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Fraternal twins with autism, severe cognitive deficit, and epilepsy: diagnostic role of chromosomal microarray analysis.

May 23, 2015 - 6:03am
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Fraternal twins with autism, severe cognitive deficit, and epilepsy: diagnostic role of chromosomal microarray analysis.

Semin Pediatr Neurol. 2014 Jun;21(2):167-71

Authors: Imitola J, Walleigh D, Anderson CE, Jethva R, Carvalho KS, Legido A, Khurana DS

Abstract
A 7-year-old child presented with atypical absence epilepsy. He also had autism and severe cognitive deficit. As part of his diagnostic workup, a chromosomal microarray analysis was performed, which showed novel biallelic deletions in the neurexin 1 gene (NRXN1). His fraternal twin sister, who also had autism and cognitive impairment, was subsequently found to have the same biallelic deletions. Deletions included a 272-282kb loss at band 2p16.3 in one allele and a smaller 135-174-kb loss on the second allele. Neurexin 1 (NRXN1) is a cell adhesion protein, forming a synaptic complex with neuroligin. This signals a pathway that is critical for activity-dependent synaptic transmission. Mutations in this gene have been associated with autism and neurodevelopmental delay. Although there are many reports of heterozygous mutations with variable expressivity, only 3 cases with biallelic NRXN1 mutations have been previously reported, all of which have a more severe phenotype. We report 2 siblings with biallelic deletions, both of which affect the promoter region and exons 1-5 in the α-NRXN1 isoform, which has a role in the Ca(2+)-dependent release of neurotransmitters in the central nervous system. Our cases expand the phenotype of biallelic α NRXN 1 mutations and emphasize the important role of NRXN1 in autism and intellectual disability. Chromosomal microarray analysis should be the clinical standard in all specialties for first-tier genetic testing in autistic spectrum disorders.

PMID: 25149956 [PubMed - indexed for MEDLINE]

Conserved and divergent processing of neuroligin and neurexin genes: from the nematode C. elegans to human.

May 21, 2015 - 6:06am
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Conserved and divergent processing of neuroligin and neurexin genes: from the nematode C. elegans to human.

Invert Neurosci. 2014 Sep;14(2):79-90

Authors: Calahorro F

Abstract
Neuroligins are cell-adhesion proteins that interact with neurexins at the synapse. This interaction may contribute to differentiation, plasticity and specificity of synapses. In humans, single mutations in neuroligin-encoding genes are implicated in autism spectrum disorder and/or mental retardation. Moreover, some copy number variations and point mutations in neurexin-encoding genes have been linked to neurodevelopmental disorders including autism. Neurexins are subject to extensive alternative splicing, highly regulated in mammals, with a great physiological importance. In addition, neuroligins and neurexins are subjected to proteolytic processes that regulate synaptic transmission modifying pre- and postsynaptic activities and may also regulate the remodelling of spines at specific synapses. Four neuroligin genes exist in mice and five in human, whilst in the nematode Caenorhabditis elegans, there is only one orthologous gene. In a similar manner, in mammals, there are three neurexin genes, each of them encoding two major isoforms named α and β, respectively. In contrast, there is one neurexin gene in C. elegans that also generates two isoforms like mammals. The complexity of the genetic organization of neurexins is due to extensive processing resulting in hundreds of isoforms. In this review, a wide comparison is made between the genes in the nematode and human with a view to better understanding the conservation of processing in these synaptic proteins in C. elegans, which may serve as a genetic model to decipher the synaptopathies underpinning neurodevelopmental disorders such as autism.

PMID: 25148907 [PubMed - indexed for MEDLINE]

Clinical, biochemical and molecular analysis of 13 Japanese patients with β-ureidopropionase deficiency demonstrates high prevalence of the c.977G > A (p.R326Q) mutation.

May 16, 2015 - 7:13am
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Clinical, biochemical and molecular analysis of 13 Japanese patients with β-ureidopropionase deficiency demonstrates high prevalence of the c.977G > A (p.R326Q) mutation.

J Inherit Metab Dis. 2014 Sep;37(5):801-12

Authors: Nakajima Y, Meijer J, Dobritzsch D, Ito T, Meinsma R, Abeling NG, Roelofsen J, Zoetekouw L, Watanabe Y, Tashiro K, Lee T, Takeshima Y, Mitsubuchi H, Yoneyama A, Ohta K, Eto K, Saito K, Kuhara T, van Kuilenburg AB

Abstract
β-ureidopropionase (βUP) deficiency is an autosomal recessive disease characterized by N-carbamyl-β-amino aciduria. To date, only 16 genetically confirmed patients with βUP deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 13 Japanese βUP deficient patients. In this group of patients, three novel missense mutations (p.G31S, p.E271K, and p.I286T) and a recently described mutation (p.R326Q) were identified. The p.R326Q mutation was detected in all 13 patients with eight patients being homozygous for this mutation. Screening for the p.R326Q mutation in 110 Japanese individuals showed an allele frequency of 0.9 %. Transient expression of mutant βUP enzymes in HEK293 cells showed that the p.E271K and p.R326Q mutations cause profound decreases in activity (≤ 1.3 %). Conversely, βUP enzymes containing the p.G31S and p.I286T mutations possess residual activities of 50 and 70 %, respectively, suggesting we cannot exclude the presence of additional mutations in the non-coding region of the UPB1 gene. Analysis of a human βUP homology model revealed that the effects of the mutations (p.G31S, p.E271K, and p.R326Q) on enzyme activity are most likely linked to improper oligomer assembly. Highly variable phenotypes ranging from neurological involvement (including convulsions and autism) to asymptomatic, were observed in diagnosed patients. High prevalence of p.R326Q in the normal Japanese population indicates that βUP deficiency is not as rare as generally considered and screening for βUP deficiency should be included in diagnosis of patients with unexplained neurological abnormalities.

PMID: 24526388 [PubMed - indexed for MEDLINE]

Recurrence rates provide evidence for sex-differential, familial genetic liability for autism spectrum disorders in multiplex families and twins.

May 15, 2015 - 6:41am

Recurrence rates provide evidence for sex-differential, familial genetic liability for autism spectrum disorders in multiplex families and twins.

Mol Autism. 2015;6:27

Authors: Werling DM, Geschwind DH

Abstract
BACKGROUND: Autism spectrum disorders (ASDs) are more prevalent in males, suggesting a multiple threshold liability model in which females are, on average, protected by sex-differential mechanisms. Under this model, autistic females are predicted to carry a more penetrant risk variant load than males and to share this greater genetic liability with their siblings. However, reported ASD recurrence rates have not demonstrated significantly increased risk to siblings of affected girls. Here, we characterize recurrence patterns in multiplex families from the Autism Genetics Resource Exchange (AGRE) to determine if risk in these families follows a female protective model.
METHODS: We assess recurrence rates and quantitative traits in full siblings from 1,120 multiplex nuclear families and concordance rates in 305 twin pairs from AGRE. We consider the first two affected children per family, and one randomly selected autistic twin per pair, as probands. We then compare recurrence rates and phenotypes between males and females and between twin pairs or families with at least one female proband (female-containing (FC)) versus those with only male probands (male-only (MO)).
RESULTS: Among children born after two probands, we observe significantly higher recurrence in males (47.5%) than in females (21.1%; relative risk, RR = 2.25; adjusted P = 6.22e-08) and in siblings of female (44.3%) versus siblings of male probands (30.4%; RR = 1.46; adj. P = 0.036). This sex-differential recurrence is also robust in dizygotic twin pairs (males = 61.5%, females = 19.1%; RR = 3.23; adj. P = 7.66e-09). Additionally, we find a significant negative relationship between interbirth interval and ASD recurrence that is driven by children in MO families.
CONCLUSIONS: By classifying families as MO or FC using two probands instead of one, we observe significant recurrence rate differences between families harboring sex-differential familial liability. However, a significant sex difference in risk to children within FC families suggests that female protective mechanisms are still operative in families carrying high genetic risk loads. Furthermore, the male-specific relationship between shorter interbirth intervals and increased ASD risk is consistent with a potentially greater contribution from environmental factors in males versus higher genetic risk in affected females and their families. Understanding the mechanisms driving these sex-differential risk profiles will be useful for treatment development and prevention.

PMID: 25973164 [PubMed]

The female protective effect in autism spectrum disorder is not mediated by a single genetic locus.

May 15, 2015 - 6:41am

The female protective effect in autism spectrum disorder is not mediated by a single genetic locus.

Mol Autism. 2015;6:25

Authors: Gockley J, Willsey AJ, Dong S, Dougherty JD, Constantino JN, Sanders SJ

Abstract
BACKGROUND: A 4:1 male to female sex bias has consistently been observed in autism spectrum disorder (ASD). Epidemiological and genetic studies suggest a female protective effect (FPE) may account for part of this bias; however, the mechanism of such protection is unknown. Quantitative assessment of ASD symptoms using the Social Responsiveness Scale (SRS) shows a bimodal distribution unique to females in multiplex families. This leads to the hypothesis that a single, common genetic locus on chromosome X might mediate the FPE and produce the ASD sex bias. Such a locus would represent a major therapeutic target and is likely to have been missed by conventional genome-wide association study (GWAS) analysis.
METHODS: To explore this possibility, we performed an association study in affected versus unaffected females, considering three tiers of single nucleotide polymorphisms (SNPs) as follows: 1) regions of chromosome X that escape X-inactivation, 2) all of chromosome X, and 3) genome-wide.
RESULTS: No evidence of a SNP meeting the criteria for a single FPE locus was observed, despite the analysis being well powered to detect this effect.
CONCLUSIONS: The results do not support the hypothesis that the FPE is mediated by a single genetic locus; however, this does not exclude the possibility of multiple genetic loci playing a role in the FPE.

PMID: 25973162 [PubMed]

Understanding autism in the light of sex/gender.

May 15, 2015 - 6:41am

Understanding autism in the light of sex/gender.

Mol Autism. 2015;6:24

Authors: Lai MC, Baron-Cohen S, Buxbaum JD

PMID: 25973161 [PubMed]

The genetics and neurobiology of ESSENCE: The third Birgit Olsson lecture.

May 15, 2015 - 6:41am

The genetics and neurobiology of ESSENCE: The third Birgit Olsson lecture.

Nord J Psychiatry. 2015 May 14;:1-9

Authors: Bourgeron T

Abstract
ESSENCE refers to early symptomatic syndromes eliciting neurodevelopmental clinical examinations. It includes a broad range of early onset neurodevelopmental disorders affecting more than 10% of children before 5 years of age. ESSENCE includes among others attention deficit hyperactivity disorder (ADHD), intellectual disability (ID) and autism spectrum disorders (ASD). Some degree of disability is the rule rather than the exception. The causes are heterogeneous ranging from extreme social deprivation, pre- and perinatal risk factors, genetic and metabolic diseases, immune and infectious disorders, nutritional factors, physical trauma, and postnatal toxic and environmental factors (and combinations/interactions of some or several of these). Treatments often involve a combination of psychoeducational interventions, home- and school-based programmes, and medication. Here, I will first briefly review our main knowledge on the biological pathways associated with early onset neurodevelopmental disorders and will provide useful links to be informed of the progress in the field. Five main pathways are associated with ASD and ID: chromatin remodelling, cytoskeleton dynamics, mRNA translation, metabolism and synapse formation/function. I will then detail three propositions coming from institutions, researchers and/or communities of patients and families to foster research: 1) to use more dimensional and quantitative data than diagnostic categories; 2) to increase data sharing and research on genetic and brain diversity in human populations; 3) to involve patients and relatives as participants for research. Finally, I will provide examples of very stimulating initiatives towards a more inclusive world for individuals with ESSENCE.

PMID: 25971862 [PubMed - as supplied by publisher]

Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders.

May 15, 2015 - 6:41am
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Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders.

Mol Autism. 2015;6:21

Authors: Codina-Solà M, Rodríguez-Santiago B, Homs A, Santoyo J, Rigau M, Aznar-Laín G, Del Campo M, Gener B, Gabau E, Botella MP, Gutiérrez-Arumí A, Antiñolo G, Pérez-Jurado LA, Cuscó I

Abstract
BACKGROUND: Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders with high heritability. Recent findings support a highly heterogeneous and complex genetic etiology including rare de novo and inherited mutations or chromosomal rearrangements as well as double or multiple hits.
METHODS: We performed whole-exome sequencing (WES) and blood cell transcriptome by RNAseq in a subset of male patients with idiopathic ASD (n = 36) in order to identify causative genes, transcriptomic alterations, and susceptibility variants.
RESULTS: We detected likely monogenic causes in seven cases: five de novo (SCN2A, MED13L, KCNV1, CUL3, and PTEN) and two inherited X-linked variants (MAOA and CDKL5). Transcriptomic analyses allowed the identification of intronic causative mutations missed by the usual filtering of WES and revealed functional consequences of some rare mutations. These included aberrant transcripts (PTEN, POLR3C), deregulated expression in 1.7% of mutated genes (that is, SEMA6B, MECP2, ANK3, CREBBP), allele-specific expression (FUS, MTOR, TAF1C), and non-sense-mediated decay (RIT1, ALG9). The analysis of rare inherited variants showed enrichment in relevant pathways such as the PI3K-Akt signaling and the axon guidance.
CONCLUSIONS: Integrative analysis of WES and blood RNAseq data has proven to be an efficient strategy to identify likely monogenic forms of ASD (19% in our cohort), as well as additional rare inherited mutations that can contribute to ASD risk in a multifactorial manner. Blood transcriptomic data, besides validating 88% of expressed variants, allowed the identification of missed intronic mutations and revealed functional correlations of genetic variants, including changes in splicing, expression levels, and allelic expression.

PMID: 25969726 [PubMed]

Assessment of severity of autism using the Indian scale for assessment of autism.

May 15, 2015 - 6:41am
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Assessment of severity of autism using the Indian scale for assessment of autism.

Indian J Psychol Med. 2015 Apr-Jun;37(2):169-74

Authors: Chakraborty S, Thomas P, Bhatia T, Nimgaonkar VL, Deshpande SN

Abstract
BACKGROUND: The Indian Scale for Assessment of Autism (ISAA) was developed to assess the severity of autism among Indian cases.
AIMS: The present study evaluated the ISAA in relation to the Childhood Autism Rating Scale (CARS) and the Developmental Disability- Children Global Assessment Scale (DD-CGAS).
MATERIALS AND METHODS: Indian children with ICD 10 diagnoses of Autistic disorder (AD, n = 50), Intellectual Disability (ID, n = 50), Attention Deficit Hyperactivity Disorder (ADHD, n = 26), other psychiatric disorders (PD-N=25) and control children without psychiatric disorders (n = 65) were evaluated using the ISAA, DD-CGAS and the CARS (total n = 216).
STATISTICAL ANALYSES: In addition to descriptive statistics and correlation, analysis of variance (ANOVA) was used to assess whether the ISAA scores were significantly different across diagnostic groups.
RESULTS: Total ISAA scores were significantly higher among children diagnosed with autistic disorder compared to four other diagnostic groups. Total ISAA scores were significantly correlated with CARS scores and DD-CGAS scores. Groups sub-divided on the basis of recommended ISAA cutoff points of severity showed significant differences in CARS scores.
CONCLUSION: The ISAA can thus be used to assess severity of AD among Indian children.

PMID: 25969602 [PubMed]

Increased brain activity to unpleasant stimuli in individuals with the 7R allele of the DRD4 gene.

May 15, 2015 - 6:41am
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Increased brain activity to unpleasant stimuli in individuals with the 7R allele of the DRD4 gene.

Psychiatry Res. 2015 Jan 30;231(1):58-63

Authors: Gehricke JG, Swanson JM, Duong S, Nguyen J, Wigal TL, Fallon J, Caburian C, Tugan Muftuler L, Moyzis RK

Abstract
The aim of the study was to examine functional brain activity in response to unpleasant images in individuals with the 7-repeat (7R) allele compared to individuals with the 4-repeat (4R) allele of the dopamine receptor D4 (DRD4) gene (VNTR in exon 3). Based on the response ready hypothesis, individuals with the DRD4-4R/7R genotype were expected to show greater functional brain activity in response to unpleasant compared to neutral stimuli in specific regions of the frontal, temporal, parietal and limbic lobes, which form the networks involved in attentional, emotional, and preparatory responses. Functional Magnetic Resonance Imaging activity was studied in 26 young adults (13 with the DRD4-4R/7R genotype and 13 with the DRD4-4R/4R genotype). Participants were asked to look at and subjectively rate unpleasant and neutral images. Results showed increased brain activity in response to unpleasant images compared to neutral images in the right temporal lobe in participants with the DRD4-4R/7R genotype versus participants with the DRD4-4R/4R genotype. The increase in right temporal lobe activity in individuals with DRD4-4R/7R suggests greater involvement in processing negative emotional stimuli. Intriguingly, no differences were found between the two genotypes in the subjective ratings of the images. The findings corroborate the response ready hypothesis, which suggests that individuals with the 7R allele are more responsive to negative emotional stimuli compared to individuals with the 4R allele of the DRD4 gene.

PMID: 25481571 [PubMed - indexed for MEDLINE]

The diverse genetic landscape of neurodevelopmental disorders.

May 15, 2015 - 6:41am
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The diverse genetic landscape of neurodevelopmental disorders.

Annu Rev Genomics Hum Genet. 2014;15:195-213

Authors: Hu WF, Chahrour MH, Walsh CA

Abstract
Advances in genetic tools and sequencing technology in the past few years have vastly expanded our understanding of the genetics of neurodevelopmental disorders. Recent high-throughput sequencing analyses of structural brain malformations, cognitive and neuropsychiatric disorders, and localized cortical dysplasias have uncovered a diverse genetic landscape beyond classic Mendelian patterns of inheritance. The underlying genetic causes of neurodevelopmental disorders implicate numerous cell biological pathways critical for normal brain development.

PMID: 25184530 [PubMed - indexed for MEDLINE]

The dopamine D3 receptor gene and posttraumatic stress disorder.

May 15, 2015 - 6:41am
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The dopamine D3 receptor gene and posttraumatic stress disorder.

J Trauma Stress. 2014 Aug;27(4):379-87

Authors: Wolf EJ, Mitchell KS, Logue MW, Baldwin CT, Reardon AF, Aiello A, Galea S, Koenen KC, Uddin M, Wildman D, Miller MW

Abstract
The dopamine D3 receptor (DRD3) gene has been implicated in schizophrenia, autism, and substance use-disorders and is related to emotion reactivity, executive functioning, and stress-responding, processes impaired in posttraumatic stress disorder (PTSD). The aim of this candidate gene study was to evaluate DRD3 polymorphisms for association with PTSD. The discovery sample was trauma-exposed White, non-Hispanic U.S. veterans and their trauma-exposed intimate partners (N = 491); 60.3% met criteria for lifetime PTSD. The replication sample was 601 trauma-exposed African American participants living in Detroit, Michigan; 23.6% met criteria for lifetime PTSD. Genotyping was based on high-density bead chips. In the discovery sample, 4 single nucleotide polymorphisms (SNPs), rs2134655, rs201252087, rs4646996, and rs9868039, showed evidence of association with PTSD and withstood correction for multiple testing. The minor alleles were associated with reduced risk for PTSD (OR range = 0.59 to 0.69). In the replication sample, rs2251177, located 149 base pairs away from the most significant SNP in the discovery sample, was nominally associated with PTSD in men (OR = 0.32). Although the precise role of the D3 receptor in PTSD is not yet known, its role in executive functioning and emotional reactivity, and the sensitivity of the dopamine system to environmental stressors could potentially explain this association.

PMID: 25158632 [PubMed - indexed for MEDLINE]

Neuroligins, synapse balance and neuropsychiatric disorders.

May 15, 2015 - 6:41am
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Neuroligins, synapse balance and neuropsychiatric disorders.

Pharmacol Rep. 2014 Oct;66(5):830-5

Authors: Maćkowiak M, Mordalska P, Wędzony K

Abstract
Neuroligins are postsynaptic adhesion molecules that are involved in the regulation of synapse organisation and function. Four neuroligin proteins have been identified (neuroligin 1, 2, 3, 4), which are differentially enriched in the postsynaptic specialisation of synapses. Neuroligin 1 is localised on excitatory (glutamatergic) synapses, whereas neuroligin 2 is located on inhibitory (GABAergic/glycinergic) synapses. Neuroligin 3 and 4 are present on both types of synapses. Recent data indicate that neuroligins are involved in synapse maturation and specification. Because of their synaptic localisation and function, neuroligins control the balance between excitatory and inhibitory synapses. Animal studies with neuroligin transgenic mice showed the involvement of neuroligin 1 in memory formation, and neuroligin 2, 3 or 4 in social behaviour. Interestingly, genetic analysis of humans showed a mutation in the neuroligin 2 gene in schizophrenic patients, while mutations in neuroligin 3 or 4 genes were found in autism.

PMID: 25149987 [PubMed - indexed for MEDLINE]

Language and traits of autism spectrum conditions: evidence of limited phenotypic and etiological overlap.

May 15, 2015 - 6:41am
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Language and traits of autism spectrum conditions: evidence of limited phenotypic and etiological overlap.

Am J Med Genet B Neuropsychiatr Genet. 2014 Oct;165B(7):587-95

Authors: Taylor MJ, Charman T, Robinson EB, Hayiou-Thomas ME, Happé F, Dale PS, Ronald A

Abstract
Language difficulties have historically been viewed as integral to autism spectrum conditions (ASC), leading molecular genetic studies to consider whether ASC and language difficulties have overlapping genetic bases. The extent of genetic, and also environmental, overlap between ASC and language is, however, unclear. We hence conducted a twin study of the concurrent association between autistic traits and receptive language abilities. Internet-based language tests were completed by ~3,000 pairs of twins, while autistic traits were assessed via parent ratings. Twin model fitting explored the association between these measures in the full sample, while DeFries-Fulker analysis tested these associations at the extremes of the sample. Phenotypic associations between language ability and autistic traits were modest and negative. The degree of genetic overlap was also negative, indicating that genetic influences on autistic traits lowered language scores in the full sample (mean genetic correlation = -0.13). Genetic overlap was also low at the extremes of the sample (mean genetic correlation = 0.14), indicating that genetic influences on quantitatively defined language difficulties were largely distinct from those on extreme autistic traits. Variation in language ability and autistic traits were also associated with largely different nonshared environmental influences. Language and autistic traits are influenced by largely distinct etiological factors. This has implications for molecular genetic studies of ASC and understanding the etiology of ASC. Additionally, these findings lend support to forthcoming DSM-5 changes to ASC diagnostic criteria that will see language difficulties separated from the core ASC communication symptoms, and instead listed as a clinical specifier.

PMID: 25088445 [PubMed - indexed for MEDLINE]

Family-based clinical associations and functional characterization of the serotonin 2A receptor gene (HTR2A) in autism spectrum disorder.

May 15, 2015 - 6:41am
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Family-based clinical associations and functional characterization of the serotonin 2A receptor gene (HTR2A) in autism spectrum disorder.

Autism Res. 2014 Aug;7(4):459-67

Authors: Smith RM, Banks W, Hansen E, Sadee W, Herman GE

Abstract
The serotonin 2A receptor gene (HTR2A) harbors two functional single nucleotide polymorphisms (SNPs) that are frequent in populations of African and European descent; rs6311, which affects mRNA expression, and rs6314, which changes the amino acid sequence of the encoded protein and affects the signaling properties of the receptor. Multiple clinical associations support a role for these SNPs in cognitive and neuropsychiatric phenotypes, although studies in autism spectrum disorder (ASD) remain equivocal. Here, we tested transmission disequilibrium of rs6311 and rs6314 in a cohort of 158 ASD trios (simplex and multiplex), observing significant under-transmission of the minor "A" allele of rs6311 to offspring with ASD (permuted P = 0.0004). Consistent with our previous findings in the dorsolateral prefrontal cortex of unaffected individuals, rs6311/A decreases expression of HTR2A mRNA with an extended 5' untranslated region (UTR) in the frontopolar cortex in brain samples from 54 ASD patients and controls. Interpreting the clinical results in the context of our mRNA expression analysis, we speculate that any risk associated with rs6311 is conferred by greater expression of the long 5'UTR mRNA isoform. The current study corroborates earlier associations between rs6311 and ASD in a family study, supporting the hypothesis that rs6311 plays a modulatory role in ASD risk.

PMID: 24753316 [PubMed - indexed for MEDLINE]

Regulation of histone H3K4 methylation in brain development and disease.

May 13, 2015 - 7:06am
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Regulation of histone H3K4 methylation in brain development and disease.

Philos Trans R Soc Lond B Biol Sci. 2014 Sep 26;369(1652)

Authors: Shen E, Shulha H, Weng Z, Akbarian S

Abstract
The growing list of mutations implicated in monogenic disorders of the developing brain includes at least seven genes (ARX, CUL4B, KDM5A, KDM5C, KMT2A, KMT2C, KMT2D) with loss-of-function mutations affecting proper regulation of histone H3 lysine 4 methylation, a chromatin mark which on a genome-wide scale is broadly associated with active gene expression, with its mono-, di- and trimethylated forms differentially enriched at promoter and enhancer and other regulatory sequences. In addition to these rare genetic syndromes, dysregulated H3K4 methylation could also play a role in the pathophysiology of some cases diagnosed with autism or schizophrenia, two conditions which on a genome-wide scale are associated with H3K4 methylation changes at hundreds of loci in a subject-specific manner. Importantly, the reported alterations for some of the diseased brain specimens included a widespread broadening of H3K4 methylation profiles at gene promoters, a process that could be regulated by the UpSET(KMT2E/MLL5)-histone deacetylase complex. Furthermore, preclinical studies identified maternal immune activation, parental care and monoaminergic drugs as environmental determinants for brain-specific H3K4 methylation. These novel insights into the epigenetic risk architectures of neurodevelopmental disease will be highly relevant for efforts aimed at improved prevention and treatment of autism and psychosis spectrum disorders.

PMID: 25135975 [PubMed - indexed for MEDLINE]

No association of Val158Met variant in the COMT gene with autism spectrum disorder in Thai children.

May 13, 2015 - 7:06am
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No association of Val158Met variant in the COMT gene with autism spectrum disorder in Thai children.

Psychiatr Genet. 2014 Oct;24(5):230-1

Authors: Limprasert P, Maisrikhaw W, Sripo T, Wirojanan J, Hansakunachai T, Roongpraiwan R, Sombuntham T, Ruangdaraganon N, Guo X

PMID: 24912046 [PubMed - indexed for MEDLINE]

Predicting future discoveries from current scientific literature.

May 13, 2015 - 7:06am
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Predicting future discoveries from current scientific literature.

Methods Mol Biol. 2014;1159:159-68

Authors: Petrič I, Cestnik B

Abstract
Knowledge discovery in biomedicine is a time-consuming process starting from the basic research, through preclinical testing, towards possible clinical applications. Crossing of conceptual boundaries is often needed for groundbreaking biomedical research that generates highly inventive discoveries. We demonstrate the ability of a creative literature mining method to advance valuable new discoveries based on rare ideas from existing literature. When emerging ideas from scientific literature are put together as fragments of knowledge in a systematic way, they may lead to original, sometimes surprising, research findings. If enough scientific evidence is already published for the association of such findings, they can be considered as scientific hypotheses. In this chapter, we describe a method for the computer-aided generation of such hypotheses based on the existing scientific literature. Our literature-based discovery of NF-kappaB with its possible connections to autism was recently approved by scientific community, which confirms the ability of our literature mining methodology to accelerate future discoveries based on rare ideas from existing literature.

PMID: 24788267 [PubMed - indexed for MEDLINE]

Oxytocin and vasopressin systems in genetic syndromes and neurodevelopmental disorders.

May 13, 2015 - 7:06am
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Oxytocin and vasopressin systems in genetic syndromes and neurodevelopmental disorders.

Brain Res. 2014 Sep 11;1580:199-218

Authors: Francis SM, Sagar A, Levin-Decanini T, Liu W, Carter CS, Jacob S

Abstract
Oxytocin (OT) and arginine vasopressin (AVP) are two small, related neuropeptide hormones found in many mammalian species, including humans. Dysregulation of these neuropeptides have been associated with changes in behavior, especially social interactions. We review how the OT and AVP systems have been investigated in Autism Spectrum Disorder (ASD), Prader-Willi Syndrome (PWS), Williams Syndrome (WS) and Fragile X syndrome (FXS). All of these neurodevelopmental disorders (NDD) are marked by social deficits. While PWS, WS and FXS have identified genetic mutations, ASD stems from multiple genes with complex interactions. Animal models of NDD are invaluable for studying the role and relatedness of OT and AVP in the developing brain. We present data from a FXS mouse model affecting the fragile X mental retardation 1 (Fmr1) gene, resulting in decreased OT and AVP staining cells in some brain regions. Reviewing the research about OT and AVP in these NDD suggests that altered OT pathways may be downstream from different etiological factors and perturbations in development. This has implications for ongoing studies of the therapeutic application of OT in NDD. This article is part of a Special Issue entitled Oxytocin and Social Behav.

PMID: 24462936 [PubMed - indexed for MEDLINE]

A homozygous mutation in a consanguineous family consolidates the role of ALDH1A3 in autosomal recessive microphthalmia.

May 13, 2015 - 7:06am
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A homozygous mutation in a consanguineous family consolidates the role of ALDH1A3 in autosomal recessive microphthalmia.

Clin Genet. 2014 Sep;86(3):276-81

Authors: Roos L, Fang M, Dali C, Jensen H, Christoffersen N, Wu B, Zhang J, Xu R, Harris P, Xu X, Grønskov K, Tümer Z

Abstract
Anomalies of eye development can lead to the rare eye malformations microphthalmia and anophthalmia (small or absent ocular globes), which are genetically very heterogeneous. Several genes have been associated with microphthalmia and anophthalmia, and exome sequencing has contributed to the identification of new genes. Very recently, homozygous variations within ALDH1A3 have been associated with autosomal recessive microphthalmia with or without cysts or coloboma, and with variable subphenotypes of developmental delay/autism spectrum disorder in eight families. In a consanguineous family where three of the five siblings were affected with microphthalmia/coloboma, we identified a novel homozygous missense mutation in ALDH1A3 using exome sequencing. Of the three affected siblings, one had intellectual disability and one had intellectual disability and autism, while the last one presented with normal development. This study contributes further to the description of the clinical spectrum associated with ALDH1A3 mutations, and illustrates the interfamilial clinical variation observed in individuals with ALDH1A3 mutations.

PMID: 24024553 [PubMed - indexed for MEDLINE]

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