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Extrarenal roles of the with-no-lysine[K] kinases (WNKs).

August 1, 2014 - 8:16am
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Extrarenal roles of the with-no-lysine[K] kinases (WNKs).

Clin Exp Pharmacol Physiol. 2013 Dec;40(12):885-94

Authors: Siew K, O'Shaughnessy KM

Abstract
Identified over a decade ago, the with-no-lysine[K] kinases (WNKs) have been the subsequent focus of intense research into the renal handling of Na(+) , Cl(-) and K(+) and several rare monogenetic diseases. However, the potential extrarenal roles for WNKs have been less well explored. Thiazides and Gordon syndrome are known to have effects on bone mineral density, Ca(2+) and PO4 (3-) homeostasis, which were originally assumed to be an indirect effect through the kidney. However, current data suggest a complex and direct role for WNKs in the physiology of bone. The WNKs also modulate systemic blood pressure at several levels, including the vascular resistance vessels, where they cause vasoconstriction by altering the abundance of the transient receptor potential canonical channel 3 and/or phosphorylation of the Na(+) -K(+) -2Cl(-) cotransporter 1 in vascular smooth muscle cells. The WNKs and many of the cation-coupled Cl(-) cotransporters they regulate are highly expressed in the central nervous system and recent work suggests that WNK dysfunction may have a role in the development of autism, schizophrenia and hereditary sensory and autonomic neuropathy Type 2. Finally, the WNK-sterile 20 kinase signalling axis represents an evolutionarily ancient mechanism for maintaining osmotic homeostasis, but a rapidly expanding body of evidence also shows a role in immunity and cellular regulation.

PMID: 23662678 [PubMed - indexed for MEDLINE]

Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability.

July 31, 2014 - 8:06am

Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability.

Eur J Hum Genet. 2014 Jul 30;

Authors: Vergult S, Dheedene A, Meurs A, Faes F, Isidor B, Janssens S, Gautier A, Le Caignec C, Menten B

Abstract
Voltage-gated calcium channels have an important role in neurotransmission. Aberrations affecting genes encoding the alpha subunit of these channels have been associated with epilepsy and neuropsychiatric disorders such as autism or schizophrenia. Here we report three patients with a genomic aberration affecting the CACNA2D1 gene encoding the α2δ subunit of these voltage-gated calcium channels. All three patients present with epilepsy and intellectual disability pinpointing the CACNA2D1 gene as an interesting candidate gene for these clinical features. Besides these characteristics, patient 2 also presents with obesity with hyperinsulinism, which is very likely to be caused by deletion of the CD36 gene.European Journal of Human Genetics advance online publication, 30 July 2014; doi:10.1038/ejhg.2014.141.

PMID: 25074461 [PubMed - as supplied by publisher]

Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome.

July 31, 2014 - 8:06am
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Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome.

Cortex. 2013 Nov-Dec;49(10):2700-10

Authors: Han JC, Thurm A, Golden Williams C, Joseph LA, Zein WM, Brooks BP, Butman JA, Brady SM, Fuhr SR, Hicks MD, Huey AE, Hanish AE, Danley KM, Raygada MJ, Rennert OM, Martinowich K, Sharp SJ, Tsao JW, Swedo SE

Abstract
In animal studies, brain-derived neurotrophic factor (BDNF) is an important regulator of central nervous system development and synaptic plasticity. WAGR (Wilms tumour, Aniridia, Genitourinary anomalies, and mental Retardation) syndrome is caused by 11p13 deletions of variable size near the BDNF locus and can serve as a model for studying human BDNF haploinsufficiency (+/-). We hypothesized that BDNF+/- would be associated with more severe cognitive impairment in subjects with WAGR syndrome. Twenty-eight subjects with WAGR syndrome (6-28 years), 12 subjects with isolated aniridia due to PAX6 mutations/microdeletions (7-54 years), and 20 healthy controls (4-32 years) received neurocognitive assessments. Deletion boundaries for the subjects in the WAGR group were determined by high-resolution oligonucleotide array comparative genomic hybridization. Within the WAGR group, BDNF+/- subjects (n = 15), compared with BDNF intact (+/+) subjects (n = 13), had lower adaptive behaviour (p = .02), reduced cognitive functioning (p = .04), higher levels of reported historical (p = .02) and current (p = .02) social impairment, and higher percentage meeting cut-off score for autism (p = .047) on Autism Diagnostic Interview-Revised. These differences remained nominally significant after adjusting for visual acuity. Using diagnostic measures and clinical judgement, 3 subjects (2 BDNF+/- and 1 BDNF+/+) in the WAGR group (10.7%) were classified with autism spectrum disorder. A comparison group of visually impaired subjects with isolated aniridia had cognitive functioning comparable to that of healthy controls. In summary, among subjects with WAGR syndrome, BDNF+/- subjects had a mean Vineland Adaptive Behaviour Compose score that was 14-points lower and a mean intelligence quotient (IQ) that was 20-points lower than BDNF+/+ subjects. Our findings support the hypothesis that BDNF plays an important role in human neurocognitive development.

PMID: 23517654 [PubMed - indexed for MEDLINE]

Prenatal detection of TAR syndrome in a fetus with compound inheritance of an RBM8A SNP and a 334‑kb deletion: a case report.

July 30, 2014 - 7:31am
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Prenatal detection of TAR syndrome in a fetus with compound inheritance of an RBM8A SNP and a 334‑kb deletion: a case report.

Mol Med Rep. 2014 Jan;9(1):163-5

Authors: Papoulidis I, Oikonomidou E, Orru S, Siomou E, Kontodiou M, Eleftheriades M, Bacoulas V, Cigudosa JC, Suela J, Thomaidis L, Manolakos E

Abstract
Thrombocytopenia‑absent radius syndrome (TAR) is a rare genetic disorder that is characterized by the absence of the radius bone in each forearm and a markedly reduced platelet count that results in life‑threatening bleeding episodes (thrombocytopenia). Tar syndrome has been associated with a deletion of a segment of 1q21.1 cytoband. The 1q21.1 deletion syndrome phenotype includes Tar and other features such as mental retardation, autism and microcephaly. This study describes a case of a prenatally diagnosed fetus with compound inheritance of a small (334 kb) deletion, as detected by array‑comparative genomic hybridization, and a 5' untranslated region (UTR) low‑frequency allele (rs139428292) in gene RBM8A as detected by Sanger sequencing. The study describes the first case of prenatal analysis of TAR syndrome in a fetus with compound inheritance of a 334‑kb deletion in the 1q21.1 region and a low‑frequency 5' UTR single nucleotide polymorphism, and provides confirmation of the causal nature of the RBM8A gene in the diagnosis of TAR syndrome.

PMID: 24220582 [PubMed - indexed for MEDLINE]

Structural variation-associated expression changes are paralleled by chromatin architecture modifications.

July 26, 2014 - 8:40am
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Structural variation-associated expression changes are paralleled by chromatin architecture modifications.

PLoS One. 2013;8(11):e79973

Authors: Gheldof N, Witwicki RM, Migliavacca E, Leleu M, Didelot G, Harewood L, Rougemont J, Reymond A

Abstract
UNLABELLED: Copy number variants (CNVs) influence the expression of genes that map not only within the rearrangement, but also to its flanks. To assess the possible mechanism(s) underlying this "neighboring effect", we compared intrachromosomal interactions and histone modifications in cell lines of patients affected by genomic disorders and control individuals. Using chromosome conformation capture (4C-seq), we observed that a set of genes flanking the Williams-Beuren Syndrome critical region (WBSCR) were often looping together. The newly identified interacting genes include AUTS2, mutations of which are associated with autism and intellectual disabilities. Deletion of the WBSCR disrupts the expression of this group of flanking genes, as well as long-range interactions between them and the rearranged interval. We also pinpointed concomitant changes in histone modifications between samples. We conclude that large genomic rearrangements can lead to chromatin conformation changes that extend far away from the structural variant, thereby possibly modulating expression globally and modifying the phenotype.
GEO SERIES ACCESSION NUMBER: GSE33784, GSE33867.

PMID: 24265791 [PubMed - indexed for MEDLINE]

Expansion of the clinical phenotype associated with mutations in activity-dependent neuroprotective protein.

July 25, 2014 - 8:13am

Expansion of the clinical phenotype associated with mutations in activity-dependent neuroprotective protein.

J Med Genet. 2014 Jul 23;

Authors: Pescosolido MF, Schwede M, Johnson Harrison A, Schmidt M, Gamsiz ED, Chen WS, Donahue JP, Shur N, Jerskey BA, Phornphutkul C, Morrow EM

PMID: 25057125 [PubMed - as supplied by publisher]

De novo CNVs in Bipolar Affective Disorder and Schizophrenia.

July 25, 2014 - 8:13am

De novo CNVs in Bipolar Affective Disorder and Schizophrenia.

Hum Mol Genet. 2014 Jul 23;

Authors: Georgieva L, Rees E, Moran JL, Chambert KD, Milanova V, Craddock N, Purcell S, Sklar P, McCarroll S, Holmans P, O'Donovan MC, Owen MJ, Kirov G

Abstract
An increased rate of de novo copy number variants (CNVs) has been found in schizophrenia (SZ), autism and developmental delay. An increased rate has also been reported in bipolar affective disorder (BD). Here, in a larger BD sample, we aimed to replicate these findings and compare de novo CNVs between SZ and BD. We used Illumina microarrays to genotype 368 BD probands, 76 SZ probands and all their parents. CNVs were called by PennCNV and filtered for frequency (<1%) and size (>10kb). Putative de novo CNVs were validated with the z-score algorithm, manual inspection of log R ratios, and qPCR probes. We found 15 de novo CNVs in BD (4.1% rate) and six in SZ (7.9% rate). Combining results with previous studies and using a cut-off of >100kb, the rate of de novo CNVs in BD was intermediate between controls and SZ: 1.5% in controls, 2.2% in BD and 4.3% in SZ. Only the differences between SZ and BD and SZ and controls were significant. The median size of de novo CNVs in BD (448kb) was also intermediate between SZ (613kb) and controls (338kb), but only the comparison between SZ and controls was significant. Only one de novo CNV in BD was in a confirmed SZ locus (16p11.2). Sporadic or early onset cases were not more likely to have de novo CNVs. We conclude that de novo CNVs play a smaller role in BD compared to SZ. Patients with a positive family history can also harbour de novo mutations.

PMID: 25055870 [PubMed - as supplied by publisher]

Reduced burden of very large and rare CNVs in bipolar affective disorder.

July 24, 2014 - 7:50am
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Reduced burden of very large and rare CNVs in bipolar affective disorder.

Bipolar Disord. 2013 Dec;15(8):893-8

Authors: Grozeva D, Kirov G, Conrad DF, Barnes CP, Hurles M, Owen MJ, O'Donovan MC, Craddock N

Abstract
OBJECTIVES: Large, rare chromosomal copy number variants (CNVs) have been shown to increase the risk for schizophrenia and other neuropsychiatric disorders including autism, attention-deficit hyperactivity disorder, learning difficulties, and epilepsy. Their role in bipolar disorder (BD) is less clear. There are no reports of an increase in large, rare CNVs in BD in general, but some have reported an increase in early-onset cases. We previously found that the rate of such CNVs in individuals with BD was not increased, even in early-onset cases. Our aim here was to examine the rate of large rare CNVs in BD in comparison with a new large independent reference sample from the same country.
METHODS: We studied the CNVs in a case-control sample consisting of 1,650 BD cases (reported previously) and 10,259 reference individuals without a known psychiatric disorder who took part in the original Wellcome Trust Case Control Consortium (WTCCC) study. The 10,259 reference individuals were affected with six non-psychiatric disorders (coronary artery disease, types 1 and 2 diabetes, hypertension, Crohn's disease, and rheumatoid arthritis). Affymetrix 500K array genotyping data were used to call the CNVs.
RESULTS: The rate of CNVs > 100 kb was not statistically different between cases and controls. The rate of very large (defined as > 1 Mb) and rare (< 1%) CNVs was significantly lower in patients with BD compared with the reference group. CNV loci associated with schizophrenia were not enriched in BD and, in fact, cases of BD had the lowest number of such CNVs compared with any of the WTCCC cohorts; this finding held even for the early-onset BD cases.
CONCLUSIONS: Schizophrenia and BD differ with respect to CNV burden and association with specific CNVs. Our findings support the hypothesis that BD is etiologically distinct from schizophrenia with respect to large, rare CNVs and the accompanying associated neurodevelopmental abnormalities.

PMID: 24127788 [PubMed - indexed for MEDLINE]

A CTNNA3 compound heterozygous deletion implicates a role for αT-catenin in susceptibility to autism spectrum disorder.

July 23, 2014 - 7:44am

A CTNNA3 compound heterozygous deletion implicates a role for αT-catenin in susceptibility to autism spectrum disorder.

J Neurodev Disord. 2014;6(1):17

Authors: Bacchelli E, Ceroni F, Pinto D, Lomartire S, Giannandrea M, D'Adamo P, Bonora E, Parchi P, Tancredi R, Battaglia A, Maestrini E

Abstract
BACKGROUND: Autism spectrum disorder (ASD) is a highly heritable, neurodevelopmental condition showing extreme genetic heterogeneity. While it is well established that rare genetic variation, both de novo and inherited, plays an important role in ASD risk, recent studies also support a rare recessive contribution.
METHODS: We identified a compound heterozygous deletion intersecting the CTNNA3 gene, encoding αT-catenin, in a proband with ASD and moderate intellectual disability. The deletion breakpoints were mapped at base-pair resolution, and segregation analysis was performed. We compared the frequency of CTNNA3 exonic deletions in 2,147 ASD cases from the Autism Genome Project (AGP) study versus the frequency in 6,639 controls. Western blot analysis was performed to get a quantitative characterisation of Ctnna3 expression during early brain development in mouse.
RESULTS: The CTNNA3 compound heterozygous deletion includes a coding exon, leading to a putative frameshift and premature stop codon. Segregation analysis in the family showed that the unaffected sister is heterozygote for the deletion, having only inherited the paternal deletion. While the frequency of CTNNA3 exonic deletions is not significantly different between ASD cases and controls, no homozygous or compound heterozygous exonic deletions were found in a sample of over 6,000 controls. Expression analysis of Ctnna3 in the mouse cortex and hippocampus (P0-P90) provided support for its role in the early stage of brain development.
CONCLUSION: The finding of a rare compound heterozygous CTNNA3 exonic deletion segregating with ASD, the absence of CTNNA3 homozygous exonic deletions in controls and the high expression of Ctnna3 in both brain areas analysed implicate CTNNA3 in ASD susceptibility.

PMID: 25050139 [PubMed]

Gene-rich large deletions are overrepresented in POAG patients of Indian and Caucasian origins.

July 23, 2014 - 7:44am
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Gene-rich large deletions are overrepresented in POAG patients of Indian and Caucasian origins.

Invest Ophthalmol Vis Sci. 2014 May;55(5):3258-64

Authors: Kaurani L, Vishal M, Kumar D, Sharma A, Mehani B, Sharma C, Chakraborty S, Jha P, Ray J, Sen A, Dash D, Ray K, Mukhopadhyay A

Abstract
PURPOSE: Large copy number variations (CNV) can contribute to increased burden for neurodegenerative diseases. In this study, we analyzed the genome-wide burden of large CNVs > 100 kb in primary open angle glaucoma (POAG), a neurodegenerative disease of the eye that is the largest cause of irreversible blindness.
METHODS: Genome-wide analysis of CNVs > 100 kb were analyzed in a total of 1720 individuals, including an Indian cohort (347 POAG cases and 345 controls) and a Caucasian cohort (624 cases and 404 controls). All the CNV data were obtained from experiments performed on Illumina 660W-Quad (infinium) arrays.
RESULTS: We observed that for both the populations CNVs > 1 Mb was significantly enriched for gene-rich regions unique to the POAG cases (P < 10(-11)). In the Indian cohort CNVs > 1 Mb (39 calls) in patients influenced 125 genes while in controls 31 such CNVs influenced only 5 genes with no overlap. In both cohorts we observed 1.9-fold gene enrichment in patients for deletions compared to duplications, while such a bias was not observed in controls (0.3-fold). Overall duplications > 1 Mb were more than deletions (Del/Dup = 0.82) confirming that the enrichment of gene-rich deletions in patients was associated with the disease. Of the 39 CNVs > 1 Mb from Indian patients, 28 (72%) also were implicated in other neurodegenerative disorders, like autism, schizophrenia, sensorineural hearing loss, and so forth. We found one large duplication encompassing CNTN4 gene in Indian and Caucasian POAG patients that was absent in the controls.
CONCLUSIONS: To our knowledge, our study is the first report on large CNV bias for gene-rich regions in glaucomatous neurodegeneration, implicating its impact across populations of contrasting ethnicities. We identified CNTN4 as a novel candidate gene for POAG.

PMID: 24764060 [PubMed - indexed for MEDLINE]

Most genetic risk for autism resides with common variation.

July 21, 2014 - 7:12am

Most genetic risk for autism resides with common variation.

Nat Genet. 2014 Jul 20;

Authors: Gaugler T, Klei L, Sanders SJ, Bodea CA, Goldberg AP, Lee AB, Mahajan M, Manaa D, Pawitan Y, Reichert J, Ripke S, Sandin S, Sklar P, Svantesson O, Reichenberg A, Hultman CM, Devlin B, Roeder K, Buxbaum JD

Abstract
A key component of genetic architecture is the allelic spectrum influencing trait variability. For autism spectrum disorder (herein termed autism), the nature of the allelic spectrum is uncertain. Individual risk-associated genes have been identified from rare variation, especially de novo mutations. From this evidence, one might conclude that rare variation dominates the allelic spectrum in autism, yet recent studies show that common variation, individually of small effect, has substantial impact en masse. At issue is how much of an impact relative to rare variation this common variation has. Using a unique epidemiological sample from Sweden, new methods that distinguish total narrow-sense heritability from that due to common variation and synthesis of results from other studies, we reach several conclusions about autism's genetic architecture: its narrow-sense heritability is ∼52.4%, with most due to common variation, and rare de novo mutations contribute substantially to individual liability, yet their contribution to variance in liability, 2.6%, is modest compared to that for heritable variation.

PMID: 25038753 [PubMed - as supplied by publisher]

An Autism Case History to Review the Systematic Analysis of Large-Scale Data to Refine the Diagnosis and Treatment of Neuropsychiatric Disorders.

July 19, 2014 - 6:42am

An Autism Case History to Review the Systematic Analysis of Large-Scale Data to Refine the Diagnosis and Treatment of Neuropsychiatric Disorders.

Biol Psychiatry. 2014 Jun 12;

Authors: Kohane IS

Abstract
Analysis of large-scale systems of biomedical data provides a perspective on neuropsychiatric disease that may be otherwise elusive. Described here is an analysis of three large-scale systems of data from autism spectrum disorder (ASD) and of ASD research as an exemplar of what might be achieved from study of such data. First is the biomedical literature that highlights the fact that there are two very successful but quite separate research communities and findings pertaining to genetics and the molecular biology of ASD. There are those studies positing ASD causes that are related to immunological dysregulation and those related to disorders of synaptic function and neuronal connectivity. Second is the emerging use of electronic health record systems and other large clinical databases that allow the data acquired during the course of care to be used to identify distinct subpopulations, clinical trajectories, and pathophysiological substructures of ASD. These systems reveal subsets of patients with distinct clinical trajectories, some of which are immunologically related and others which follow pathologies conventionally thought of as neurological. The third is genome-wide genomic and transcriptomic analyses which show molecular pathways that overlap neurological and immunological mechanisms. The convergence of these three large-scale data perspectives illustrates the scientific leverage that large-scale data analyses can provide in guiding researchers in an approach to the diagnosis of neuropsychiatric disease that is inclusive and comprehensive.

PMID: 25034947 [PubMed - as supplied by publisher]

Role of the PTEN signaling pathway in autism spectrum disorder.

July 19, 2014 - 6:42am
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Role of the PTEN signaling pathway in autism spectrum disorder.

Neurosci Bull. 2013 Dec;29(6):773-8

Authors: Lv JW, Cheng TL, Qiu ZL, Zhou WH

Abstract
Autism is an etiologically heterogeneous group of neurodevelopmental disorders, diagnosed mostly by the clinical behavioral phenotypes. The concept that the tumor-related gene PTEN plays a critical role in autism spectrum disorder has emerged over the last decade. In this review, we focus on the essential role of the PTEN signaling pathway in neuronal differentiation and the formation of neural circuitry, as well as genetic mouse models with Pten manipulations. Particularly, accumulated data suggest that the effect of PTEN on neural stem-cell development contributes significantly to the pathophysiology of autism spectrum disorders.

PMID: 24136242 [PubMed - indexed for MEDLINE]

Susceptibility genes are enriched in those of the herpes simplex virus 1/host interactome in psychiatric and neurological disorders.

July 19, 2014 - 6:42am
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Susceptibility genes are enriched in those of the herpes simplex virus 1/host interactome in psychiatric and neurological disorders.

Pathog Dis. 2013 Dec;69(3):240-61

Authors: Carter CJ

Abstract
Herpes simplex virus 1 (HSV-1) can promote beta-amyloid deposition and tau phosphorylation, demyelination or cognitive deficits relevant to Alzheimer's disease or multiple sclerosis and to many neuropsychiatric disorders with which it has been implicated. A seroprevalence much higher than disease incidence has called into question any primary causal role. However, as also the case with risk-promoting polymorphisms (also present in control populations), any causal effects are likely to be conditional. During its life cycle, the virus binds to many proteins and modifies the expression of multiple genes creating a host/pathogen interactome involving 1347 host genes. This data set is heavily enriched in the susceptibility genes for multiple sclerosis (P = 1.3E-99) > Alzheimer's disease > schizophrenia > Parkinsonism > depression > bipolar disorder > childhood obesity > chronic fatigue > autism > and anorexia (P = 0.047) but not attention deficit hyperactivity disorder, a relationship maintained for genome-wide association study data sets in multiple sclerosis and Alzheimer's disease. Overlapping susceptibility gene/interactome data sets disrupt signalling networks relevant to each disease, suggesting that disease susceptibility genes may filter the attentions of the pathogen towards particular pathways and pathologies. In this way, the same pathogen could contribute to multiple diseases in a gene-dependent manner and condition the risk-promoting effects of the genes whose function it disrupts.

PMID: 23913659 [PubMed - indexed for MEDLINE]

Seizures and EEG pattern in the 22q13.3 deletion syndrome: Clinical report of six Italian cases.

July 17, 2014 - 6:47am

Seizures and EEG pattern in the 22q13.3 deletion syndrome: Clinical report of six Italian cases.

Seizure. 2014 Jul 1;

Authors: Figura MG, Coppola A, Bottitta M, Calabrese G, Grillo L, Luciano D, Del Gaudio L, Torniero C, Striano S, Elia M

Abstract
PURPOSE: The 22q13.3 deletion syndrome, also known as Phelan-McDermid syndrome, is a rare genetic disorder characterized by hypotonia, severely impaired development of speech and language, autistic-like behaviour, and minor dysmorphic features. Neurologic problems may include seizures of different types, such as febrile, generalized tonic-clonic, focal, and absence seizures. No peculiar EEG features have been associated with 22q13 deletion syndrome to date. In order to verify if a peculiar clinical and EEG pattern is present in 22q13.3 deletion syndrome, we studied six Italian patients with this chromosome abnormality.
METHOD: Array CGH analysis was carried out in the six subjects (1 male, 5 females, age range 11-30 years, median 19.5). They underwent a complete general and neurologic examinations. The EEG study consisted of at least one awake and one nap-sleep video-EEG recordings and evaluation of other EEGs performed elsewhere.
RESULTS: Three subjects suffered from myoclonic or generalized tonic-clonic seizures with a rather benign course; all showed multifocal paroxysmal abnormalities on EEG recording, predominant over the frontal-temporal regions, activated during sleep.
CONCLUSION: 22q13.3 deletion syndrome seems to be associated, at least in a subgroup of patients, with a peculiar clinical and EEG pattern, characterized by a childhood epilepsy with a rather benign evolution and with multifocal paroxysmal EEG abnormalities activated by sleep.

PMID: 25027555 [PubMed - as supplied by publisher]

Role of parental occupation in autism spectrum disorder diagnosis and severity.

July 16, 2014 - 8:37am
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Role of parental occupation in autism spectrum disorder diagnosis and severity.

Res Autism Spectr Disord. 2014 Sep 1;8(9):997-1007

Authors: Dickerson AS, Pearson DA, Loveland KA, Rahbar MH, Filipek PA

PMID: 25024741 [PubMed - as supplied by publisher]

Autism susceptibility genes and the transcriptional landscape of the human brain.

July 16, 2014 - 8:37am
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Autism susceptibility genes and the transcriptional landscape of the human brain.

Int Rev Neurobiol. 2013;113:303-18

Authors: Miyauchi S, Voineagu I

Abstract
Autism is the most severe end of a spectrum of neurodevelopmental conditions, autism spectrum disorders (ASD). ASD are genetically heterogeneous, and hundreds of genes have been implicated in the etiology of the disease. Here, we discuss the contribution of brain transcriptome studies in advancing our understanding of the genetic mechanisms of ASD and review recent work characterizing the spatial and temporal variation of the human brain transcriptome, with a focus on the relevance of these data to autism susceptibility genes.

PMID: 24290390 [PubMed - indexed for MEDLINE]

Orchestration of neurodevelopmental programs by RBFOX1: implications for autism spectrum disorder.

July 16, 2014 - 8:37am
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Orchestration of neurodevelopmental programs by RBFOX1: implications for autism spectrum disorder.

Int Rev Neurobiol. 2013;113:251-67

Authors: Bill BR, Lowe JK, Dybuncio CT, Fogel BL

Abstract
Neurodevelopmental and neuropsychiatric disorders result from complex interactions between critical genetic factors and as-yet-unknown environmental components. To gain clinical insight, it is critical to develop a comprehensive understanding of these genetic components. RBFOX1, an RNA splicing factor, regulates expression of large genetic networks during early neuronal development, and haploinsufficiency causes severe neurodevelopmental phenotypes including autism spectrum disorder (ASD), intellectual disability, and epilepsy. Genomic testing in individuals and large patient cohorts has identified phenotypically similar cases possessing copy number variations in RBFOX1, implicating the gene as an important cause of neurodevelopmental disease. However, a significant proportion of the observed structural variation is inherited from phenotypically normal individuals, raising questions regarding overall pathogenicity of variation at the RBFOX1 locus. In this chapter, we discuss the molecular, cellular, and clinical evidence supporting the role of RBFOX1 in neurodevelopment and present a comprehensive model for the contribution of structural variation in RBFOX1 to ASD.

PMID: 24290388 [PubMed - indexed for MEDLINE]

Transcriptional dysregulation of neocortical circuit assembly in ASD.

July 16, 2014 - 8:37am
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Transcriptional dysregulation of neocortical circuit assembly in ASD.

Int Rev Neurobiol. 2013;113:167-205

Authors: Kwan KY

Abstract
Autism spectrum disorders (ASDs) impair social cognition and communication, key higher-order functions centered in the human neocortex. The assembly of neocortical circuitry is a precisely regulated developmental process susceptible to genetic alterations that can ultimately affect cognitive abilities. Because ASD is an early onset neurodevelopmental disorder that disrupts functions executed by the neocortex, miswiring of neocortical circuits has been hypothesized to be an underlying mechanism of ASD. This possibility is supported by emerging genetic findings and data from imaging studies. Recent research on neocortical development has identified transcription factors as key determinants of neocortical circuit assembly, mediating diverse processes including neuronal specification, migration, and wiring. Many of these TFs (TBR1, SOX5, FEZF2, and SATB2) have been implicated in ASD. Here, I will discuss the functional roles of these transcriptional programs in neocortical circuit development and their neurobiological implications for the emerging etiology of ASD.

PMID: 24290386 [PubMed - indexed for MEDLINE]

MET receptor tyrosine kinase as an autism genetic risk factor.

July 16, 2014 - 8:37am
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MET receptor tyrosine kinase as an autism genetic risk factor.

Int Rev Neurobiol. 2013;113:135-65

Authors: Peng Y, Huentelman M, Smith C, Qiu S

Abstract
In this chapter, we will briefly discuss recent literature on the role of MET receptor tyrosine kinase (RTK) in brain development and how perturbation of MET signaling may alter normal neurodevelopmental outcomes. Recent human genetic studies have established MET as a risk factor for autism, and the molecular and cellular underpinnings of this genetic risk are only beginning to emerge from obscurity. Unlike many autism risk genes that encode synaptic proteins, the spatial and temporal expression pattern of MET RTK indicates this signaling system is ideally situated to regulate neuronal growth, functional maturation, and establishment of functional brain circuits, particularly in those brain structures involved in higher levels of cognition, social skills, and executive functions.

PMID: 24290385 [PubMed - indexed for MEDLINE]

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