A family-based association study does not support DYX1C1 on 15q21.3 as a candidate gene in developmental dyslexia

Department of Child Psychiatry, Scientific Institute 'Eugenio Medea', via Don L Monza 20, 23842 Bosisio Parini, Italy.
European Journal of HumanGenetics (Impact Factor: 4.35). 04/2005; 13(4):491-9. DOI: 10.1038/sj.ejhg.5201356
Source: PubMed


We applied a family-based association approach to investigate the role of the DYX1C1 gene on chromosome 15q as a candidate gene for developmental dyslexia (DD) to 158 families containing at least one dyslexic child. We directly sequenced exons 2 and 10 of the DYX1C1 gene and found eight single nucleotide polymorphism (SNPs), three of which (-3G>A, 1249 G>T, 1259 C>G) were suitable for the genetic analyses. We performed single- and multimarker association analyses with DD as a categorical trait by FBAT version 1.4 and TRANSMIT version 2.5.4 programs. Our sample had a power of at least 80% to detect an association between the selected phenotypes and the informative polymorphisms at a significance level of 5%. The results of the categorical analyses did not support the involvement of the DYX1C1 gene variants in this sample of dyslexics and their relatives. Quantitative and multimarker analyses, which provide greater power to detect loci with a minor effect, consistently yielded nonsignificant results. While D1X1C1 is a good candidate gene for DD, we were unable to replicate the original findings between DYX1C1 gene and DD, perhaps due to genetic heterogeneity.

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Available from: Marco Battaglia, Mar 11, 2014
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    • "The dyslexia susceptibility 1 candidate gene 1 (DYX1C1) is the first gene implicated as a candidate gene for dyslexia [1]. Although mixed replication results for DYX1C1 in dyslexia were first reported, several independent studies that followed later have confirmed its association to dyslexia, verbal short term memory and orthographic skills in many populations [2], [3], [4], [5], [6], [7], [8], [9], [10]. "
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    ABSTRACT: DYX1C1, a susceptibility gene for dyslexia, encodes a tetratricopeptide repeat domain containing protein that has been implicated in neuronal migration in rodent models. The developmental role of this gene remains unexplored. To understand the biological function(s) of zebrafish dyx1c1 during embryonic development, we cloned the zebrafish dyx1c1 and used morpholino-based knockdown strategy. Quantitative real-time PCR analysis revealed the presence of dyx1c1 transcripts in embryos, early larval stages and in a wide range of adult tissues. Using mRNA in situ hybridization, we show here that dyx1c1 is expressed in many ciliated tissues in zebrafish. Inhibition of dyx1c1 produced pleiotropic phenotypes characteristically associated with cilia defects such as body curvature, hydrocephalus, situs inversus and kidney cysts. We also demonstrate that in dyx1c1 morphants, cilia length is reduced in several organs including Kupffer's vesicle, pronephros, spinal canal and olfactory placode. Furthermore, electron microscopic analysis of cilia in dyx1c1 morphants revealed loss of both outer (ODA) and inner dynein arms (IDA) that have been shown to be required for cilia motility. Considering all these results, we propose an essential role for dyx1c1 in cilia growth and function.
    Full-text · Article · May 2013 · PLoS ONE
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    • "DYX1C1 was identified by mapping the chromosome translocation breakpoint . Initially, DYX1C1 had been implicated in dyslexia in a group of Finnish families (Taipale et al., 2003), but not in English or Italian families (Bellini et al., 2005; Marino et al., 2005; Scerri et al., 2004). More recently, however, Marino et al. (2007) reanalysed their sample reported in 2005, and found that DYX1C1 influences a broader phenotypic definition of dyslexia in Italian families. "
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    ABSTRACT: Behavioural studies have shown that dyslexics are a heterogeneous population and between-group comparisons are thus inadequate. Some subjects do not develop dyslexia despite having a deficit implicated in this disorder, which points to protective factors. Dyslexia co-occurs with ADHD, DCD, SLI, and SSD, so that future behavioural studies will need to screen and/or statistically control for other disorders. Studies of multiple cases of DPs with other developmental disorders are necessary. Neuroimaging findings show structural and/or functional brain abnormalities in language areas, V5/MT and the cerebellum. Future neuroimaging studies need to investigate the whole reading network and multiple cases. Six dyslexia risk genes have been found, mostly involved in neural migration, which may suggest dyslexia is a deficit of neuronal migration. However, it is not clear how these genes can restrict migration to specific brain areas. As a complex and heterogeneous disorder, dyslexia is likely to be associated with several mutated genes. ADHD and SSD are characterised by genetic risk factors which are partially shared with dyslexia, resulting in comorbidity. Future genetic studies need to focus on identifying other risk genes and pleiotropic genes involved in comorbidities, and linking genotypes implicated in dyslexia with brain structure. Any theory of dyslexia needs to take into account a multitude of risk and protective factors across behavioural, neural and genetic domains.
    Full-text · Article · Aug 2012 · Acta Neuropsychologica
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    • "Multiple groups have investigated the relationship of alleles of both polymorphisms to dyslexia phenotypes. Association of one of these putative functional alleles with dyslexia was found in a study of Chinese children (Lim et al., 2011) and with short-term memory in Italian dyslexics (Marino et al., 2007), but other groups found only modest association with the major alleles (Scerri et al., 2004; Wigg et al., 2004; Brkanac et al., 2007), and yet others failed to detect an association with any of the alleles (Bellini et al., 2005; Cope et al., 2005b; Marino et al., 2005; Meng et al., 2005a; Bates et al., 2010), suggesting that none of these SNPs is the susceptibility determinant. However, expression of a construct containing the −3A allele of rs3743205 was lower than one containing the −3G allele when transfected into a neuroblastoma cell line (Tapia-Páez et al., 2008). "
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    ABSTRACT: This article provides an overview of (a) issues in definition and diagnosis of specific reading disabilities at the behavioral level that may occur in different constellations of developmental and phenotypic profiles (patterns); (b) rapidly expanding research on genetic heterogeneity and gene candidates for dyslexia and other reading disabilities; (c) emerging research on gene-brain relationships; and (d) current understanding of epigenetic mechanisms whereby environmental events may alter behavioral expression of genetic variations. A glossary of genetic terms (denoted by bold font) is provided for readers not familiar with the technical terms.
    Full-text · Article · Jan 2012 · Frontiers in Psychology
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