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A proof-of-concept study: exon-level expression profiling and alternative splicing in autism using lymphoblastoid cell lines.

August 2, 2014 - 6:02am
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A proof-of-concept study: exon-level expression profiling and alternative splicing in autism using lymphoblastoid cell lines.

Psychiatr Genet. 2014 Feb;24(1):1-9

Authors: Talebizadeh Z, Aldenderfer R, Wen Chen X

Abstract
OBJECTIVE: Autism is a complex, heterogeneous neurobehavioral disorder with many causes and varying degrees of severity. Some genetic implications related to autism may involve gene-regulatory processes such as alternative splicing. Here, we assess the feasibility of profiling exon-level gene expression in autism using the Affymetrix Human exon 1.0 ST array.
METHODS: We examined lymphoblastoid cell line-derived RNAs from five patients with autism compared with five controls.
RESULTS: Analysis of variance and Bonferroni multiple test correction identified 57 genes exhibiting differential exon-level expression, suggesting potential changes in the resultant alternatively spliced transcripts in autism compared with controls. Genes with differentially expressed exons included CYFIP1, a previously reported autism susceptibility gene. Furthermore, several genes recently reported to have deregulated alternative splicing in autism brain samples showed differential exon expression in our autism group.
CONCLUSION: The paucity of autism brain samples and extensive phenotypic heterogeneity of autism demands finding ways to also identify autism-related genomic events in accessible nonbrain resources, which may contribute in biomarker identifications. This proof-of-concept study shows that the analysis of alternative splicing in lymphoblastoid cell line samples has a potential to reveal at least a subset of brain-related deregulation of splicing machinery that might be implicated in autism.

PMID: 23838881 [PubMed - indexed for MEDLINE]

Delineating the 15q13.3 microdeletion phenotype: a case series and comprehensive review of the literature.

August 1, 2014 - 8:16am

Delineating the 15q13.3 microdeletion phenotype: a case series and comprehensive review of the literature.

Genet Med. 2014 Jul 31;

Authors: Lowther C, Costain G, Stavropoulos DJ, Melvin R, Silversides CK, Andrade DM, So J, Faghfoury H, Lionel AC, Marshall CR, Scherer SW, Bassett AS

Abstract
Purpose:Recurrent 15q13.3 deletions are enriched in multiple neurodevelopmental conditions including intellectual disability, autism, epilepsy, and schizophrenia. However, the 15q13.3 microdeletion syndrome remains ill-defined.Methods:We systematically compiled all cases of 15q13.3 deletion published before 2014. We also examined three locally available cohorts to identify new adults with 15q13.3 deletions.Results:We identified a total of 246 cases (133 children, 113 adults) with deletions overlapping or within the 15q13.3 (breakpoint (BP)4-BP5) region, including seven novel adult cases from local cohorts. No BP4-BP5 deletions were identified in 23,838 adult controls. Where known, 15q13.3 deletions were typically inherited (85.4%) and disproportionately of maternal origin (P < 0.0001). Overall, 198 cases (121 children, 77 adults; 80.5%) had at least one neuropsychiatric diagnosis. Accounting for ascertainment, developmental disability/intellectual disability was present in 57.7%, epilepsy/seizures in 28.0%, speech problems in 15.9%, autism spectrum disorder in 10.9%, schizophrenia in 10.2%, mood disorder in 10.2%, and attention deficit hyperactivity disorder in 6.5%. By contrast, major congenital malformations, including congenital heart disease (2.4%), were uncommon. Placenta previa occurred in the pregnancies of four cases.Conclusion:The 15q13.3 microdeletion syndrome is predominantly characterized by neuropsychiatric expression. There are implications for pre- and postnatal detection, genetic counseling, and anticipatory care.Genet Med advance online publication 31 July 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.83.

PMID: 25077648 [PubMed - as supplied by publisher]

Brain region-specific methylation in the promoter of the murine oxytocin receptor gene is involved in its expression regulation.

August 1, 2014 - 8:16am
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Brain region-specific methylation in the promoter of the murine oxytocin receptor gene is involved in its expression regulation.

Psychoneuroendocrinology. 2014 Jan;39:121-31

Authors: Harony-Nicolas H, Mamrut S, Brodsky L, Shahar-Gold H, Barki-Harrington L, Wagner S

Abstract
Oxytocin is a nine amino acid neuropeptide that is known to play a critical role in fetal expulsion and breast-feeding, and has been recently implicated in mammalian social behavior. The actions of both central and peripheral oxytocin are mediated through the oxytocin receptor (Oxtr), which is encoded by a single gene. In contrast to the highly conserved expression of oxytocin in specific hypothalamic nuclei, the expression of its receptor in the brain is highly diverse among different mammalian species or even within individuals of the same species. The diversity in the pattern of brain Oxtr expression among mammals is thought to contribute to the broad range of social systems and organizations. Yet, the mechanisms underlying this diversity are poorly understood. DNA methylation is a major epigenetic mechanism that regulates gene transcription, and has been linked to reduced expression levels of the Oxtr in individuals with autism. Here we hypothesize that DNA methylation is involved in the expression regulation of Oxtr in the mouse brain. By combining bisulfite DNA conversion and Next-Generation Sequencing we found that specific CpG sites are differentially methylated between distinct brain regions expressing different levels of Oxtr mRNA. Some of these CpG sites are located within putative binding sites of transcription factors known to regulate Oxtr expression, including estrogen receptor α (ERα) and SP1. Specifically, methylation of the SP1 site was found to positively correlate with Oxtr expression. Furthermore, we revealed that the methylation levels of these sites in the various brain regions predict the relationship between ERα and Oxtr mRNA levels. Collectively, our results suggest that brain region-specific expression of the mouse Oxtr gene is epigenetically regulated by DNA methylation of its promoter.

PMID: 24275011 [PubMed - indexed for MEDLINE]

Genetic counseling for susceptibility loci and neurodevelopmental disorders: the del15q11.2 as an example.

August 1, 2014 - 8:16am
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Genetic counseling for susceptibility loci and neurodevelopmental disorders: the del15q11.2 as an example.

Am J Med Genet A. 2013 Nov;161A(11):2846-54

Authors: De Wolf V, Brison N, Devriendt K, Peeters H

Abstract
In recent years, several recurrent copy number variations (CNVs) that confer risk of neurodevelopmental disorders have been identified (e.g., del and dup 16p11.2, del15q13.3, del and dup 1q21.1, del16p13.3, del15q11.2). They are often inherited from an unaffected parent and lack phenotypic specificity. Although there is growing evidence from association studies to consider them as susceptibility CNVs, their clinical utility is debated. Yet the clinician is frequently challenged to deal with these counseling situations without guidelines or consensus. In this report, counseling issues and research opportunities are discussed, with the recurrent 15q11.2 BP1-BP2 (including CYFIP1, NIPA1, NIPA2, TUBGCP5) as an example. Several clinical reports have been published describing patients with del15q11.2 featuring intellectual disability, developmental delay, neurological problems, autism spectrum disorder (ASD), attention problems, speech delay, and dysmorphism. The del15q11.2 was found to be significantly associated with intellectual disability, schizophrenia, epilepsy, and ASD. In this report we discuss how patient-specific and family-specific information may alter the interpretation of del15q11.2 as a contributing factor to the disorder in practical counseling situations. In addition, an association study for ASD in a Belgian Flemish cohort and an overview of reported association studies, clinical reports and genomics data for del15q11.2 are presented.

PMID: 24123946 [PubMed - indexed for MEDLINE]

Fragile X syndrome: From protein function to therapy.

August 1, 2014 - 8:16am
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Fragile X syndrome: From protein function to therapy.

Am J Med Genet A. 2013 Nov;161A(11):2809-21

Authors: Bagni C, Oostra BA

Abstract
Fragile X syndrome (FXS) is the leading monogenic cause of intellectual disability and autism. The FMR1 gene contains a CGG repeat present in the 5'-untranslated region which can be unstable upon transmission to the next generation. The repeat is up to 55 CGGs long in the normal population. In patients with fragile X syndrome (FXS), a repeat length exceeding 200 CGGs generally leads to methylation of the repeat and the promoter region, which is accompanied by silencing of the FMR1 gene. The disease is a result of lack of expression of the fragile X mental retardation protein leading to severe symptoms, including intellectual disability, hyperactivity, and autistic-like behavior. The FMR1 protein (FMRP) has a number of functions. The translational dysregulation of a subset of mRNAs targeted by FMRP is probably the major contribution to FXS. FMRP is also involved in mRNA transport to synapses where protein synthesis occurs. For some FMRP-bound mRNAs, FMRP is a direct modulator of mRNA stability either by sustaining or preventing mRNA decay. Increased knowledge about the role of FMRP has led to the identification of potential treatments for fragile X syndrome that were often tested first in the different animal models. This review gives an overview about the present knowledge of the function of FMRP and the therapeutic strategies in mouse and man.

PMID: 24115651 [PubMed - indexed for MEDLINE]

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]

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