The Xp Contiguous Deletion Syndrome and Autism

Department of Molecular and Human Genetics, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas 77030, USA.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 06/2009; 149A(6):1138-48. DOI: 10.1002/ajmg.a.32833
Source: PubMed


Xp22 nullisomy in males causes a phenotype consistent with the loss of one or more of the genes located in this chromosomal region. Females with similar Xp deletions rarely manifest the same phenotype. Here we describe a 10-year-old girl with a de novo interstitial deletion encompassing Xp22.2p22.32 who presented with autism, moderate mental retardation, and some dysmorphic features. The deletion was delineated by FISH and STR analyses, and the breakpoints were determined using the Agilent 244 K oligonucleotide array. We found that the 5.5 Mb deletion is located on the paternal X chromosome and encompasses 18 genes. Further molecular and cytogenetic analyses showed unfavorable skewing of X-inactivation of the maternal (intact) chromosome. The phenotype of our patient was compared with previously reported female patients with deletions encompassing the same chromosomal region. We discuss the potential role of the genes in the deleted region and X chromosome inactivation in the pathogenesis of the phenotypic abnormalities seen in our patient. Our findings suggest that the severity and the variability of the clinical findings are determined by the size and the parental origin of the deletions as well as the X-inactivation status.

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    • "In congruence with this idea is the fact that 3 of the 4 women who were diagnosed with ASD (Shinawi et al., 2009; Thomas et al., 1999) showed markedly skewed X-inactivation patterns biased towards the abnormal X chromosome. The link between autism and Xp22.3 is not straightforward, however, as many males with deletions or duplications in Xp22.3 (including NLGN4X) do not show signs of ASD (Kent et al., 2008; Macarov et al., 2007; Mochel et al., 2008; Yan et al., 2005). "
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    ABSTRACT: The male predominance of autism spectrum disorders (ASD) is one of the best-known, and at the same time, one of the least understood characteristics of these disorders. In this paper we review genetic, epigenetic, hormonal, and environmental mechanisms underlying this male preponderance. Sex-specific effects of Y-linked genes (including SRY expression leading to testicular development), balanced and skewed X-inactivation, genes that escape X-inactivation, parent-of-origin allelic imprinting, and the hypothetical heterochromatin sink are reviewed. These mechanisms likely contribute to etiology, instead of being simply causative to ASD. Environments, both internal and external, also play important roles in ASD's etiology. Early exposure to androgenic hormones and early maternal immune activation comprise environmental factors affecting sex-specific susceptibility to ASD. The gene-environment interactions underlying ASD, suggested here, implicate early prenatal stress as being especially detrimental to boys with a vulnerable genotype.
    Frontiers in Neuroendocrinology 04/2014; 35(3). DOI:10.1016/j.yfrne.2014.03.006 · 7.04 Impact Factor
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    • "Potentially pathogenic cytogenetic deletions within Xp22.3 are relatively common in patients with autistic spectrum disorders (ASDs) (Thomas et al., 1999; Chocholska et al., 2006; Vorstman et al., 2006; Kent et al., 2008; Shinawi et al., 2009), characterised by social/communication impairments, restricted interests or repetitive/stereotyped behaviours, hyperactivity and anxiety (O'Hare, 2009). Xp22.3 deletions have also been reported in cases of attention deficit hyperactivity disorder (ADHD) (Boycott et al., 2003; Lonardo et al., 2007; Kent et al., 2008), a second neurodevelopmental condition characterised by inattention, pathological impulsivity and hyperactivity (Thapar et al., 2012) which is commonly comorbid with autism and which is thought to share overlapping genetic aetiology (Rommelse et al., 2010); individuals with ADHD may also display a heightened tendency towards behavioural perseveration (Fischer et al., 2005; Tsuchiya et al., 2005). "
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    ABSTRACT: Chromosomal deletions at Xp22.3 appear to influence vulnerability to the neurodevelopmental disorders attention deficit hyperactivity disorder (ADHD) and autism. 39,X(Y*)O mice, which lack the murine orthologue of the Xp22.3 ADHD candidate gene STS (encoding steroid sulfatase), exhibit behavioural phenotypes relevant to such disorders (e.g. hyperactivity), elevated hippocampal serotonin (5-HT) levels, and reduced serum levels of dehydroepiandrosterone (DHEA). Here we initially show that 39,X(Y*)O mice are also deficient for the recently-characterised murine orthologue of the Xp22.3 autism candidate gene ASMT (encoding acetylserotonin-O-methyltransferase). Subsequently, to specify potential behavioural correlates of elevated hippocampal 5-HT arising due to the genetic lesion, we compared 39,X(Y*)O MF1 mice to 40,XY MF1 mice on behavioural tasks taxing hippocampal and/or 5-HT function (a 'foraging' task, an object-location task, and the 1-choice serial reaction time task of impulsivity). Although Sts/Asmt deficiency did not influence foraging behaviour, reactivity to familiar objects in novel locations, or 'ability to wait', it did result in markedly increased response rates; these rates correlated with hippocampal 5-HT levels and are likely to index behavioural perseveration, a frequent feature of neurodevelopmental disorders. Additionally, we show that whilst there was no systematic relationship between serum DHEA levels and hippocampal 5-HT levels across 39,X(Y*)O and 40,XY mice, there was a significant inverse linear correlation between serum DHEA levels and activity. Our data suggest that deficiency for genes within Xp22.3 could influence core behavioural features of neurodevelopmental disorders via dissociable effects on hippocampal neurochemistry and steroid hormone levels, and that the mediating neurobiological mechanisms may be investigated in the 39,X(Y*)O model.
    Psychoneuroendocrinology 12/2012; 38(8). DOI:10.1016/j.psyneuen.2012.12.002 · 4.94 Impact Factor
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    • "Our results highlight the importance of targeted sequencing of both coding and noncoding regions of candidate genes for complex, polygenic traits. Genetic studies of the X-chromosome have suggested that both rare and common X-linked variation may contribute to ASD [16,17,31,99-101], but much remains to be discovered. Although exome sequencing studies are now identifying point mutations, small indels, and de novo variants that contribute to ASD [35-37], these studies are limited by the regions they include in their exome capture chips, as well as biases in the capture efficiency of paralogous genes. "
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    ABSTRACT: Background Autism spectrum disorder (ASD) is highly heritable, but the genetic risk factors for it remain largely unknown. Although structural variants with large effect sizes may explain up to 15% ASD, genome-wide association studies have failed to uncover common single nucleotide variants with large effects on phenotype. The focus within ASD genetics is now shifting to the examination of rare sequence variants of modest effect, which is most often achieved via exome selection and sequencing. This strategy has indeed identified some rare candidate variants; however, the approach does not capture the full spectrum of genetic variation that might contribute to the phenotype. Methods We surveyed two loci with known rare variants that contribute to ASD, the X-linked neuroligin genes by performing massively parallel Illumina sequencing of the coding and noncoding regions from these genes in males from families with multiplex autism. We annotated all variant sites and functionally tested a subset to identify other rare mutations contributing to ASD susceptibility. Results We found seven rare variants at evolutionary conserved sites in our study population. Functional analyses of the three 3’ UTR variants did not show statistically significant effects on the expression of NLGN3 and NLGN4X. In addition, we identified two NLGN3 intronic variants located within conserved transcription factor binding sites that could potentially affect gene regulation. Conclusions These data demonstrate the power of massively parallel, targeted sequencing studies of affected individuals for identifying rare, potentially disease-contributing variation. However, they also point out the challenges and limitations of current methods of direct functional testing of rare variants and the difficulties of identifying alleles with modest effects.
    Molecular Autism 09/2012; 3(1):8. DOI:10.1186/2040-2392-3-8 · 5.41 Impact Factor
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