Genetic linkage analysis of the X chromosome in autism, with emphasis on the fragile X region

Developmental Psychiatry Section, University of Cambridge, Cambridge, England, United Kingdom
Psychiatric Genetics (Impact Factor: 1.94). 07/2005; 15(2):83-90. DOI: 10.1097/00041444-200506000-00004
Source: PubMed


The higher prevalence of autism in males than in females suggests the possible involvement of the X chromosome. To test the hypothesis that there are mutations increasing susceptibility to autism on the X chromosome, and in particular the distal portion of the long arm that encompasses the FMRI and MECP2 loci, a genetic linkage study was performed. Twenty-two fragile X-negative families multiplex for autism and related disorders were used for the study. Linkage analysis, for markers in the Xq27-q28 region, using model-free likelihood-based analysis, produced a maximum MLOD of 1.7 for the narrowest diagnostic category of the typical autism/severe autism spectrum, and nonparametric analysis produced a maximum non-parametric lod (NPL) score of 2.1 for a broad phenotype diagnostic model. Thus, this study offers modest support for a susceptibility locus for autism within the Xq27-q28 region. Further genetic investigations of this region are warranted.

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    • "The genetic architecture of autism is highly complex and heterogeneous. About 10% patients with ASD were comorbid with other syndromic disorders with known causative genetic defects, such as Rett's syndrome, fragile-X syndrome, tuberous sclerosis, Prader–Willi and Angelman syndromes, and Klinefelter syndrome [Veltman et al., 2005; Vincent et al., 2005; Jha et al., 2007; Young et al., 2008; Bishop et al., 2011]. However, the genetic causes of most idiopathic ASD remain unclear. "
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    ABSTRACT: Autism spectrum disorders (ASD) are childhood-onset neurodevelopmental disorders characterized by verbal communication impairments, social reciprocity deficits, and the presence of restricted interests and stereotyped behaviors. Genetic factors contribute to the incidence of ASD evidently. However, the genetic spectrum of ASD is highly heterogeneous. Chromosomal abnormalities contribute significantly to the genetic deficits of syndromic and non-syndromic ASD. In this study, we conducted karyotyping analysis in a sample of 500 patients (447 males, 53 females) with ASD from Taiwan, the largest cohort in Asia, to the best of our knowledge. We found three patients having sex chromosome aneuploidy, including two cases of 47, XXY and one case of 47, XYY. In addition, we detected a novel reciprocal chromosomal translocation between long arms of chromosomes 4 and 14, designated t(4;14)(q31.3;q24.1), in a patient with Asperger's disorder. This translocation was inherited from his unaffected father, suggesting it might not be pathogenic or it needs further hits to become pathogenic. In line with other studies, our study revealed that subjects with sex chromosomal aneuploidy are liable to neurodevelopmental disorders, including ASD, and conventional karyotyping analysis is still a useful tool in detecting chromosomal translocation in patients with ASD, given that array-based comparative genomic hybridization technology can provide better resolution in detecting copy number variations of genomic DNA. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · Oct 2013 · American Journal of Medical Genetics Part B Neuropsychiatric Genetics
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    • "One limitation of this study should be considered. Nine missense/nonsense mutations and 3 deletions within NLGN4 or NLGN3 have been reported by different studies involving about 1500 ASD cases, indicating a low frequency (no more than 1%) of rare variants within NLGN3 and NLGN4 in ASD [4], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24]. Based on these data, our sample size was relatively small to find rare variants. "
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    ABSTRACT: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication, absence or delay in language development, and stereotyped or repetitive behaviors. Genetic studies show that neurexin-neuroligin (NRXN-NLGN) pathway genes contribute susceptibility to ASD, which include cell adhesion molecules , and scaffolding proteins and . Neuroligin proteins play an important role in synaptic function and trans-synaptic signaling by interacting with presynaptic neurexins. Shank proteins are scaffolding molecules of excitatory synapses, which function as central organizers of the postsynaptic density. Sequence level mutations and structural variations in these genes have been identified in ASD cases, while few studies were performed in Chinese population. In this study, we examined the copy numbers of four genes and in 285 ASD cases using multiplex fluorescence competitive polymerase chain reaction (PCR). We also screened the regulatory region including the promoter region and 5'/3' untranslated regions (UTR) and the entire coding region of in a cohort of 285 ASD patients and 384 controls by direct sequencing of genomic DNA using the Sanger method. DNA copy number calculation in four genes showed no deletion or duplication in our cases. No missense mutations in were identified in our cohort. Association analysis of 6 common SNPs in did not find significant difference between ASD cases and controls. These findings showed that these genes may not be major disease genes in Chinese ASD cases.
    Full-text · Article · Feb 2013 · PLoS ONE
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    • "While some findings have suggested X-chromosome involvement (Jacquemont, et al., 2006; Jamain, et al., 2003; Klauck, et al., 2006; Laumonnier, et al., 2004; Liu, et al., 2001; Marshall, et al., 2008; Shao, et al., 2002; Thomas, et al., 1999; Vincent, et al., 2005), no consistent Xchromosome cause has been identified excluding Rett's disorder (O'Roak & State, 2008). "
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    ABSTRACT: Although gender disparity in ASD has been long documented, research addressing gender related to core ASD symptomatology (e.g., domains, severity, breadth, etc.) is scant. The present research examined gender differences in ASD symptomatology in three populations: infants and toddlers at risk for developmental disability, children and adolescents, and adults with intellectual disability (ID). No significant gender differences in ASD symptoms were found in the infant/toddler or child/adolescent populations. In the adult population, in participants with ID alone, females had higher endorsements of social (i.e., participation in social games, sports, and activities; interest in other’s side of the conversation; and imitation) and communication (i.e., interest in other’s side of the conversation and reading body language) impairments compared to males. This study has considerable implications in both the clinical and research realms as for diagnostic and assessment validity and prioritized treatment needs for females with ASD, as well as stimulating a future research agenda (i.e., considerations such as cognitive ability, comorbidity, course and age, qualitative symptom differences, social/environmental gender biases) in this area. KeywordsAutism spectrum symptoms–Gender differences–Intellectual disability–Lifespan
    Full-text · Article · Oct 2011 · Journal of Developmental and Physical Disabilities
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