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Atypical enterovirus encephalitis causing behavioral changes and autism-like clinical manifestations: case report.

February 20, 2016 - 8:25am
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Atypical enterovirus encephalitis causing behavioral changes and autism-like clinical manifestations: case report.

Acta Neurol Belg. 2016 Feb 19;

Authors: Akcakaya NH, Tekturk P, Cagatay A, Tur EK, Yapici Z

PMID: 26895551 [PubMed - as supplied by publisher]

Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation.

February 20, 2016 - 8:25am
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Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation.

Elife. 2016;5

Authors: Covarrubias AJ, Aksoylar HI, Yu J, Snyder NW, Worth AJ, Iyer SS, Wang J, Ben-Sahra I, Byles V, Polynne-Stapornkul T, Espinosa EC, Lamming D, Manning BD, Zhang Y, Blair IA, Horng T

Abstract
Macrophage activation/polarization to distinct functional states is critically supported by metabolic shifts. How polarizing signals coordinate metabolic and functional reprogramming, and the potential implications for control of macrophage activation, remains poorly understood. Here we show that IL-4 signaling co-opts the Akt-mTORC1 pathway to regulate Acly, a key enzyme in Ac-CoA synthesis, leading to increased histone acetylation and M2 gene induction. Only a subset of M2 genes is controlled in this way, including those regulating cellular proliferation and chemokine production. Moreover, metabolic signals impinge on the Akt-mTORC1 axis for such control of M2 activation. We propose that Akt-mTORC1 signaling calibrates metabolic state to energetically demanding aspects of M2 activation, which may define a new role for metabolism in supporting macrophage activation.

PMID: 26894960 [PubMed - as supplied by publisher]

Regulatory consequences of neuronal ELAV-like protein binding to coding and non-coding RNAs in human brain.

February 20, 2016 - 8:25am
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Regulatory consequences of neuronal ELAV-like protein binding to coding and non-coding RNAs in human brain.

Elife. 2016;5

Authors: Scheckel C, Drapeau E, Frias MA, Park CY, Fak J, Zucker-Scharff I, Kou Y, Haroutunian V, Ma'ayan A, Buxbaum JD, Darnell RB

Abstract
Neuronal ELAV-like (nELAVL) RNA binding proteins have been linked to numerous neurological disorders. We performed crosslinking-immunoprecipitation and RNAseq on human brain, and identified nELAVL binding sites on 8681 transcripts. Using knockout mice and RNAi in human neuroblastoma cells, we showed that nELAVL intronic and 3' UTR binding regulates human RNA splicing and abundance. We validated hundreds of nELAVL targets among which were important neuronal and disease-associated transcripts, including Alzheimer's disease (AD) transcripts. We therefore investigated RNA regulation in AD brain, and observed differential splicing of 150 transcripts, which in some cases correlated with differential nELAVL binding. Unexpectedly, the most significant change of nELAVL binding was evident on non-coding Y RNAs. nELAVL/Y RNA complexes were specifically remodeled in AD and after acute UV stress in neuroblastoma cells. We propose that the increased nELAVL/Y RNA association during stress may lead to nELAVL sequestration, redistribution of nELAVL target binding, and altered neuronal RNA splicing.

PMID: 26894958 [PubMed - as supplied by publisher]

The contribution of protein intrinsic disorder to understand the role of genetic variants uncovered by autism spectrum disorders exome studies.

February 20, 2016 - 8:25am
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The contribution of protein intrinsic disorder to understand the role of genetic variants uncovered by autism spectrum disorders exome studies.

Am J Med Genet B Neuropsychiatr Genet. 2016 Feb 19;

Authors: Schuch JB, Paixão-Côrtes VR, Friedrich DC, Tovo-Rodrigues L

Abstract
Several autism spectrum disorders (ASD) exome studies suggest that coding single nucleotide variants (SNVs) play an important role on ASD etiology. Usually, the pathogenic effect of missense mutations is estimated through predictors that lose accuracy for those SNVs placed in intrinsically disordered regions of protein. Here, we used bioinformatics tools to investigate the effect of mutations described in ASD published exome studies (549 mutations) in protein disorder, considering post-translational modification, PEST and Molecular Recognition Features (MoRFs) motifs. Schizophrenia and type 2 diabetes (T2D) datasets were created for comparison purposes. The frequency of mutations predicted as disordered was comparable among the three datasets (38.1% in ASD, 35.7% in schizophrenia, 46.4% in T2D). However, the frequency of SNVs predicted to lead a gain or loss of functional sites or change intrinsic disorder tendencies was higher in ASD and schizophrenia than T2D (46.9%, 36.4%, and 23.1%, respectively). The results obtained by SIFT and PolyPhen-2 indicated that 38.9% and 34.4% of the mutations predicted, respectively, as tolerated and benign showed functional alterations in disorder properties. Given the frequency of mutations placed in IDRs and their functional impact, this study suggests that alterations in intrinsic disorder properties might play a role in ASD and schizophrenia etiologies. They should be taken into consideration when researching the pathogenicity of mutations in neurodevelopmental and psychiatric diseases. Finally, mutations with functional alterations in disorder properties must be potential targets for in vitro and in vivo functional studies. © 2016 Wiley Periodicals, Inc.

PMID: 26892727 [PubMed - as supplied by publisher]

Gene expression in human brain implicates sexually dimorphic pathways in autism spectrum disorders.

February 20, 2016 - 8:25am
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Gene expression in human brain implicates sexually dimorphic pathways in autism spectrum disorders.

Nat Commun. 2016;7:10717

Authors: Werling DM, Parikshak NN, Geschwind DH

Abstract
Autism spectrum disorder (ASD) is more prevalent in males, and the mechanisms behind this sex-differential risk are not fully understood. Two competing, but not mutually exclusive, hypotheses are that ASD risk genes are sex-differentially regulated, or alternatively, that they interact with characteristic sexually dimorphic pathways. Here we characterized sexually dimorphic gene expression in multiple data sets from neurotypical adult and prenatal human neocortical tissue, and evaluated ASD risk genes for evidence of sex-biased expression. We find no evidence for systematic sex-differential expression of ASD risk genes. Instead, we observe that genes expressed at higher levels in males are significantly enriched for genes upregulated in post-mortem autistic brain, including astrocyte and microglia markers. This suggests that it is not sex-differential regulation of ASD risk genes, but rather naturally occurring sexually dimorphic processes, potentially including neuron-glial interactions, that modulate the impact of risk variants and contribute to the sex-skewed prevalence of ASD.

PMID: 26892004 [PubMed - in process]

Commentary: Not just genes - reclaiming a role for environmental influences on aetiology and outcome in autism. A commentary on Mandy and Lai (2016).

February 19, 2016 - 8:22am

Commentary: Not just genes - reclaiming a role for environmental influences on aetiology and outcome in autism. A commentary on Mandy and Lai (2016).

J Child Psychol Psychiatry. 2016 Mar;57(3):293-295

Authors: Charman T, Chakrabarti B

Abstract
Mandy and Lai (2015) do the field a service in 'reclaiming' the role of pre- and postnatal environmental influences on the aetiology and course of autism spectrum conditions (ASC). This follows several decades where now discredited theories about putative psychogenic and biological disease models held sway, not least in the public mind. We discuss issues that arise from their review; including the need to identify how large the environmental influences on ASC are likely to be; the specificity of these environmental influences to ASC as opposed to a broader range of neurodevelopmental conditions and outcomes; how best to study complex interactions between genetic and environmental influences; and the promise of novel insights into their mechanisms of action. The review highlights current research that aims to better our understanding of the role of environmental factors in the aetiology and course of ASC and, in the near future, may offer the potential for personalised medicine approaches to intervention based on these discoveries.

PMID: 26889893 [PubMed - as supplied by publisher]

Zebrafish Reel in Phenotypic Suppressors of Autism.

February 19, 2016 - 8:22am

Zebrafish Reel in Phenotypic Suppressors of Autism.

Neuron. 2016 Feb 17;89(4):673-675

Authors: Biran J, Levkowitz G

Abstract
Chemical genetics can help decipher novel pathways underlying neurodevelopmental psychiatric impairments. Hoffman et al. (2016) utilized behavioral profiling of psychoactive compounds in zebrafish and identified estrogens as suppressors of a phenotype resulting from loss of an autism risk gene.

PMID: 26889805 [PubMed - as supplied by publisher]

Selective Disruption of Metabotropic Glutamate Receptor 5-Homer Interactions Mimics Phenotypes of Fragile X Syndrome in Mice.

February 19, 2016 - 8:22am

Selective Disruption of Metabotropic Glutamate Receptor 5-Homer Interactions Mimics Phenotypes of Fragile X Syndrome in Mice.

J Neurosci. 2016 Feb 17;36(7):2131-47

Authors: Guo W, Molinaro G, Collins KA, Hays SA, Paylor R, Worley PF, Szumlinski KK, Huber KM

Abstract
UNLABELLED: Altered function of the Gq-coupled, Group 1 metabotropic glutamate receptors, specifically mGlu5, is implicated in multiple mouse models of autism and intellectual disability. mGlu5 dysfunction has been most well characterized in the fragile X syndrome mouse model, the Fmr1 knock-out (KO) mouse, where pharmacological and genetic reduction of mGlu5 reverses many phenotypes. mGlu5 is less associated with its scaffolding protein Homer in Fmr1 KO mice, and restoration of mGlu5-Homer interactions by genetic deletion of a short, dominant negative of Homer, H1a, rescues many phenotypes of Fmr1 KO mice. These results suggested that disruption of mGlu5-Homer leads to phenotypes of FXS. To test this idea, we examined mice with a knockin mutation of mGlu5 (F1128R; mGlu5(R/R)) that abrogates binding to Homer. Although FMRP levels were normal, mGlu5(R/R) mice mimicked multiple phenotypes of Fmr1 KO mice, including reduced mGlu5 association with the postsynaptic density, enhanced constitutive mGlu5 signaling to protein synthesis, deficits in agonist-induced translational control, protein synthesis-independent LTD, neocortical hyperexcitability, audiogenic seizures, and altered behaviors, including anxiety and sensorimotor gating. These results reveal new roles for the Homer scaffolds in regulation of mGlu5 function and implicate a specific molecular mechanism in a complex brain disease.
SIGNIFICANCE STATEMENT: Abnormal function of the metabotropic, or Gq-coupled, glutamate receptor 5 (mGlu5) has been implicated in neurodevelopmental disorders, including a genetic cause of intellectual disability and autism called fragile X syndrome. In brains of a mouse model of fragile X, mGlu5 is less associated with its binding partner Homer, a scaffolding protein that regulates mGlu5 localization to synapses and its ability to activate biochemical signaling pathways. Here we show that a mouse expressing a mutant mGlu5 that cannot bind to Homer is sufficient to mimic many of the biochemical, neurophysiological, and behavioral symptoms observed in the fragile X mouse. This work provides strong evidence that Homer-mGlu5 binding contributes to symptoms associated with neurodevelopmental disorders.

PMID: 26888925 [PubMed - in process]

Overlapping 16p13.11 deletion and gain of copies variations associated with childhood onset psychosis include genes with mechanistic implications for autism associated pathways: Two case reports.

February 19, 2016 - 8:22am

Overlapping 16p13.11 deletion and gain of copies variations associated with childhood onset psychosis include genes with mechanistic implications for autism associated pathways: Two case reports.

Am J Med Genet A. 2016 Feb 16;

Authors: Brownstein CA, Kleiman RJ, Engle EC, Towne MC, D'Angelo EJ, Yu TW, Beggs AH, Picker J, Fogler JM, Carroll D, Schmitt RC, Wolff RR, Shen Y, Lip V, Bilguvar K, Kim A, Tembulkar S, O'Donnell K, Gonzalez-Heydrich J

Abstract
Copy number variability at 16p13.11 has been associated with intellectual disability, autism, schizophrenia, epilepsy, and attention-deficit hyperactivity disorder. Adolescent/adult- onset psychosis has been reported in a subset of these cases. Here, we report on two children with CNVs in 16p13.11 that developed psychosis before the age of 7. The genotype and neuropsychiatric abnormalities of these patients highlight several overlapping genes that have possible mechanistic relevance to pathways previously implicated in Autism Spectrum Disorders, including the mTOR signaling and the ubiquitin-proteasome cascades. A careful screening of the 16p13.11 region is warranted in patients with childhood onset psychosis. © 2016 Wiley Periodicals, Inc.

PMID: 26887912 [PubMed - as supplied by publisher]

The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment.

February 19, 2016 - 8:22am
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The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment.

Nat Commun. 2015;6:6404

Authors: Cotney J, Muhle RA, Sanders SJ, Liu L, Willsey AJ, Niu W, Liu W, Klei L, Lei J, Yin J, Reilly SK, Tebbenkamp AT, Bichsel C, Pletikos M, Sestan N, Roeder K, State MW, Devlin B, Noonan JP

Abstract
Recent studies implicate chromatin modifiers in autism spectrum disorder (ASD) through the identification of recurrent de novo loss of function mutations in affected individuals. ASD risk genes are co-expressed in human midfetal cortex, suggesting that ASD risk genes converge in specific regulatory networks during neurodevelopment. To elucidate such networks, we identify genes targeted by CHD8, a chromodomain helicase strongly associated with ASD, in human midfetal brain, human neural stem cells (hNSCs) and embryonic mouse cortex. CHD8 targets are strongly enriched for other ASD risk genes in both human and mouse neurodevelopment, and converge in ASD-associated co-expression networks in human midfetal cortex. CHD8 knockdown in hNSCs results in dysregulation of ASD risk genes directly targeted by CHD8. Integration of CHD8-binding data into ASD risk models improves detection of risk genes. These results suggest loss of CHD8 contributes to ASD by perturbing an ancient gene regulatory network during human brain development.

PMID: 25752243 [PubMed - indexed for MEDLINE]

Attention Bias to Emotional Faces Varies by IQ and Anxiety in Williams Syndrome.

February 18, 2016 - 8:18am

Attention Bias to Emotional Faces Varies by IQ and Anxiety in Williams Syndrome.

J Autism Dev Disord. 2016 Feb 17;

Authors: McGrath LM, Oates JM, Dai YG, Dodd HF, Waxler J, Clements CC, Weill S, Hoffnagle A, Anderson E, MacRae R, Mullett J, McDougle CJ, Pober BR, Smoller JW

Abstract
Individuals with Williams syndrome (WS) often experience significant anxiety. A promising approach to anxiety intervention has emerged from cognitive studies of attention bias to threat. To investigate the utility of this intervention in WS, this study examined attention bias to happy and angry faces in individuals with WS (N = 46). Results showed a significant difference in attention bias patterns as a function of IQ and anxiety. Individuals with higher IQ or higher anxiety showed a significant bias toward angry, but not happy faces, whereas individuals with lower IQ or lower anxiety showed the opposite pattern. These results suggest that attention bias interventions to modify a threat bias may be most effectively targeted to anxious individuals with WS with relatively high IQ.

PMID: 26886469 [PubMed - as supplied by publisher]

Heritability of non-speech auditory processing skills.

February 18, 2016 - 8:18am

Heritability of non-speech auditory processing skills.

Eur J Hum Genet. 2016 Feb 17;

Authors: Brewer CC, Zalewski CK, King KA, Zobay O, Riley A, Ferguson MA, Bird JE, McCabe MM, Hood LJ, Drayna D, Griffith AJ, Morell RJ, Friedman TB, Moore DR

Abstract
Recent insight into the genetic bases for autism spectrum disorder, dyslexia, stuttering, and language disorders suggest that neurogenetic approaches may also reveal at least one etiology of auditory processing disorder (APD). A person with an APD typically has difficulty understanding speech in background noise despite having normal pure-tone hearing sensitivity. The estimated prevalence of APD may be as high as 10% in the pediatric population, yet the causes are unknown and have not been explored by molecular or genetic approaches. The aim of our study was to determine the heritability of frequency and temporal resolution for auditory signals and speech recognition in noise in 96 identical or fraternal twin pairs, aged 6-11 years. Measures of auditory processing (AP) of non-speech sounds included backward masking (temporal resolution), notched noise masking (spectral resolution), pure-tone frequency discrimination (temporal fine structure sensitivity), and nonsense syllable recognition in noise. We provide evidence of significant heritability, ranging from 0.32 to 0.74, for individual measures of these non-speech-based AP skills that are crucial for understanding spoken language. Identification of specific heritable AP traits such as these serve as a basis to pursue the genetic underpinnings of APD by identifying genetic variants associated with common AP disorders in children and adults.European Journal of Human Genetics advance online publication, 17 February 2016; doi:10.1038/ejhg.2015.277.

PMID: 26883091 [PubMed - as supplied by publisher]

Peripheral Attentional Targets under Covert Attention Lead to Paradoxically Enhanced Alpha Desynchronization in Neurofibromatosis Type 1.

February 18, 2016 - 8:18am
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Peripheral Attentional Targets under Covert Attention Lead to Paradoxically Enhanced Alpha Desynchronization in Neurofibromatosis Type 1.

PLoS One. 2016;11(2):e0148600

Authors: Silva G, Ribeiro MJ, Costa GN, Violante I, Ramos F, Saraiva J, Castelo-Branco M

Abstract
The limited capacity of the human brain to process the full extent of visual information reaching the visual cortex requires the recruitment of mechanisms of information selection through attention. Neurofibromatosis type-1 (NF1) is a neurodevelopmental disease often exhibiting attentional deficits and learning disabilities, and is considered to model similar impairments common in other neurodevelopmental disorders such as autism. In a previous study, we found that patients with NF1 are more prone to miss targets under overt attention conditions. This finding was interpreted as a result of increased occipito-parietal alpha oscillations. In the present study, we used electroencephalography (EEG) to study alpha power modulations and the performance of patients with NF1 in a covert attention task. Covert attention was required in order to perceive changes (target offset) of a peripherally presented stimulus. Interestingly, alpha oscillations were found to undergo greater desynchronization under this task in the NF1 group compared with control subjects. A similar pattern of desynchronization was found for beta frequencies while no changes in gamma oscillations could be identified. These results are consistent with the notion that different attentional states and task demands generate different patterns of abnormal modulation of alpha oscillatory processes in NF1. Under covert attention conditions and while target offset was reported with relatively high accuracy (over 90% correct responses), excessive desynchronization was found. These findings suggest an abnormal modulation of oscillatory activity and attentional processes in NF1. Given the known role of alpha in modulating attention, we suggest that alpha patterns can show both abnormal increases and decreases that are task and performance dependent, in a way that enhanced alpha desynchronization may reflect a compensatory mechanism to keep performance at normal levels. These results suggest that dysregulation of alpha oscillations may occur in NF1 both in terms of excessive or diminished activation patterns.

PMID: 26881921 [PubMed - in process]

The parvalbumin/somatostatin ratio is increased in Pten mutant mice and by human PTEN ASD alleles.

February 18, 2016 - 8:18am
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The parvalbumin/somatostatin ratio is increased in Pten mutant mice and by human PTEN ASD alleles.

Cell Rep. 2015 May 12;11(6):944-56

Authors: Vogt D, Cho KK, Lee AT, Sohal VS, Rubenstein JL

Abstract
Mutations in the phosphatase PTEN are strongly implicated in autism spectrum disorder (ASD). Here, we investigate the function of Pten in cortical GABAergic neurons using conditional mutagenesis in mice. Loss of Pten results in a preferential loss of SST(+) interneurons, which increases the ratio of parvalbumin/somatostatin (PV/SST) interneurons, ectopic PV(+) projections in layer I, and inhibition onto glutamatergic cortical neurons. Pten mutant mice exhibit deficits in social behavior and changes in electroencephalogram (EEG) power. Using medial ganglionic eminence (MGE) transplantation, we test for cell-autonomous functional differences between human PTEN wild-type (WT) and ASD alleles. The PTEN ASD alleles are hypomorphic in regulating cell size and the PV/SST ratio in comparison to WT PTEN. This MGE transplantation/complementation assay is efficient and is generally applicable for functional testing of ASD alleles in vivo.

PMID: 25937288 [PubMed - indexed for MEDLINE]

GRM7 regulates embryonic neurogenesis via CREB and YAP.

February 18, 2016 - 8:18am
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GRM7 regulates embryonic neurogenesis via CREB and YAP.

Stem Cell Reports. 2015 May 12;4(5):795-810

Authors: Xia W, Liu Y, Jiao J

Abstract
Metabotropic glutamate receptor 7 (GRM7) has recently been identified to be associated with brain developmental defects, such as attention deficit hyperactivity disorder (ADHD) and autism. However, the function of GRM7 during brain development remains largely unknown. Here, we used gain- and loss-of-function strategies to investigate the role of GRM7 in early cortical development. We demonstrate that Grm7 knockdown increases neural progenitor cell (NPC) proliferation, decreases terminal mitosis and neuronal differentiation, and leads to abnormal neuronal morphology. GRM7 regulates the phosphorylation of cyclic AMP response element-binding protein (CREB) and the expression of Yes-associated protein (YAP) by directly interacting with CaM, which subsequently regulates the expression of CyclinD1 and ultimately affects early cortical development. These defects in neurogenesis are ameliorated by Grm7 overexpression, Creb knockdown, or Yap knockdown. Thus, our findings indicate that GRM7 signaling via CREB and YAP is necessary for neurogenesis in the brain.

PMID: 25921811 [PubMed - indexed for MEDLINE]

Delineation of the KIAA2022 mutation phenotype: two patients with X-linked intellectual disability and distinctive features.

February 18, 2016 - 8:18am
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Delineation of the KIAA2022 mutation phenotype: two patients with X-linked intellectual disability and distinctive features.

Am J Med Genet A. 2015 Jun;167(6):1349-53

Authors: Kuroda Y, Ohashi I, Naruto T, Ida K, Enomoto Y, Saito T, Nagai J, Wada T, Kurosawa K

Abstract
Next-generation sequencing has enabled the screening for a causative mutation in X-linked intellectual disability (XLID). We identified KIAA2022 mutations in two unrelated male patients by targeted sequencing. We selected 13 Japanese male patients with severe intellectual disability (ID), including four sibling patients and nine sporadic patients. Two of thirteen had a KIAA2022 mutation. Patient 1 was a 3-year-old boy. He had severe ID with autistic behavior and hypotonia. Patient 2 was a 5-year-old boy. He also had severe ID with autistic behavior, hypotonia, central hypothyroidism, and steroid-dependent nephrotic syndrome. Both patients revealed consistent distinctive features, including upswept hair, narrow forehead, downslanting eyebrows, wide palpebral fissures, long nose, hypoplastic alae nasi, open mouth, and large ears. De novo KIAA2022 mutations (p.Q705X in Patient 1, p.R322X in Patient 2) were detected by targeted sequencing and confirmed by Sanger sequencing. KIAA2022 mutations and alterations have been reported in only four families with nonsyndromic ID and epilepsy. KIAA2022 is highly expressed in the fetal and adult brain and plays a crucial role in neuronal development. These additional patients support the evidence that KIAA2022 is a causative gene for XLID.

PMID: 25900396 [PubMed - indexed for MEDLINE]

Familial transmission of 5p13.2 duplication due to maternal der(X)ins(X;5).

February 18, 2016 - 8:18am
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Familial transmission of 5p13.2 duplication due to maternal der(X)ins(X;5).

Eur J Med Genet. 2015 May;58(5):305-9

Authors: Walters-Sen LC, Windemuth K, Angione K, Nandhlal J, Milunsky JM

Abstract
Submicroscopic duplications of 5p13 have been recently reported in several cases, warranting the description of a new clinical entity (Chromosome 5p13 Duplication Syndrome; MIM 613174). These microduplications, while variable in size, all contain at least part of the NIPBL gene. Patients with duplications in this region present with intellectual disability/developmental delay (ID/DD) and dysmorphic facies. In addition, skeletal and brain abnormalities have been variably reported, as well as propensity for obesity in adulthood and hypotonia. We report a family with two affected sons and two affected daughters, each carrying a duplication at 5p13.2 encompassing the 3' portion of SLC1A3 and the 5' portion of NIPBL. Upon confirming the SNP microarray finding by FISH in the proband, it was discovered that the 5p13.2 duplication was located on the short arm of the X chromosome. Further FISH studies on the family demonstrated that all affected children and their mother carried a derivative X chromosome with insertion of material from 5p13.2 into the intermediate region of Xp [der(X)ins(X;5)(p2?2.1;p13.2p13.2)]. To our knowledge, this is the first report of an inherited duplication of 5p13.2 with multiple affected family members. This family underscores the need to confirm array findings by FISH, both in the proband and family members, to discern implications for pathogenicity and more accurately define the recurrence risk.

PMID: 25858703 [PubMed - indexed for MEDLINE]

Microdeletion of the escape genes KDM5C and IQSEC2 in a girl with severe intellectual disability and autistic features.

February 18, 2016 - 8:18am
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Microdeletion of the escape genes KDM5C and IQSEC2 in a girl with severe intellectual disability and autistic features.

Eur J Med Genet. 2015 May;58(5):324-7

Authors: Fieremans N, Van Esch H, de Ravel T, Van Driessche J, Belet S, Bauters M, Froyen G

Abstract
Intellectual disability (ID) is a very heterogeneous disorder with over 100 ID genes located on the X chromosome alone. Of these, KDM5C and IQSEC2 are located adjacent to each other at the Xp11.22 locus. While mutations in either of these genes are associated with severe ID in males, female carriers are mostly unaffected. Here, we report on a female patient with severe ID and autistic features carrying a de novo 0.4 Mb deletion containing six coding genes including KDM5C and IQSEC2. X-inactivation analysis revealed skewing in a lymphocyte-derived cell line from this patient with preferential inactivation of the mutant X chromosome. As the brain-expressed KDM5C and IQSEC2 genes escape X-inactivation, deletion of these alleles could still be detrimental despite skewing of X-inactivation. Indeed, mutations in either of both genes have been reported in a few female ID patients. Expression analysis in the patients' cell line revealed decreased KDM5C mRNA levels compared to female controls. IQSEC2 levels could not be compared due to very low expression in blood. Overall, our data suggest that heterozygous loss-of-function of the escape genes KDM5C and/or IQSEC2 can contribute to severe ID in female patients and should be taken into account in diagnostics.

PMID: 25858702 [PubMed - indexed for MEDLINE]

De novo exon 1 deletion of AUTS2 gene in a patient with autism spectrum disorder and developmental delay: a case report and a brief literature review.

February 18, 2016 - 8:18am
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De novo exon 1 deletion of AUTS2 gene in a patient with autism spectrum disorder and developmental delay: a case report and a brief literature review.

Am J Med Genet A. 2015 Jun;167(6):1381-5

Authors: Liu Y, Zhao D, Dong R, Yang X, Zhang Y, Tammimies K, Uddin M, Scherer SW, Gai Z

Abstract
Exonic deletions disrupting the autism susceptibility candidate 2 (AUTS2) gene have been demonstrated as causal variants leading to neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and developmental delay (DD). Here, we report on 830 kb de novo deletion at chromosome 7q11.22 in a 4-year-old male patient with ASD and DD. This deletion disrupts the promoter region and exon 1 of AUTS2, potentially leading to complete haploinsuffiency of the gene. In addition, we discuss the clinical presentation of the de novo deletion in the light of the previous studies describing deletions of AUTS2 in NDDs.

PMID: 25851617 [PubMed - indexed for MEDLINE]

Characterization of a 520 kb deletion on chromosome 15q26.1 including ST8SIA2 in a patient with behavioral disturbance, autism spectrum disorder, and epilepsy: additional information.

February 18, 2016 - 8:18am
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Characterization of a 520 kb deletion on chromosome 15q26.1 including ST8SIA2 in a patient with behavioral disturbance, autism spectrum disorder, and epilepsy: additional information.

Am J Med Genet A. 2015 Jun;167(6):1424

Authors: Kamien B, Harraway J, Lundie B, Smallhorne L, Gibbs V, Heath A, Fullerton JM

PMID: 25846131 [PubMed - indexed for MEDLINE]

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