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Speech/Language Disorders Database

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Gene / phenotype associations for ROBO1

  • Click column headers to sort. Click to expand any row to see more details about the particular assertion of an association between variants of ROBO1 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
6091 ROBO1 3p12 Dyslexia Reduced expression of ROBO1 on chromosomes from dyslexics Hannula-Jouppi et al 2005 JSON | XML

Conflicting Studies:

  • Venkatesh et al (2013) - Failed to find association between 6227 C>A, 6483 T>A, or 6923 T>G and dyslexia.
  • Basic Study Type:  - Candidate gene sequencing - FISH (fluorescent in situ hybridization)

    Study Cohort: 
    (1) "A multiplex four-generation family with severe dyslexia segregating in a dominant fashion. . .Detailed psychological evaluation of this family has been reported elsewhere [19]."

    (2) "A dyslexic individual with a balanced reciprocal translocation t (3;8) (p12;q11) came to our attention because of infertility and was diagnosed with oligoteratozoospermia. He has three siblings, and all four children have been neuropsychologically evaluated at a specialist hospital. However, the family members were not available for retesting and thus our data are based on the clinical records. The translocation carrier and his sister were diagnosed with severe dyslexia while the other two siblings had subnormal intelligence, but not dyslexia. The mother was reported as a good reader, but no information on reading performance was available on the deceased father. The other three siblings have a normal karyotype, whereas the parents were not available for karyotyping. Because the index case presented with infertility, but no such history or miscarriages were recorded for his mother, it is likely that the translocation had arisen de novo."

    (3) "For association studies, dyslexic and non-dyslexic individuals were recruited from 23 unrelated families and 33 unrelated dyslexic and non-dyslexic couples from the Department of Pediatric Neurology at the Hospital for Children and Adolescents, University of Helsinki, and the Child Research Centre, Jyva¨ skyla , Finland. Additional population controls consisted of 100 anonymous blood donors."

    Genotyping Methods: 
    (1) In the four-generation family:
    "All ROBO1 and DUTT1 exons were PCR-amplified and sequenced from genomic DNA and the cDNA of selected individuals from the large linkage pedigree (Figure 2A). In addition, the novel exonic sequences were identified and 2 kb of ROBO1 promoter region upstream of the novel exon a and the 3' UTR of ROBO1 variant 2 were sequenced. BACs corresponding to exons were identified through BLAST searches. Primate DNA samples were obtained from the Coriell Institute (Camden, New Jersey, United States) (Primate Panel PRP00001) and orthologs of ROBO1 were sequenced directly after PCR with human-specific primers.

    "RNA was extracted from EBV transformed lymphocyte cell lines from four dyslexic and four normal readers by Ficoll gradient centrifugation (Qiagen Rneasy purification kit) and RT-PCR was used to amplify cDNA segments containing heterozygous SNPs in genomic DNA. As controls, we used genomic DNA samples from the same individuals as well as brain mRNA (Clontech, Palo Alto, California, United States). All sequencing was performed using dye-terminator chemistry and automated sequencers (ABI, Columbia, Maryland, United States)."

    (2) To identify translocation breakpoint in the individual:
    "YAC clones A136E9 (Washington University, St. Louis, Missouri, United States), 34FC9, 15AC10, 39F13, 2DG9, 25DH8, 35AH8 (ICI/Zeneca), 912A11, 934E8, 422A6, 959F5, 650C2, 938D4, and BAC RP11-143B12 were used as probes in fluorescence in situ hybridization experiments. The genomic sequence of clone RP11-143B12 was obtained by BLAST search with the BAC 5' and 3' ends (AQ373182, T7, and AQ373179 Sp6, respectively) to a Chromosome 3 scaffold sequence on the Celera public database (http://public.celera.com/cds/login.cfm) and to BACs in the National Center for Biotechnology CBI database (http://www.ncbi.nlm.nih.gov/).

    "Southern hybridization probes were PCR-amplified genomic fragments from non-repetitive regions on the BAC clone RP11-143B12. The repeats in the clone sequence were detected by RepeatMasker (http://repeatmasker.genome.washington.edu/cgi-bin/RepeatMasker) and PCR primers were designed by Primer3 (http://frodo.wi.mit.edu/cgi-bin/primer3/primer3_www.cgi) to encompass non-repetitive segments of 700–1,000 bp (primer sequences available from authors on request). PCR assays were performed under standard conditions and 10 ng of the purified PCR products (Qiagen PCR purification kit) (Qiagen, Valencia, California, United States) and 10 ng of the purified probes were labeled with [a-32P] dCTP (Rediprime DNA Labeling System, Amersham Biosciences, Little Chalfont, United Kingdom). Southern blotting and hybridizations were performed by standard protocols with seven µg of DNA from the translocation patient and a healthy control individual digested in separate reactions with BamHI, BglII, EarI, EcoRI, HaeII, HindIII, NcoI, and PstI (New England Biolabs, Beverly, Massachusetts, United States)."

    Other Details: 
    Diagnostic criteria:

    (1) In multiplex family: "Dyslexia was diagnosed in 27 out of 74 family members by thorough testing including an intelligence test, a Finnish reading and writing test for adults and for children according to their school grade, and a neuropsychological test battery [49–52]."

    (2) The individual with the translocation was diagnosed with severe dyslexia.

    (3) For association studies: "The diagnosis and degree of dyslexia were determined by Finnish reading and spelling tests designed for children and adults [49,50]. Intelligence was estimated by Wechsler tests for adults (WAIS-R) or for children (WISC-R) [51,52]. The diagnostic criteria for dyslexia included normal performance intelligence quotient (PIQ > 85) and remarkable deviation (depending on age, at least two years) in reading skills."


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    6091 ROBO1 3p12 Nonword repetition Bates 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: 
    "Twins were initially recruited from primary schools in the greater Brisbane area, by media appeals and word of mouth, as part of ongoing studies of melanoma risk factors and cognition (McGregor et al. 1999; Wright et al. 2001). Data were also gathered from non-twin siblings of twins, with families comprising up to five siblings (including twins)."

    "Data were available for 1177 individuals (1111 for the language assessment) with relevant phenotype and genotyping data. In the case of the reading phenotype, this comprised 538 families, and 136 MZ pairs, 343 DZ twin pairs and a further 11 triplets ranging in age from 12.3 to 25.1 years (mean = 17.9, SD = 2.9), 54.5% of whom were female. Numbers were slightly lower for the language phenotype (1111 individuals, 505 families, 126 MZ and 326 DZ pairs, and 9 triplets, mean age 20.1 (SD = 3.4), again 54.5% female)."

    "The sample is 98% Caucasian by self-report, predominantly Anglo-Celtic (~82%) and is typical of the Queensland population on a range of traits including intellectual ability (Schousboe et al. 2003)."

    Genotyping Methods: 
    "DNA was extracted from blood samples and genotyped with Illumina 610K chips. Data-checking procedures were based on exclusion of unreliable samples and SNPs, as described in Benyamin et al. (2009). These included deviation from Hardy–Weinberg equilibrium at P<10-6, minor allele frequency < 0.01, and Mendelian errors. Subjects found to be of non-European ancestry by principal components analysis of the genotyping data were also excluded. One hundred and sixty-six tag SNPs covering the ROBO1 region were selected via Tagger (de Bakker et al., 2005). Of these, 144 were available on the chip and passed quality checks."

    Analysis Methods: 
    "Association analysis of SNPs in the ROBO1 region was conducted using MERLIN (Chen and Abecasis 2007). These analyses model the additive genotypic effect at each SNP as a fixed effect in the means model. These analyses concurrently account for the relatedness among participants by explicitly modeling the covariance structure assuming an AE background genetic model. These analyses also included adjustments for the fixed effects of age (and age squared), sex, performance IQ, and tester within the means model."

    Other Details: 
    Exclusion criteria:

    "Parental report of significant head injury, neurological or psychiatric illness, substance abuse or dependence, or current use of psychoactive medication in either twin. Participants had normal or corrected to normal vision (better than 6/12 Snellen equivalent)."

    Associated Markers:
    rs6803202  (P = 0.000087)  - survives multiple comparisons correction
    rs4535189  (P = 0.000093)  - survives multiple comparisons correction
    rs7653197  (P = 0.0001)
    rs1387665  (P = 0.0001)
    rs7628757  (P = 0.0002)
    rs4130991  (P = 0.0002)
    rs4680960  (P = 0.0002)
    rs6548628  (P = 0.0007)
    rs6548621  (P = 0.0011)
    rs6802848  (P = 0.0014)
    rs7612183  (P = 0.0033)
    rs7356113  (P = 0.0035)
    rs6548651  (P = 0.0037)
    rs7622444  (P = 0.0038)
    rs7429525  (P = 0.0052)
    rs9853895  (P = 0.0052)
    rs9857859  (P = 0.0053)
    rs7623728  (P = 0.0160)
    rs7637338  (P = 0.0190)
    rs7614913  (P = 0.0220)
    rs4264688  (P = 0.0460)


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    6091 ROBO1 3p12 Letter-number sequencing task Bates et al 2011 JSON | XML

    Additional Phenotype Details: A measure of working memory

    Basic Study Type: Association study

    Study Cohort: 
    "Twins were initially recruited from primary schools in the greater Brisbane area, by media appeals and word of mouth, as part of ongoing studies of melanoma risk factors and cognition (McGregor et al. 1999; Wright et al. 2001). Data were also gathered from non-twin siblings of twins, with families comprising up to five siblings (including twins)."

    "Data were available for 1177 individuals (1111 for the language assessment) with relevant phenotype and genotyping data. In the case of the reading phenotype, this comprised 538 families, and 136 MZ pairs, 343 DZ twin pairs and a further 11 triplets ranging in age from 12.3 to 25.1 years (mean = 17.9, SD = 2.9), 54.5% of whom were female. Numbers were slightly lower for the language phenotype (1111 individuals, 505 families, 126 MZ and 326 DZ pairs, and 9 triplets, mean age 20.1 (SD = 3.4), again 54.5% female)."

    "The sample is 98% Caucasian by self-report, predominantly Anglo-Celtic (~82%) and is typical of the Queensland population on a range of traits including intellectual ability (Schousboe et al. 2003)."

    Genotyping Methods: 
    "DNA was extracted from blood samples and genotyped with Illumina 610K chips. Data-checking procedures were based on exclusion of unreliable samples and SNPs, as described in Benyamin et al. (2009). These included deviation from Hardy–Weinberg equilibrium at P<10-6, minor allele frequency < 0.01, and Mendelian errors. Subjects found to be of non-European ancestry by principal components analysis of the genotyping data were also excluded. One hundred and sixty-six tag SNPs covering the ROBO1 region were selected via Tagger (de Bakker et al., 2005). Of these, 144 were available on the chip and passed quality checks."

    Analysis Methods: 
    "Association analysis of SNPs in the ROBO1 region was conducted using MERLIN (Chen and Abecasis 2007). These analyses model the additive genotypic effect at each SNP as a fixed effect in the means model. These analyses concurrently account for the relatedness among participants by explicitly modeling the covariance structure assuming an AE background genetic model. These analyses also included adjustments for the fixed effects of age (and age squared), sex, performance IQ, and tester within the means model."

    Other Details: 
    Exclusion criteria:

    "Parental report of significant head injury, neurological or psychiatric illness, substance abuse or dependence, or current use of psychoactive medication in either twin. Participants had normal or corrected to normal vision (better than 6/12 Snellen equivalent)."

    Associated Markers:
    rs7644521  (P = 0.046)
    rs333491  (P = 0.004)
    rs9309819  (P = 0.021)
    rs11127636  (P = 0.023)
    rs162870  (P = 0.040)


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    6091 ROBO1 3p12 Principal component reading and spelling CORE score Bates et al 2011 JSON | XML

    Additional Phenotype Details: Principal component obtained from Components of Reading Examination (CORE)

    Basic Study Type: Association study

    Study Cohort: 
    "Twins were initially recruited from primary schools in the greater Brisbane area, by media appeals and word of mouth, as part of ongoing studies of melanoma risk factors and cognition (McGregor et al. 1999; Wright et al. 2001). Data were also gathered from non-twin siblings of twins, with families comprising up to five siblings (including twins)."

    "Data were available for 1177 individuals (1111 for the language assessment) with relevant phenotype and genotyping data. In the case of the reading phenotype, this comprised 538 families, and 136 MZ pairs, 343 DZ twin pairs and a further 11 triplets ranging in age from 12.3 to 25.1 years (mean = 17.9, SD = 2.9), 54.5% of whom were female. Numbers were slightly lower for the language phenotype (1111 individuals, 505 families, 126 MZ and 326 DZ pairs, and 9 triplets, mean age 20.1 (SD = 3.4), again 54.5% female)."

    "The sample is 98% Caucasian by self-report, predominantly Anglo-Celtic (~82%) and is typical of the Queensland population on a range of traits including intellectual ability (Schousboe et al. 2003)."

    Genotyping Methods: 
    "DNA was extracted from blood samples and genotyped with Illumina 610K chips. Data-checking procedures were based on exclusion of unreliable samples and SNPs, as described in Benyamin et al. (2009). These included deviation from Hardy–Weinberg equilibrium at P<10-6, minor allele frequency < 0.01, and Mendelian errors. Subjects found to be of non-European ancestry by principal components analysis of the genotyping data were also excluded. One hundred and sixty-six tag SNPs covering the ROBO1 region were selected via Tagger (de Bakker et al., 2005). Of these, 144 were available on the chip and passed quality checks."

    Analysis Methods: 
    "Association analysis of SNPs in the ROBO1 region was conducted using MERLIN (Chen and Abecasis 2007). These analyses model the additive genotypic effect at each SNP as a fixed effect in the means model. These analyses concurrently account for the relatedness among participants by explicitly modeling the covariance structure assuming an AE background genetic model. These analyses also included adjustments for the fixed effects of age (and age squared), sex, performance IQ, and tester within the means model."

    Other Details: 
    Exclusion criteria:

    "Parental report of significant head injury, neurological or psychiatric illness, substance abuse or dependence, or current use of psychoactive medication in either twin. Participants had normal or corrected to normal vision (better than 6/12 Snellen equivalent)."

    Associated Markers:
    rs1995402  (P = 0.040)


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    6091 ROBO1 3p12 Digits-forward memory span Bates et al 2011 JSON | XML

    Additional Phenotype Details: Wechsler Adult Intelligence Scale (WAIS) Digit-Span Forwards Task, a measure of verbal short-term memory

    Basic Study Type: Association study

    Study Cohort: 
    "Twins were initially recruited from primary schools in the greater Brisbane area, by media appeals and word of mouth, as part of ongoing studies of melanoma risk factors and cognition (McGregor et al. 1999; Wright et al. 2001). Data were also gathered from non-twin siblings of twins, with families comprising up to five siblings (including twins)."

    "Data were available for 1177 individuals (1111 for the language assessment) with relevant phenotype and genotyping data. In the case of the reading phenotype, this comprised 538 families, and 136 MZ pairs, 343 DZ twin pairs and a further 11 triplets ranging in age from 12.3 to 25.1 years (mean = 17.9, SD = 2.9), 54.5% of whom were female. Numbers were slightly lower for the language phenotype (1111 individuals, 505 families, 126 MZ and 326 DZ pairs, and 9 triplets, mean age 20.1 (SD = 3.4), again 54.5% female)."

    "The sample is 98% Caucasian by self-report, predominantly Anglo-Celtic (~82%) and is typical of the Queensland population on a range of traits including intellectual ability (Schousboe et al. 2003)."

    Genotyping Methods: 
    "DNA was extracted from blood samples and genotyped with Illumina 610K chips. Data-checking procedures were based on exclusion of unreliable samples and SNPs, as described in Benyamin et al. (2009). These included deviation from Hardy–Weinberg equilibrium at P<10-6, minor allele frequency < 0.01, and Mendelian errors. Subjects found to be of non-European ancestry by principal components analysis of the genotyping data were also excluded. One hundred and sixty-six tag SNPs covering the ROBO1 region were selected via Tagger (de Bakker et al., 2005). Of these, 144 were available on the chip and passed quality checks."

    Analysis Methods: 
    "Association analysis of SNPs in the ROBO1 region was conducted using MERLIN (Chen and Abecasis 2007). These analyses model the additive genotypic effect at each SNP as a fixed effect in the means model. These analyses concurrently account for the relatedness among participants by explicitly modeling the covariance structure assuming an AE background genetic model. These analyses also included adjustments for the fixed effects of age (and age squared), sex, performance IQ, and tester within the means model."

    Other Details: 
    Exclusion criteria:

    "Parental report of significant head injury, neurological or psychiatric illness, substance abuse or dependence, or current use of psychoactive medication in either twin. Participants had normal or corrected to normal vision (better than 6/12 Snellen equivalent)."

    Associated Markers:
    rs6803202  (P = 0.0088)
    rs4535189  (P = 0.0084)
    rs7653197  (P = 0.0057)
    rs1387665  (P = 0.0111)
    rs7628757  (P = 0.0078)
    rs4130991  (P = 0.0074)
    rs4680960  (P = 0.0070)
    rs6548621  (P = 0.0380)
    rs6802848  (P = 0.0170)
    rs7612183  (P = 0.0124)
    rs9853895  (P = 0.0440)
    rs9857859  (P = 0.0440)
    rs7623728  (P = 0.0380)
    rs7614913  (P = 0.0160)
    rs4264688  (P = 0.0074)
    rs7644521  (P = 0.0002)
    rs4564923  (P = 0.0054)
    rs7629503  (P = 0.0062)
    rs9849596  (P = 0.0160)
    rs9309828  (P = 0.0250)
    rs1447833  (P = 0.0420)
    rs723766  (P = 0.0470)


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    Negative evidence for association with ROBO1

    Conflicting Ref Year Original Report Failed Association Comment
    Venkatesh et al 2013 Hannula-Jouppi et al (2005) Reduced expression of ROBO1 on chromosomes from dyslexics (Dyslexia) Failed to find association between 6227 C>A, 6483 T>A, or 6923 T>G and dyslexia.