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Role of metabolic genes in blood arsenic concentrations of Jamaican children with and without autism spectrum disorder.

April 1, 2015 - 6:39am
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Role of metabolic genes in blood arsenic concentrations of Jamaican children with and without autism spectrum disorder.

Int J Environ Res Public Health. 2014 Aug;11(8):7874-95

Authors: Rahbar MH, Samms-Vaughan M, Ma J, Bressler J, Loveland KA, Ardjomand-Hessabi M, Dickerson AS, Grove ML, Shakespeare-Pellington S, Beecher C, McLaughlin W, Boerwinkle E

Abstract
Arsenic is a toxic metalloid with known adverse effects on human health. Glutathione-S-transferase (GST) genes, including GSTT1, GSTP1, and GSTM1, play a major role in detoxification and metabolism of xenobiotics. We investigated the association between GST genotypes and whole blood arsenic concentrations (BASC) in Jamaican children with and without autism spectrum disorder (ASD). We used data from 100 ASD cases and their 1:1 age- and sex-matched typically developing (TD) controls (age 2-8 years) from Jamaica. Using log-transformed BASC as the dependent variable in a General Linear Model, we observed a significant interaction between GSTP1 and ASD case status while controlling for several confounding variables. However, for GSTT1 and GSTM1 we did not observe any significant associations with BASC. Our findings indicate that TD children who had the Ile/Ile or Ile/Val genotype for GSTP1 had a significantly higher geometric mean BASC than those with genotype Val/Val (3.67 µg/L vs. 2.69 µg/L, p < 0.01). Although, among the ASD cases, this difference was not statistically significant, the direction of the observed difference was consistent with that of the TD control children. These findings suggest a possible role of GSTP1 in the detoxification of arsenic.

PMID: 25101770 [PubMed - indexed for MEDLINE]

Loss of COMMD1 and copper overload disrupt zinc homeostasis and influence an autism-associated pathway at glutamatergic synapses.

April 1, 2015 - 6:39am
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Loss of COMMD1 and copper overload disrupt zinc homeostasis and influence an autism-associated pathway at glutamatergic synapses.

Biometals. 2014 Aug;27(4):715-30

Authors: Baecker T, Mangus K, Pfaender S, Chhabra R, Boeckers TM, Grabrucker AM

Abstract
Recent studies suggest that synaptic pathology in autism spectrum disorder (ASD) might be caused by the disruption of a signaling pathway at excitatory glutamatergic synapses, which can be influenced by environmental factors. Some factors, such as prenatal zinc deficiency, dysfunction of metallothioneins as well as deletion of COMMD1, all affect brain metal-ion homeostasis and have been associated with ASD. Given that COMMD1 regulates copper levels and that copper and zinc have antagonistic properties, here, we followed the idea that copper overload might induce a local zinc deficiency affecting key players of a putative ASD pathway such as ProSAP/Shank proteins as reported before. Our results show that increased copper levels indeed interfere with intracellular zinc concentrations and affect synaptic ProSAP/Shank levels, which similarly are altered by manipulation of copper and zinc levels through overexpression and knockdown of COMMD1. In line with this, acute and prenatal copper overload lead to local zinc deficiencies in mice. Pups exposed to prenatal copper overload furthermore show a reduction in ProSAP/Shank protein levels in the brain as well as a decreased NMDAR subunit 1 concentration. Thus, it might be likely that brain metal ion status influences a distinct pathway in excitatory synapses associated with genetic forms of ASD.

PMID: 25007851 [PubMed - indexed for MEDLINE]

Brain MRI abnormalities and spectrum of neurological and clinical findings in three patients with proximal 16p11.2 microduplication.

April 1, 2015 - 6:39am
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Brain MRI abnormalities and spectrum of neurological and clinical findings in three patients with proximal 16p11.2 microduplication.

Am J Med Genet A. 2014 Aug;164A(8):2003-12

Authors: Filges I, Sparagana S, Sargent M, Selby K, Schlade-Bartusiak K, Lueder GT, Robichaux-Viehoever A, Schlaggar BL, Shimony JS, Shinawi M

Abstract
The phenotype of recurrent ∼600 kb microdeletion and microduplication on proximal 16p11.2 is characterized by a spectrum of neurodevelopmental impairments including developmental delay and intellectual disability, epilepsy, autism and psychiatric disorders which are all subject to incomplete penetrance and variable expressivity. A variety of brain MRI abnormalities were reported in patients with 16p11.2 rearrangements, but no systematic correlation has been studied among patients with similar brain anomalies, their neurodevelopmental and clinical phenotypes. We present three patients with the proximal 16p11.2 microduplication exhibiting significant developmental delay, anxiety disorder and other variable clinical features. Our patients have abnormal brain MRI findings of cerebral T2 hyperintense foci (3/3) and ventriculomegaly (2/3). The neuroradiological or neurological findings in two cases prompted an extensive diagnostic work-up. One patient has exhibited neurological regression and progressive vision impairment and was diagnosed with juvenile neuronal ceroid-lipofuscinosis. We compare the clinical course and phenotype of these patients in regard to the clinical significance of the cerebral lesions and the need for MRI surveillance. We conclude that in all three patients the lesions were not progressive, did not show any sign of malignant transformation and could not be correlated to specific clinical features. We discuss potential etiologic mechanisms that may include overexpression of genes within the duplicated region involved in control of cell proliferation and complex molecular mechanisms such as the MAPK/ERK pathway. Systematic studies in larger cohorts are needed to confirm our observation and to establish the prevalence and clinical significance of these neuroanatomical abnormalities in patients with 16p11.2 duplications.

PMID: 24891046 [PubMed - indexed for MEDLINE]

New insights into the molecular pathophysiology of fragile X syndrome and therapeutic perspectives from the animal model.

April 1, 2015 - 6:39am
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New insights into the molecular pathophysiology of fragile X syndrome and therapeutic perspectives from the animal model.

Int J Biochem Cell Biol. 2014 Aug;53:121-6

Authors: Busquets-Garcia A, Maldonado R, Ozaita A

Abstract
Fragile X syndrome is the most common monogenetic form of intellectual disability and is a leading cause of autism. This syndrome is produced by the reduced transcription of the fragile X mental retardation (FMR1) gene, and it is characterized by a range of symptoms heterogeneously expressed in patients such as cognitive impairment, seizure susceptibility, altered pain sensitivity and anxiety. The recent advances in the understanding of the pathophysiological mechanisms involved have opened novel potential therapeutic approaches identified in preclinical rodent models as a necessary preliminary step for the subsequent evaluation in patients. Among those possible therapeutic approaches, the modulation of the metabotropic glutamate receptor signaling or the GABA receptor signaling have focused most of the attention. New findings in the animal models open other possible therapeutic approaches such as the mammalian target of rapamycin signaling pathway or the endocannabinoid system. This review summarizes the emerging data recently obtained in preclinical models of fragile X syndrome supporting these new therapeutic perspectives.

PMID: 24831882 [PubMed - indexed for MEDLINE]

Intragenic rearrangements in X-linked intellectual deficiency: results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes.

April 1, 2015 - 6:39am
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Intragenic rearrangements in X-linked intellectual deficiency: results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes.

Am J Med Genet A. 2014 Aug;164A(8):1991-7

Authors: Mignon-Ravix C, Cacciagli P, Choucair N, Popovici C, Missirian C, Milh M, Mégarbané A, Busa T, Julia S, Girard N, Badens C, Sigaudy S, Philip N, Villard L

Abstract
High-resolution array comparative genomic hybridization (a-CGH) enables the detection of intragenic rearrangements, such as single exon deletion or duplication. This approach can lead to the identification of new disease genes. We report on the analysis of 54 male patients presenting with intellectual deficiency (ID) and a family history suggesting X-linked (XL) inheritance or maternal skewed X-chromosome inactivation (XCI), using a home-made X-chromosome-specific microarray covering the whole human X-chromosome at high resolution. The majority of patients had whole genome array-CGH prior to the selection and we did not include large rearrangements such as MECP2 and FMR1 duplications. We identified four rearrangements considered as causative or potentially pathogenic, corresponding to a detection rate of 8%. Two CNVs affected known XLID genes and were therefore considered as causative (IL1RAPL1 and OPHN1 intragenic deletions). Two new CNVs were considered as potentially pathogenic as they affected interesting candidates for ID. The first CNV is a deletion of the first exon of the TRPC5 gene, encoding a cation channel implicated in dendrite growth and patterning, in a child presenting with ID and an autism spectrum disorder (ASD). The second CNV is a partial deletion of KLHL15, in a patient with severe ID, epilepsy, and anomalies of cortical development. In both cases, in spite of strong arguments for clinical relevance, we were not able at this stage to confirm pathogenicity of the mutations, and the causality of the variants identified in XLID remains to be confirmed.

PMID: 24817631 [PubMed - indexed for MEDLINE]

Phenotypic features in patients with 15q11.2(BP1-BP2) deletion: further delineation of an emerging syndrome.

April 1, 2015 - 6:39am
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Phenotypic features in patients with 15q11.2(BP1-BP2) deletion: further delineation of an emerging syndrome.

Am J Med Genet A. 2014 Aug;164A(8):1916-22

Authors: Cafferkey M, Ahn JW, Flinter F, Ogilvie C

Abstract
15q11.2 deletions flanked by BP1 and BP2 of the Prader-Willi/Angelman syndrome region have recently been linked to a range of neurodevelopment disorders including intellectual disability, speech and language delay, motor delay, autism spectrum disorders, epilepsy, and schizophrenia. Array CGH analysis of 14,605 patients referred for diagnostic cytogenetic testing found that 83 patients (0.57%) carried the 15q11.2(BP1-BP2) deletion. Phenotypic frequencies in the deleted cohort (n = 83) were compared with frequencies in the non-deleted cohort (n = 14,522); developmental delay, motor delay, and speech and language delay were all more prevalent in the deleted cohort. Notably, motor delay was significantly more common (OR = 6.37). These data indicate that developmental delay, motor delay, and speech and language delay are common clinical features associated with this deletion, providing substantial evidence to support this CNV as a susceptibility locus for a spectrum of neurodevelopmental disorders. © 2014 Wiley Periodicals, Inc.

PMID: 24715682 [PubMed - indexed for MEDLINE]

MeCP2: multifaceted roles in gene regulation and neural development.

March 31, 2015 - 6:11am
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MeCP2: multifaceted roles in gene regulation and neural development.

Neurosci Bull. 2014 Aug;30(4):601-9

Authors: Cheng TL, Qiu Z

Abstract
Methyl-CpG-binding protein 2 (MeCP2) is a classic methylated-DNA-binding protein, dysfunctions of which lead to various neurodevelopmental disorders such as Rett syndrome and autism spectrum disorder. Initially recognized as a transcriptional repressor, MeCP2 has been studied extensively and its functions have been expanded dramatically in the past two decades. Recently, it was found to be involved in gene regulation at the post-transcriptional level. MeCP2 represses nuclear microRNA processing by interacting directly with the Drosha/DGCR8 complex. In addition to its multifaceted functions, MeCP2 is remarkably modulated by posttranslational modifications such as phosphorylation, SUMOylation, and acetylation, providing more regulatory dimensions to its functions. The role of MeCP2 in the central nervous system has been studied extensively, from neurons to glia. Future investigations combining molecular, cellular, and physiological methods are necessary for defining the roles of MeCP2 in the brain and developing efficient treatments for MeCP2-related brain disorders.

PMID: 25082535 [PubMed - indexed for MEDLINE]

Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule.

March 31, 2015 - 6:11am
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Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule.

Orphanet J Rare Dis. 2014;9:124

Authors: Hébert B, Pietropaolo S, Même S, Laudier B, Laugeray A, Doisne N, Quartier A, Lefeuvre S, Got L, Cahard D, Laumonnier F, Crusio WE, Pichon J, Menuet A, Perche O, Briault S

Abstract
BACKGROUND: Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and is also associated with autism spectrum disorders. Previous studies implicated BKCa channels in the neuropathogenesis of FXS, but the main question was whether pharmacological BKCa stimulation would be able to rescue FXS neurobehavioral phenotypes.
METHODS AND RESULTS: We used a selective BKCa channel opener molecule (BMS-204352) to address this issue in Fmr1 KO mice, modeling the FXS pathophysiology. In vitro, acute BMS-204352 treatment (10 μM) restored the abnormal dendritic spine phenotype. In vivo, a single injection of BMS-204352 (2 mg/kg) rescued the hippocampal glutamate homeostasis and the behavioral phenotype. Indeed, disturbances in social recognition and interaction, non-social anxiety, and spatial memory were corrected by BMS-204352 in Fmr1 KO mice.
CONCLUSION: These results demonstrate that the BKCa channel is a new therapeutic target for FXS. We show that BMS-204352 rescues a broad spectrum of behavioral impairments (social, emotional and cognitive) in an animal model of FXS. This pharmacological molecule might open new ways for FXS therapy.

PMID: 25079250 [PubMed - indexed for MEDLINE]

Translational control in synaptic plasticity and cognitive dysfunction.

March 31, 2015 - 6:11am
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Translational control in synaptic plasticity and cognitive dysfunction.

Annu Rev Neurosci. 2014;37:17-38

Authors: Buffington SA, Huang W, Costa-Mattioli M

Abstract
Activity-dependent changes in the strength of synaptic connections are fundamental to the formation and maintenance of memory. The mechanisms underlying persistent changes in synaptic strength in the hippocampus, specifically long-term potentiation and depression, depend on new protein synthesis. Such changes are thought to be orchestrated by engaging the signaling pathways that regulate mRNA translation in neurons. In this review, we discuss the key regulatory pathways that govern translational control in response to synaptic activity and the mRNA populations that are specifically targeted by these pathways. The critical contribution of regulatory control over new protein synthesis to proper cognitive function is underscored by human disorders associated with either silencing or mutation of genes encoding proteins that directly regulate translation. In light of these clinical implications, we also consider the therapeutic potential of targeting dysregulated translational control to treat cognitive disorders of synaptic dysfunction.

PMID: 25032491 [PubMed - indexed for MEDLINE]

The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters.

March 31, 2015 - 6:11am
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The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters.

Sci Signal. 2014 Jul 15;7(334):re3

Authors: Alessi DR, Zhang J, Khanna A, Hochdörfer T, Shang Y, Kahle KT

Abstract
The WNK-SPAK/OSR1 kinase complex is composed of the kinases WNK (with no lysine) and SPAK (SPS1-related proline/alanine-rich kinase) or the SPAK homolog OSR1 (oxidative stress-responsive kinase 1). The WNK family senses changes in intracellular Cl(-) concentration, extracellular osmolarity, and cell volume and transduces this information to sodium (Na(+)), potassium (K(+)), and chloride (Cl(-)) cotransporters [collectively referred to as CCCs (cation-chloride cotransporters)] and ion channels to maintain cellular and organismal homeostasis and affect cellular morphology and behavior. Several genes encoding proteins in this pathway are mutated in human disease, and the cotransporters are targets of commonly used drugs. WNKs stimulate the kinases SPAK and OSR1, which directly phosphorylate and stimulate Cl(-)-importing, Na(+)-driven CCCs or inhibit the Cl(-)-extruding, K(+)-driven CCCs. These coordinated and reciprocal actions on the CCCs are triggered by an interaction between RFXV/I motifs within the WNKs and CCCs and a conserved carboxyl-terminal docking domain in SPAK and OSR1. This interaction site represents a potentially druggable node that could be more effective than targeting the cotransporters directly. In the kidney, WNK-SPAK/OSR1 inhibition decreases epithelial NaCl reabsorption and K(+) secretion to lower blood pressure while maintaining serum K(+). In neurons, WNK-SPAK/OSR1 inhibition could facilitate Cl(-) extrusion and promote γ-aminobutyric acidergic (GABAergic) inhibition. Such drugs could have efficacy as K(+)-sparing blood pressure-lowering agents in essential hypertension, nonaddictive analgesics in neuropathic pain, and promoters of GABAergic inhibition in diseases associated with neuronal hyperactivity, such as epilepsy, spasticity, neuropathic pain, schizophrenia, and autism.

PMID: 25028718 [PubMed - indexed for MEDLINE]

Disruption of Mbd5 in mice causes neuronal functional deficits and neurobehavioral abnormalities consistent with 2q23.1 microdeletion syndrome.

March 31, 2015 - 6:11am
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Disruption of Mbd5 in mice causes neuronal functional deficits and neurobehavioral abnormalities consistent with 2q23.1 microdeletion syndrome.

EMBO Mol Med. 2014;6(8):1003-15

Authors: Camarena V, Cao L, Abad C, Abrams A, Toledo Y, Araki K, Araki M, Walz K, Young JI

Abstract
2q23.1 microdeletion syndrome is characterized by intellectual disability, motor delay, autistic-like behaviors, and a distinctive craniofacial phenotype. All patients carry a partial or total deletion of methyl-CpG-binding domain protein 5 (MBD5), suggesting that haploinsufficiency of this gene is responsible for the phenotype. To confirm this hypothesis and to examine the role of MBD5 in vivo, we have generated and characterized an Mbd5 gene-trap mouse model. Our study indicates that the Mbd5(+/) (GT) mouse model recapitulates most of the hallmark phenotypes observed in 2q23.1 deletion carriers including abnormal social behavior, cognitive impairment, and motor and craniofacial abnormalities. In addition, neuronal cultures uncovered a deficiency in neurite outgrowth. These findings support a causal role of MBD5 in 2q23.1 microdeletion syndrome and suggest a role for MBD5 in neuronal processes. The Mbd5(+/) (GT) mouse model will advance our understanding of the abnormal brain development underlying the emergence of 2q23.1 deletion-associated behavioral and cognitive symptoms.

PMID: 25001218 [PubMed - indexed for MEDLINE]

Screening individuals with intellectual disability, autism and Tourette's syndrome for KCNK9 mutations and aberrant DNA methylation within the 8q24 imprinted cluster.

March 31, 2015 - 6:11am
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Screening individuals with intellectual disability, autism and Tourette's syndrome for KCNK9 mutations and aberrant DNA methylation within the 8q24 imprinted cluster.

Am J Med Genet B Neuropsychiatr Genet. 2014 Sep;165B(6):472-8

Authors: Sánchez Delgado M, Camprubí C, Tümer Z, Martínez F, Milà M, Monk D

Abstract
The phenotype overlap between autism spectrum disorders (ASD) & intellectual disabilities (ID) is mirrored at the genetic level, with common genes being reported mutated in variety of developmental disabilities. However despite widespread genetic screening for mutations, in approximately 40-60% of childhood developmental disorders the genetic cause remains unknown. Several genome-wide linkage screens in ASD have identified a locus mapping to distal 8q. We have recently identified a novel brain-specific imprinted cluster at this location, which contains the reciprocally expressed maternal KCNK9 and paternally expressed non-coding PEG13 transcripts, the latter located within an intron of TRAPPC9. Interestingly, mutations of KCNK9 and TRAPPC9 have been reported in Birk-Barel mental retardation and non-syndromic familial forms of ID, respectively. Here, we report a genetic screen for KCNK9 coding mutations and potential epigenetic aberrations that could result in deregulated imprinting in a cohort of 120 ID, 86 ASD and 86 Tourette syndrome patients. Fifteen of the ID patients had clinical characteristics overlapping with Birk-Barel syndrome. Sequencing of the two coding exons of KCNK9 failed to identify pathologic mutations, with only one variant, rs2615374, being present with allele frequencies similar to those described in dbSNP database. DNA methylation profiling of the KCNK9 and TRAPPC9 promoters, the maternally methylated PEG13 DMR and a long-range enhancer region were normal in all patients. Our findings suggest that mutations of KCNK9 or epigenetic disturbances within the PEG13 imprinted cluster do not significantly contribute to the cause of the developmental disabilities tested in this study.

PMID: 24980697 [PubMed - indexed for MEDLINE]

Introduction of the human AVPR1A gene substantially alters brain receptor expression patterns and enhances aspects of social behavior in transgenic mice.

March 31, 2015 - 6:11am
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Introduction of the human AVPR1A gene substantially alters brain receptor expression patterns and enhances aspects of social behavior in transgenic mice.

Dis Model Mech. 2014 Aug;7(8):1013-22

Authors: Charles R, Sakurai T, Takahashi N, Elder GA, Gama Sosa MA, Young LJ, Buxbaum JD

Abstract
Central arginine vasopressin receptor 1A (AVPR1A) modulates a wide range of behaviors, including stress management and territorial aggression, as well as social bonding and recognition. Inter- and intra-species variations in the expression pattern of AVPR1A in the brain and downstream differential behavioral phenotypes have been attributed to differences in the non-coding regions of the AVPR1A gene, including polymorphic elements within upstream regulatory areas. Gene association studies have suggested a link between AVPR1A polymorphisms and autism, and AVPR1A has emerged as a potential pharmacological target for treatment of social cognitive impairments and mood and anxiety disorders. To further investigate the genetic mechanism giving rise to species differences in AVPR1A expression patterns and associated social behaviors, and to create a preclinical mouse model useful for screening drugs targeting AVPR1A, we engineered and extensively characterized bacterial artificial chromosome (BAC) transgenic mice harboring the entire human AVPR1A locus with the surrounding regulatory elements. Compared with wild-type animals, the humanized mice displayed a more widely distributed ligand-AVPR1A binding pattern, which overlapped with that of primates. Furthermore, humanized AVPR1A mice displayed increased reciprocal social interactions compared with wild-type animals, but no differences in social approach and preference for social novelty were observed. Aspects of learning and memory, specifically novel object recognition and spatial relocation recognition, were unaffected. The biological alterations in humanized AVPR1A mice resulted in the rescue of the prepulse inhibition impairments that were observed in knockout mice, indicating conserved functionality. Although further behavioral paradigms and additional cohorts need to be examined in humanized AVPR1A mice, the results demonstrate that species-specific variations in the genomic content of regulatory regions surrounding the AVPR1A locus are responsible for differential receptor protein expression patterns across species and that they are likely to contribute to species-specific behavioral variation. The humanized AVPR1A mouse is a potential preclinical model for further understanding the regulation of receptor gene expression and the impact of variation in receptor expression on behaviors, and should be useful for screening drugs targeting human AVPR1A, taking advantage of the expression of human AVPR1A in human-relevant brain regions.

PMID: 24924430 [PubMed - indexed for MEDLINE]

Mutation screening of the neurexin 1 gene in thai patients with intellectual disability and autism spectrum disorder.

March 31, 2015 - 6:11am
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Mutation screening of the neurexin 1 gene in thai patients with intellectual disability and autism spectrum disorder.

Genet Test Mol Biomarkers. 2014 Jul;18(7):510-5

Authors: Yangngam S, Plong-On O, Sripo T, Roongpraiwan R, Hansakunachai T, Wirojanan J, Sombuntham T, Ruangdaraganon N, Limprasert P

Abstract
AIM: Neurexin 1 has two major protein isoforms using alternative promoters, coding for the alpha-neurexin 1 (α-NRXN1) and beta-neurexin 1 (β-NRXN1) genes. This study is to explore the possibility that variants of the NRXN1 gene predispose to intellectual disability (ID) and autism spectrum disorder (ASD).
METHODS: The coding regions in 24 exons and exon-intron boundaries of the NRXN1 gene were investigated in 115 Thai patients with ID and ASD by direct DNA sequencing.
RESULTS: Nine novel variants of the NRXN1 gene were identified. Four novel variants were found in the β-NRXN1 gene, one variant of six GGC repeats in exon 1, and three variants at the 5'UTR. Five novel variants were identified in the α-NRXN1 gene, four intronic variants and one missense variant in exon 14 (c.2713T>A or p.F905I).
CONCLUSION: Mutation screening of the NRXN1gene in patients with ID and ASD may be useful to identify potential variants predisposing to ID and ASD. However, further studies utilizing protein functional analysis of the novel variants are required for a more definite conclusion.

PMID: 24832020 [PubMed - indexed for MEDLINE]

A 1.37-Mb 12p11.22-p11.21 deletion coincident with a 367-kb 22q11.2 duplication detected by array comparative genomic hybridization in an adolescent girl with autism and difficulty in self-care of menstruation.

March 31, 2015 - 6:11am
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A 1.37-Mb 12p11.22-p11.21 deletion coincident with a 367-kb 22q11.2 duplication detected by array comparative genomic hybridization in an adolescent girl with autism and difficulty in self-care of menstruation.

Taiwan J Obstet Gynecol. 2014 Mar;53(1):74-8

Authors: Chen CP, Lin SP, Chern SR, Wu PS, Su JW, Lee CC, Wang W

Abstract
OBJECTIVE: To present an array comparative genomic hybridization (aCGH) characterization of a 12p11.22-p11.21 microdeletion and 22q11.2 microduplication in an adolescent girl with autism, mental retardation, facial dysmorphism, microcephaly, behavior problems, and an apparently balanced reciprocal translocation of t(8;12)(q24.3;p11.2).
MATERIALS AND METHODS: A 13-year-old girl was referred to the hospital because of autism, mental retardation, and difficulty in the self-care of her menstruation. Cytogenetic analysis revealed an apparently balanced reciprocal translocation and a karyotype of 46,XX,t(8;12) (q24.3;p11.2)dn. The girl manifested microcephaly, hypertelorism, flat facial profile, prominent forehead, thick scalp hair, upslanting palpebral fissures, broad nasal bridge, bulbous nose, right simian crease, bilateral clinodactyly of the fifth fingers, bilateral pes cavus, learning difficulties, mental retardation, emotional instability, cognitive impairment, behavior problems, jumping-like gaits, and autistic spectrum disorder. aCGH was performed to evaluate genomic imbalance in this patient.
RESULTS: aCGH analysis revealed a 1.37-Mb 12p11.22-p11.21 microdeletion or arr [hg 19] 12p11.22-p11.21 (30,645,008-32,014,774)×1 and a 367-kb 22q11.21 microduplication or arr [hg 19] 22q11.21 (18,657,470-19,024,306)×3. The 1.37-Mb 12p11.22-p11.21 microdeletion encompassed 26 genes including IPO8, CAPRIN2, and DDX11, and the 367-kb 22q11.21 microduplication encompassed 20 genes including USP18, DGCR6, PRODH, and DGCR2.
CONCLUSION: An apparently balanced translocation may be in fact affected by concurrent deletion and duplication in two different chromosomal regions. Our presentation provides information on diagnostic phenotype of 12p11.22-p11.21 microdeletion and 22q11.2 microduplication.

PMID: 24767651 [PubMed - indexed for MEDLINE]

An assessment of time involved in pre-test case review and counseling for a whole genome sequencing clinical research program.

March 31, 2015 - 6:11am
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An assessment of time involved in pre-test case review and counseling for a whole genome sequencing clinical research program.

J Genet Couns. 2014 Aug;23(4):516-21

Authors: Williams JL, Faucett WA, Smith-Packard B, Wagner M, Williams MS

Abstract
Whole genome sequencing (WGS) is being used for evaluation of individuals with undiagnosed disease of suspected genetic origin. Implementing WGS into clinical practice will place an increased burden upon care teams with regard to pre-test patient education and counseling about results. To quantitate the time needed for appropriate pre-test evaluation of participants in WGS testing, we documented the time spent by our clinical research group on various activities related to program preparation, participant screening, and consent prior to WGS. Participants were children or young adults with autism, intellectual or developmental disability, and/or congenital anomalies, who have remained undiagnosed despite previous evaluation, and their biologic parents. Results showed that significant time was spent in securing allocation of clinical research space to counsel participants and families, and in acquisition and review of participant's medical records. Pre-enrollment chart review identified two individuals with existing diagnoses resulting in savings of $30,000 for the genome sequencing alone, as well as saving hours of personnel time for genome interpretation and communication of WGS results. New WGS programs should plan for costs associated with additional pre-test administrative planning and patient evaluation time that will be required to provide high quality care.

PMID: 24573557 [PubMed - indexed for MEDLINE]

Novel methylation markers of the dysexecutive-psychiatric phenotype in FMR1 premutation women.

March 27, 2015 - 7:51am

Novel methylation markers of the dysexecutive-psychiatric phenotype in FMR1 premutation women.

Neurology. 2015 Mar 25;

Authors: Cornish KM, Kraan CM, Bui QM, Bellgrove MA, Metcalfe SA, Trollor JN, Hocking DR, Slater HR, Inaba Y, Li X, Archibald AD, Turbitt E, Cohen J, Godler DE

Abstract
OBJECTIVE: To examine the epigenetic basis of psychiatric symptoms and dysexecutive impairments in FMR1 premutation (PM: 55 to 199 CGG repeats) women.
METHODS: A total of 35 FMR1 PM women aged between 22 and 55 years and 35 age- and IQ-matched women controls (CGG <45) participated in this study. All participants completed a range of executive function tests and self-reported symptoms of psychiatric disorders. The molecular measures included DNA methylation of the FMR1 CpG island in blood, presented as FMR1 activation ratio (AR), and 9 CpG sites located at the FMR1 exon1/intron 1 boundary, CGG size, and FMR1 mRNA levels.
RESULTS: We show that FMR1 intron 1 methylation levels could be used to dichotomize PM women into greater and lower risk categories (p = 0.006 to 0.037; odds ratio = 14-24.8), with only FMR1 intron 1 methylation, and to a lesser extent AR, being significantly correlated with the likelihood of probable dysexecutive or psychiatric symptoms (p < 0.05). Furthermore, the significant relationships between methylation and social anxiety were found to be mediated by executive function performance, but only in PM women. FMR1 exon 1 methylation, CGG size, and FMR1 mRNA could not predict probable dysexecutive/psychiatric disorders in PM women.
CONCLUSIONS: This is the first study supporting presence of specific epigenetic etiology associated with increased risk of developing comorbid dysexecutive and social anxiety symptoms in PM women. These findings could have implications for early intervention and risk estimate recommendations aimed at improving the outcomes for PM women and their families.

PMID: 25809302 [PubMed - as supplied by publisher]

"New insights into Brunner syndrome and potential for targeted therapy".

March 27, 2015 - 7:51am

"New insights into Brunner syndrome and potential for targeted therapy".

Clin Genet. 2015 Mar 23;

Authors: Palmer EE, Leffler M, Rogers C, Shaw M, Carroll R, Earl J, Cheung NW, Champion B, Hu H, Haas SA, Kalscheuer VM, Gecz J, Field M

Abstract
We report two families with Brunner syndrome living in one state of Australia. The first family had a predicted protein-truncating variant of MAOA (p.S251KfsX2). Affected males had mild intellectual disability (ID), obsessive behavior, limited friendships and were introverted and placid during clinical interview. The family disclosed episodic explosive aggression after a diagnosis was made. The second family had a missense variant in MAOA (p.R45W). Affected males had borderline-mild ID, attention deficit disorder and limited friendships. One had a history of explosive aggression in childhood, and episodic symptoms of flushing, headaches and diarrhoea. Their carrier mother had normal intelligence but similar episodic symptoms. Characteristic biochemical abnormalities included high serum serotonin and urinary metanephrines and low urinary 5-HIAA and VMA. Symptomatic individuals in the second family had particularly high serotonin levels and treatment with a serotonin reuptake inhibitor and dietary modification resulted in reversal of biochemical abnormalities, reduction of 'serotonergic' symptoms and behavioral improvement. Brunner syndrome should be considered as a cause of mild ID with paroxysmal behavioral symptoms. It can be screened for with serum/urine metanephrine and serotonin measurement. Cautious treatment with a serotonin reuptake inhibitor, dietary modifications and avoidance of medications contraindicated in patients on monoamine oxidase inhibitors can improve symptoms.

PMID: 25807999 [PubMed - as supplied by publisher]

Strong genetic influences on the stability of autistic traits in childhood.

March 27, 2015 - 7:51am
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Strong genetic influences on the stability of autistic traits in childhood.

J Am Acad Child Adolesc Psychiatry. 2014 Feb;53(2):221-30

Authors: Holmboe K, Rijsdijk FV, Hallett V, Happé F, Plomin R, Ronald A

Abstract
OBJECTIVE: Disorders on the autism spectrum, as well as autistic traits in the general population, have been found to be both highly stable across age and highly heritable at individual ages. However, little is known about the overlap in genetic and environmental influences on autistic traits across age and the contribution of such influences to trait stability itself. The present study investigated these questions in a general population sample of twins.
METHOD: More than 6,000 twin pairs were rated on an established scale of autistic traits by their parents at 8, 9, and 12 years of age and by their teachers at 9 and 12 years of age. Data were analyzed using structural equation modeling.
RESULTS: The results indicated that, consistently across raters, not only were autistic traits stable, and moderately to highly heritable at individual ages, but there was also a high degree of overlap in genetic influences across age. Furthermore, autistic trait stability could largely be accounted for by genetic factors, with the environment unique to each twin playing a minor role. The environment shared by twins had virtually no effect on the longitudinal stability in autistic traits.
CONCLUSIONS: Autistic traits are highly stable across middle childhood. and this stability is caused primarily by genetic factors.

PMID: 24472256 [PubMed - indexed for MEDLINE]

Loss of δ-catenin function in severe autism.

March 26, 2015 - 7:06am

Loss of δ-catenin function in severe autism.

Nature. 2015 Mar 25;

Authors: Turner TN, Sharma K, Oh EC, Liu YP, Collins RL, Sosa MX, Auer DR, Brand H, Sanders SJ, Moreno-De-Luca D, Pihur V, Plona T, Pike K, Soppet DR, Smith MW, Cheung SW, Martin CL, State MW, Talkowski ME, Cook E, Huganir R, Katsanis N, Chakravarti A

Abstract
Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated δ-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as female-enriched multiplex families, are of innate value in multifactorial disorders.

PMID: 25807484 [PubMed - as supplied by publisher]

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