI Consortium studies where past or current language performance was used to identify probands [3]. Further, the lowest performance estimate captures the late talker status of siblings."

Diagnostic criteria:

"Probands were identified as SLI based on language performance one standard deviation or more below the mean on an age appropriate language test."

Tests used:

Woodcock and GORT (reading)
GFTA (articulation)
MLU, TEGI, CTOPP, PPVT and the Omnibus language score ("facets of language").

Associated Markers:
rs12705970  (P = 0.0295)  - Allele: C; FBAT


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93986 FOXP2 7q31 SLI General language skills Rice et al 2009 JSON | XML

Additional Phenotype Details: 

The following are examples of standardized tests for various aspects of language ability:

Clinical Evaluation of Language Fundamentals (CELF)
Test of Language Development (TOLD)
Test of Early Grammatical Impairment (TEGI)
Comprehensive Test of Phonological Processing subtest (CTOPP)
Peabody Picture Vocabulary Test (PPVT)

Additional measures include utterance length and performance on a non-word repetition task (NWR).

Basic Study Type:  Linkage and association studies

Study Cohort: 
Summary:

322 subjects (86 probands, 134 siblings, 102 parents and other relatives)

Detail:

Participants "were drawn from an ongoing longitudinal study of Specific Language Impairment. . .There were 86 probands, mean ages 6;1 to 8;10 across variables, ascertained from school speech pathology caseloads followed by assessment to meet the requirements of the study. There were a total of 134 siblings: 77 males, mean age 8;6; 57 females, mean age 8;5. Previous studies report longitudinal outcomes for part of this sample, documenting that the children’s language impairments persist into adolescence [13, 69–72]."

Genotyping Methods: 
For linkage study:

"Several extended families were included, and some phenotypes were available for relatives besides siblings. The pair counts for each phenotype by the type of relative are shown in Table 3, and these data were included in the linkage analyses. . .Well-characterized microsatellite markers in the critical regions of linkage were identified through the NCBI UNISTS website, with intermarker centimorgan distances taken from the Rutgers Combined Linkage-Physical map v2 [89]. Markers were selected to be about 2 cM apart, particularly targeting the candidate genes. The positions and heterogeneity of each marker are shown in Table 4.

"Fluorescent labeled primers for the selected markers were obtained from Applied Biosystems (Foster City, CA) or IDT (Coralville, IA) and genotyping was done on an AB 3730 DNA Analyzer (Applied Biosystems, Foster City, CA). Allele calls were reviewed by two experienced technologists and were checked for inheritance and recombination errors using the programs GAS [90] and MERLIN [91]. Any markers with unresolvable genotypes were re-run and re-evaluated or eliminated from the analysis."

For association study:

"We genotyped 53 SNPs covering the candidate genes DCDC2 and KIAA0319 on chromosome 6p22 and the FOXP2 region of chromosome 7. SNPs were selected which tag regions of linkage disequilibrium using the Tagger function on HapMap (URL), along with SNPs selected to replicate previously reported associations and haplotypes with RD. In all, 36 SNPs were genotyped on chromosome six spanning the genes DCDC2, KIAA0319, and TTRAP. On chromosome 7, we genotyped 17 SNPs spanning FOXP2, including the region upstream of the gene. . .Genotyping was done on a Sequenom MassArray iPlex system."

Analysis Methods: 
Linkage analysis:

The authors performed linkage analysis with both quantitative and categorical measures, using MERLIN and verifying the results by running the same quantitative analysis using the DeFries-Fulker Augmented analysis.

Association analysis:

"Only quantitative traits were used in this analysis, and analysis was again done by two methods: QTDT and FBAT. The same quantitative measures were used as in the linkage analyses. "

Other Details: 
Inclusion criteria:

"Probands met four entrance screening criteria. The first was nonverbal intelligence above 85. For children ages 3;6 to 6;11 it was measured with the Columbia Mental Maturity Scales [73] and for children ages 7–17, the performance IQ scales from the Wechsler Intelligence Test for Children [74] were utilized. Parents and children ages 17 years and older were evaluated with the performance scales for the Wechsler Intelligence Test for Adults [75]. Probands met exclusionary criteria for nonverbal intelligence; this requirement was not met for parents and siblings whose intellectual status was an outcome of the study. The second criterion for the probands was normal hearing acuity. The third was no history of neurological disorders or diagnosis of autism. The fourth was intelligible speech sufficient for language transcription and production of target phonemes used in word final morphology, as in “goes” and “talks.” Probands were identified as SLI based on language performance one standard deviation or more below the mean on an age appropriate language test. All probands were screened for articulation to ensure they could produce the phonemes needed for morphological measurement and sufficient intelligibility for reliable spontaneous language transcription. Family members received age appropriate speech, language, and reading assessments. Siblings were recruited from age 2 years to adulthood. Within age levels, all participants received the same assessments. The probands and siblings received multiple times of measurement as part of the longitudinal study. For the phenotyping in this study, the lowest value of each variable of interest was selected. This is in keeping with the methods used in the SLI Consortium studies where past or current language performance was used to identify probands [3]. Further, the lowest performance estimate captures the late talker status of siblings."

Diagnostic criteria:

"Probands were identified as SLI based on language performance one standard deviation or more below the mean on an age appropriate language test."

Tests used:

Woodcock and GORT (reading)
GFTA (articulation)
MLU, TEGI, CTOPP, PPVT and the Omnibus language score ("facets of language").

Associated Markers:
rs17137124  (P = 0.0408)  - Allele: T; FBAT


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93986 FOXP2 7q31 SCZD Poverty of speech Tolosa et al 2010 JSON | XML

Additional Phenotype Details: Meaured using the Manchester scale.

Basic Study Type:  - Candidate gene sequencing - Screening for potential expansion of trinucleotide repeats - Methylation analysis of CpG island (postmortem) - qRT-PCR (quantitative real-time polymerase chain reaction) (postmortem)

Study Cohort: 
"For the association study, 293 patients and 340 healthy unrelated controls were analyzed. All patients and controls were Caucasians of Spanish descent."

"For methylation and expression analyses, human brain samples were kindly donated by the London Neurodegenerative Diseases Brain Bank at the Institute of Psychiatry. Grey tissue from both hemispheres of the superior temporal gyrus, parahippocampus gyrus and cingulate gyrus was obtained. For methylation analyses, one sample for each region was analyzed for both patients and controls. For expression analyses, 13 samples from patients (6 from the right hemisphere and 7 from the left hemisphere) and 12 samples from controls (9 from the right and 3 from the left hemisphere) were analyzed."

Genotyping Methods: 
"A total of 27 polymorphisms were analyzed, 10 of them by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and 17 by an iPLEX genotyping assay (Sequenom, CA, USA). Details of the primer sequences, PCR conditions and restriction enzymes are described in Additional files 1 and 2.
"Three regions were screened for potential trinucleotide expansions: two polyQ tracts of 40 and 10 residues, located respectively in exons 5 and 6 of FOXP2, and a CGG-rich region in intron s1 close to the transcription start site. Primers flanking the three regions were designed (see Additional file 1). One primer in each pair was 5’-labeled with 6-FAM or HEX fluorophores. Fluorescent amplicons were electrophoresed with internal lane size standards in an ABI PRISM® 3700 DNA Analyzer (Applied Biosystems Inc.) and length of fragments was analyzed with the GeneScan-v3.7 (Applied Biosystems, Inc.)."

Methylation analysis

"DNA from brain samples was extracted using a Nucleon® Genomic DNA Extraction Kit (Tepnel Life
Sciences). DNA from leukocyte samples was extracted using the Puregene kit (Gentra Systems).
DNA was fragmented with EcoRI (New England Biolabs) prior to overnight digestion with Proteinase K
(Sigma Aldrich). DNA was cleaned, purified and concentrated using a Qiaex II kit (Qiagen). The processed DNA samples were treated with either the CpGenome™ DNA Modification Kit (Chemicon® International) or the EpiTect Bisulfite Kit (Qiagen) in accordance with the supplier’s guidelines.
"DNA was amplified with specific primers for bisulphite-converted DNA (see Additional file 1). PCR fragments were cloned into the PCR 2.1 vector using the TOPO cloning kit (Invitrogen), or pGEM-T® vector using the pGEM-T® Easy Vector System (Promega), and sequenced with T7 and SP6 universal primers."

Analysis Methods: 
"Statistical and genetic analyses were performed using Haploview v4.1, UNPHASED 3.10, and SSPS v13 software. Bonferroni correction was used for multiple tests. For the haplotype association study, four marker sliding windows were used, with the exception of a five marker haplotype, for which association had been detected in a previous study [24]."

Other Details: 
"Exclusion criteria included organic brain syndromes, mental retardation, severe drug abuse, or inability to understand simple questions. Participants with previous psychiatric treatment were excluded as controls."


Diagnostic criteria

"All patients met DSM-IV criteria for schizophrenia. The Manchester scale [25], and the psychotic symptom rating scale (PSYRATS) [26], were used respectively, to assess the clinical psychotic symptoms, with particular attention to the Poverty of speech item, and the intensity of auditory hallucinations."

Expression analysis

"Total RNA was extracted with the RNeasy Lipid Tissue Mini Kit (Qiagen). Reverse transcription of 1 µg of RNA was performed using SuperScriptTM III Reverse Transcriptase (Invitrogen) and random primer hexanucleotides (Promega).
"Quantitative RT-PCR was performed in triplicate for each sample on an iCycler iQ Real Time PCR System (Qiagen) with Power SYBR® Green PCR Master Mix (Applied Biosystems) using a standard protocol. Specific cDNA primers for FOXP2 and RPII, used as a control gene, were designed. Sequences and PCR conditions are shown in Additional file 1. The comparative CT method (delta delta CT) was used to measure the relative gene expression."

Associated Markers:
rs2253478  (P = 0.038)  - After Bonferroni correction


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93986 FOXP2 7q31 SCZD Methylation on a CpG island in the first exon higher in left than right parahippocampal gyrus Tolosa et al 2010 JSON | XML

Basic Study Type:  - Candidate gene sequencing - Screening for potential expansion of trinucleotide repeats - Methylation analysis of CpG island (postmortem) - qRT-PCR (quantitative real-time polymerase chain reaction) (postmortem)

Study Cohort: 
"For the association study, 293 patients and 340 healthy unrelated controls were analyzed. All patients and controls were Caucasians of Spanish descent."

"For methylation and expression analyses, human brain samples were kindly donated by the London Neurodegenerative Diseases Brain Bank at the Institute of Psychiatry. Grey tissue from both hemispheres of the superior temporal gyrus, parahippocampus gyrus and cingulate gyrus was obtained. For methylation analyses, one sample for each region was analyzed for both patients and controls. For expression analyses, 13 samples from patients (6 from the right hemisphere and 7 from the left hemisphere) and 12 samples from controls (9 from the right and 3 from the left hemisphere) were analyzed."

Genotyping Methods: 
"A total of 27 polymorphisms were analyzed, 10 of them by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and 17 by an iPLEX genotyping assay (Sequenom, CA, USA). Details of the primer sequences, PCR conditions and restriction enzymes are described in Additional files 1 and 2.
"Three regions were screened for potential trinucleotide expansions: two polyQ tracts of 40 and 10 residues, located respectively in exons 5 and 6 of FOXP2, and a CGG-rich region in intron s1 close to the transcription start site. Primers flanking the three regions were designed (see Additional file 1). One primer in each pair was 5’-labeled with 6-FAM or HEX fluorophores. Fluorescent amplicons were electrophoresed with internal lane size standards in an ABI PRISM® 3700 DNA Analyzer (Applied Biosystems Inc.) and length of fragments was analyzed with the GeneScan-v3.7 (Applied Biosystems, Inc.)."

Methylation analysis

"DNA from brain samples was extracted using a Nucleon® Genomic DNA Extraction Kit (Tepnel Life
Sciences). DNA from leukocyte samples was extracted using the Puregene kit (Gentra Systems).
DNA was fragmented with EcoRI (New England Biolabs) prior to overnight digestion with Proteinase K
(Sigma Aldrich). DNA was cleaned, purified and concentrated using a Qiaex II kit (Qiagen). The processed DNA samples were treated with either the CpGenome™ DNA Modification Kit (Chemicon® International) or the EpiTect Bisulfite Kit (Qiagen) in accordance with the supplier’s guidelines.
"DNA was amplified with specific primers for bisulphite-converted DNA (see Additional file 1). PCR fragments were cloned into the PCR 2.1 vector using the TOPO cloning kit (Invitrogen), or pGEM-T® vector using the pGEM-T® Easy Vector System (Promega), and sequenced with T7 and SP6 universal primers."

Analysis Methods: 
"Statistical and genetic analyses were performed using Haploview v4.1, UNPHASED 3.10, and SSPS v13 software. Bonferroni correction was used for multiple tests. For the haplotype association study, four marker sliding windows were used, with the exception of a five marker haplotype, for which association had been detected in a previous study [24]."

Other Details: 
"Exclusion criteria included organic brain syndromes, mental retardation, severe drug abuse, or inability to understand simple questions. Participants with previous psychiatric treatment were excluded as controls."


Diagnostic criteria

"All patients met DSM-IV criteria for schizophrenia. The Manchester scale [25], and the psychotic symptom rating scale (PSYRATS) [26], were used respectively, to assess the clinical psychotic symptoms, with particular attention to the Poverty of speech item, and the intensity of auditory hallucinations."

Expression analysis

"Total RNA was extracted with the RNeasy Lipid Tissue Mini Kit (Qiagen). Reverse transcription of 1 µg of RNA was performed using SuperScriptTM III Reverse Transcriptase (Invitrogen) and random primer hexanucleotides (Promega).
"Quantitative RT-PCR was performed in triplicate for each sample on an iCycler iQ Real Time PCR System (Qiagen) with Power SYBR® Green PCR Master Mix (Applied Biosystems) using a standard protocol. Specific cDNA primers for FOXP2 and RPII, used as a control gene, were designed. Sequences and PCR conditions are shown in Additional file 1. The comparative CT method (delta delta CT) was used to measure the relative gene expression."


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93986 FOXP2 7q31 Dyslexia Finger succession-dominant hand (FS-D) task Peter et al 2011 JSON | XML

Additional Phenotype Details: 
Task in which subject touches thumb to each finger in succession. Score is time for five repetitions in dominant hand.

Reference

Berninger VW, Rutberg J. Relationship of finger function to beginning writing: application to diagnosis of writing disabilities. Dev Med Child Neurol. 1992;34(3):198–215.

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:
rs923875  (P = 0.0211, 0.0035)  - Entire sample and parent cohort only, respectively. Linear association modeling; based on QQ evidence.
rs7782412  (P = 0.0456)  - QTDT
rs936146  (P = 0.0253)  - Parent cohort only; linear association modeling
rs12533005  (P = 0.0223)  - Parent cohort only; linear association modeling; based on QQ evidence


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93986 FOXP2 7q31 Dyslexia Rapid alternating place of articulation Peter et al 2011 JSON | XML

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:
rs12533005  (P = 0.0061)  - Parent cohort only; linear association modeling
rs10230558  (P = 0.0498)  - Parent cohort only; linear association modeling


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93986 FOXP2 7q31 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:
rs7782412  (P = 0.0174)  - QTDT; based on QQ evidnce
rs936146  (P = 0.0067)  - Proband cohort only; linear association modeling; based on QQ evidence.


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93986 FOXP2 7q31 Dyslexia Real-word reading Peter et al 2011 JSON | XML

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:
rs923875  (P = 0.0046)  - Parent cohort only; linear association modeling; based on QQ evidence
rs7782412  (P = 0.042, 0.0086, 0.001)  - First value: QTDT Second value: Linear association modeling within entire sample; based on QQ evidence Third value: Linear association modeling in proband cohort only; based on QQ evidence


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