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A girl with West syndrome and autistic features harboring a de novo TBL1XR1 mutation.

July 3, 2015 - 6:59am
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A girl with West syndrome and autistic features harboring a de novo TBL1XR1 mutation.

J Hum Genet. 2014 Oct;59(10):581-3

Authors: Saitsu H, Tohyama J, Walsh T, Kato M, Kobayashi Y, Lee M, Tsurusaki Y, Miyake N, Goto Y, Nishino I, Ohtake A, King MC, Matsumoto N

Abstract
Recently, de novo mutations in TBL1XR1 were found in two patients with autism spectrum disorders. Here, we report on a Japanese girl presenting with West syndrome, Rett syndrome-like and autistic features. Her initial development was normal until she developed a series of spasms at 5 months of age. Electroencephalogram at 7 months showed a pattern of hypsarrhythmia, which led to a diagnosis of West syndrome. Stereotypic hand movements appeared at 8 months of age, and autistic features such as deficits in communication, hyperactivity and excitability were observed later, at 4 years and 9 months. Whole exome sequencing of the patient and her parents revealed a de novo TBL1XR1 mutation [c.209 G>A (p.Gly70Asp)] occurring at an evolutionarily conserved amino acid in an F-box-like domain. Our report expands the clinical spectrum of TBL1XR1 mutations to West syndrome with Rett-like features, together with autistic features.

PMID: 25102098 [PubMed - indexed for MEDLINE]

CNVs in neuropsychiatric disorders.

July 2, 2015 - 8:52am
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CNVs in neuropsychiatric disorders.

Hum Mol Genet. 2015 Jun 30;

Authors: Kirov G

Abstract
Over the last few years at least 11 copy number variations (CNVs) have been shown convincingly to increase risk to developing schizophrenia: deletions at 1q21.1, NRXN1, 3q29, 15q11.2, 15q13.3 and 22q11.2, and duplications at 1q21.1, 7q11.23, 15q11.2-q13.1, 16p13.1 and proximal 16p11.2. They are very rare, found cumulatively in 2.4% of patients with schizophrenia and in only 0.5% of controls. They all increase risk for other neurodevelopmental disorders, such as developmental delay and autism spectrum disorders, where they are found at higher rates (3.3%). Their involvement in bipolar affective disorder is much less prominent. All of them affect multiple genes (apart from NRXN1) and cause substantial increases in risk to develop schizophrenia (odds ratios of 2 to over 50). Their penetrance for any neurodevelopmental disorder is high, from ∼10% to nearly 100%. Carriers of these CNVs display cognitive deficits, even when free of neuropsychiatric disorders.

PMID: 26130694 [PubMed - as supplied by publisher]

Melatonin in Children with Autism Spectrum Disorders: How Does the Evidence Fit Together?

June 30, 2015 - 6:38am
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Melatonin in Children with Autism Spectrum Disorders: How Does the Evidence Fit Together?

J Nat Sci. 2015;1(7):e125

Authors: Veatch OJ, Goldman SE, Adkins KW, Malow BA

Abstract
Autism spectrum disorders (ASD) are prevalent neurodevelopmental conditions, affecting 1 in 68 children in the United States alone. Sleep disturbance, particularly insomnia, is very common in children diagnosed with ASD, with evidence supporting overlapping neurobiological and genetic underpinnings. One of the most well studied mechanisms related to ASD and insomnia is dysregulation of the melatonin pathway, which has been observed in many individuals with ASD compared to typically developing controls. Furthermore, variation in genes whose products regulate endogenous melatonin modify sleep patterns in humans and have also been implicated in some cases of ASD. However, the relationship between comorbid insomnia, melatonin processing, and genes that regulate endogenous melatonin levels in ASD is complex and requires further study to fully elucidate. The aim of this review is to provide an overview of the current findings related to the effects of genetic variation in the melatonergic pathway on risk for expression of sleep disorders in children with ASD. In addition, functional findings related to endogenous levels of melatonin and pharmacokinetic profiles in this patient population are evaluated.

PMID: 26120597 [PubMed - as supplied by publisher]

No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contactin-Associated Proteins or Contactins.

June 30, 2015 - 6:38am
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No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contactin-Associated Proteins or Contactins.

PLoS Genet. 2015 Jan;11(1):e1004852

Authors: Murdoch JD, Gupta AR, Sanders SJ, Walker MF, Keaney J, Fernandez TV, Murtha MT, Anyanwu S, Ober GT, Raubeson MJ, DiLullo NM, Villa N, Waqar Z, Sullivan C, Gonzalez L, Willsey AJ, Choe SY, Neale BM, Daly MJ, State MW

Abstract
Contactins and Contactin-Associated Proteins, and Contactin-Associated Protein-Like 2 (CNTNAP2) in particular, have been widely cited as autism risk genes based on findings from homozygosity mapping, molecular cytogenetics, copy number variation analyses, and both common and rare single nucleotide association studies. However, data specifically with regard to the contribution of heterozygous single nucleotide variants (SNVs) have been inconsistent. In an effort to clarify the role of rare point mutations in CNTNAP2 and related gene families, we have conducted targeted next-generation sequencing and evaluated existing sequence data in cohorts totaling 2704 cases and 2747 controls. We find no evidence for statistically significant association of rare heterozygous mutations in any of the CNTN or CNTNAP genes, including CNTNAP2, placing marked limits on the scale of their plausible contribution to risk.

PMID: 25621974 [PubMed - indexed for MEDLINE]

Self-injury in autism spectrum disorder: an effect of serotonin transporter gene promoter variants.

June 30, 2015 - 6:38am
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Self-injury in autism spectrum disorder: an effect of serotonin transporter gene promoter variants.

Psychiatry Res. 2014 Dec 30;220(3):987-90

Authors: Kolevzon A, Lim T, Schmeidler J, Martello T, Cook EH, Silverman JM

Abstract
Self-injurious behavior in autism spectrum disorder (ASD) has been associated with lower whole blood serotonin levels and the role of serotonin transporter gene promoter region (5HTTLPR) polymorphisms is of interest because of their effects on transporter functioning. This study examined the association between self-injurious behavior in ASD and allelic frequencies of 5HTTLPR. Sixty-four children and adolescents with ASD who were not taking serotonergic medication at the time of the assessment were included in the analysis. Self-injury was assessed using the Autism Diagnostic Interview-Revised (ADI-R) and whole blood serotonin levels were measured using high-pressure liquid chromatography (HPLC) with fluorometic detection. DNA was extracted from saliva and PCR amplified with fluorescent primers. Self-injury significantly increased with the number of La alleles of the 5HTTLPR and decreased with the number of Lg alleles. Self-injury in ASD may be associated with a specific genotype of the serotonin transporter gene promoter region. Future studies should continue to explore subgroups to clarify the underlying clinical and genetic heterogeneity in ASD.

PMID: 25446464 [PubMed - indexed for MEDLINE]

Interaction between MAOA and FOXP2 in association with autism and verbal communication in a Korean population.

June 30, 2015 - 6:38am
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Interaction between MAOA and FOXP2 in association with autism and verbal communication in a Korean population.

J Child Neurol. 2014 Dec;29(12):NP207-11

Authors: Park Y, Won S, Nam M, Chung JH, Kwack K

Abstract
Expression levels of monoamine oxidase A (MAOA), the enzyme that related to monoamine neurotransmitters metabolism such as serotonin, are related to schizophrenia and autism spectrum disorder. Forkhead box protein P2 (FOXP2), a transcription factor, is associated with abnormal language development and is expressed in several areas of the central nervous system in response to serotonin. For this reason, we undertook interaction analysis between MAOA and FOXP2 in autism spectrum disorder, including testing the verbal communication score of the childhood autism rating scale. In interaction analysis, the FOXP2-TCGC (rs12531289-rs1350135-rs10230087-rs2061183) diplotype and MAOA-TCG (rs6323-rs1801291-rs3027407) haplotype were significantly associated with autism spectrum disorder in males. However, when the interaction term was omitted, neither MAOA nor FOXP2 was associated with autism spectrum disorder or verbal communication. These results indicate that language and speech ability is affected by an interaction between FOXP2 and MAOA, but not by either gene separately.

PMID: 24356376 [PubMed - indexed for MEDLINE]

Case report: Neuronal migration disorder associated with chromosome 15q13.3 duplication in a boy with autism and seizures.

June 30, 2015 - 6:38am
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Case report: Neuronal migration disorder associated with chromosome 15q13.3 duplication in a boy with autism and seizures.

J Child Neurol. 2014 Dec;29(12):NP186-8

Authors: Beal JC

Abstract
Neuronal migration disorders are a group of disorders that cause structural brain abnormalities and varying degrees of neurocognitive impairment, resulting from abnormal neuronal migration during brain development. There are several mutations that have been associated with these disorders. Here the case of a 4-year-old autistic boy is presented, who was found to have evidence of a neuronal migration disorder on magnetic resonance imaging (MRI) during a workup for seizures. Genetic testing did not reveal any of the gene mutations known to be associated with neuronal migration disorders but did reveal a microduplication at chromosome 15q13.3, a locus that has been previously associated with autism, cognitive impairment, and seizures. Although the concurrent presence of the genetic and structural abnormalities does not necessarily imply causality, the simultaneous independent occurrence of both conditions is certainly unusual. It is possible that there may be an association between this duplication syndrome and aberrant neuronal migration.

PMID: 24282185 [PubMed - indexed for MEDLINE]

Phylogenetic analysis supports a link between DUF1220 domain number and primate brain expansion.

June 27, 2015 - 8:18am
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Phylogenetic analysis supports a link between DUF1220 domain number and primate brain expansion.

Genome Biol Evol. 2015 Jun 25;

Authors: Zimmer F, Montgomery SH

Abstract
The expansion of DUF1220 domain copy number during human evolution is a dramatic example of rapid and repeated domain duplication. Although patterns of expression, homology and disease associations suggest a role in cortical development, this hypothesis has not been robustly tested using phylogenetic methods. Here, we estimate DUF1220 domain counts across 12 primate genomes using a nucleotide Hidden Markov Model. We then test a series of hypotheses designed to examine the potential evolutionary significance of DUF1220 copy number expansion. Our results suggest a robust association with brain size, and more specifically neocortex volume. In contradiction to previous hypotheses we find a strong association with postnatal brain development, but not with prenatal brain development. Our results provide further evidence of a conserved association between specific loci and brain size across primates, suggesting human brain evolution may have occurred through a continuation of existing processes.

PMID: 26112965 [PubMed - as supplied by publisher]

Mothers' appreciation of chromosomal microarray analysis for autism spectrum disorder.

June 27, 2015 - 8:18am
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Mothers' appreciation of chromosomal microarray analysis for autism spectrum disorder.

J Spec Pediatr Nurs. 2015 Jun 26;

Authors: Giarelli E, Reiff M

Abstract
PURPOSE: The aim of this study was to examine mothers' experiences with chromosomal microarray analysis (CMA) for a child with autism spectrum disorder (ASD).
DESIGN AND METHODS: This is a descriptive qualitative study using thematic content analysis of in-depth interview with 48 mothers of children who had genetic testing for ASD.
RESULTS: The principal theme, "something is missing," included missing knowledge about genetics, information on use of the results, explanations of the relevance to the diagnosis, and relevance to life-long care. Two subordinate themes were (a) disappreciation of the helpfulness of scientific information to explain the diagnosis, and (b) returning to personal experience for interpretation.
PRACTICE IMPLICATIONS: The test "appreciated" in value when results could be linked to the phenotype.

PMID: 26112659 [PubMed - as supplied by publisher]

A CGG-repeat expansion mutation in ZNF713 causes FRA7A: association with autistic spectrum disorder in two families.

June 27, 2015 - 8:18am
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A CGG-repeat expansion mutation in ZNF713 causes FRA7A: association with autistic spectrum disorder in two families.

Hum Mutat. 2014 Nov;35(11):1295-300

Authors: Metsu S, Rainger JK, Debacker K, Bernhard B, Rooms L, Grafodatskaya D, Weksberg R, Fombonne E, Taylor MS, Scherer SW, Kooy RF, FitzPatrick DR

Abstract
We report de novo occurrence of the 7p11.2 folate-sensitive fragile site FRA7A in a male with an autistic spectrum disorder (ASD) due to a CGG-repeat expansion mutation (∼450 repeats) in a 5' intron of ZNF713. This expanded allele showed hypermethylation of the adjacent CpG island with reduced ZNF713 expression observed in a proband-derived lymphoblastoid cell line (LCL). His unaffected mother carried an unmethylated premutation (85 repeats). This CGG-repeat showed length polymorphism in control samples (five to 22 repeats). In a second unrelated family, three siblings with ASD and their unaffected father were found to carry FRA7A premutations, which were partially or mosaically methylated. In one of the affected siblings, mitotic instability of the premutation was observed. ZNF713 expression in LCLs in this family was increased in three of these four premutation carriers. A firm link cannot yet be established between ASD and the repeat expansion mutation but plausible pathogenic mechanisms are discussed.

PMID: 25196122 [PubMed - indexed for MEDLINE]

Partial tetrasomy of the proximal long arm of chromosome 15 in two patients: the significance of the gene dosage in terms of phenotype.

June 26, 2015 - 6:11am
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Partial tetrasomy of the proximal long arm of chromosome 15 in two patients: the significance of the gene dosage in terms of phenotype.

Mol Cytogenet. 2015;8:41

Authors: Szabo A, Czako M, Hadzsiev K, Duga B, Komlosi K, Melegh B

Abstract
BACKGROUND: Large amounts of low copy number repeats in the 15q11.2q13.3 chromosomal region increase the possibility of misalignments and unequal crossover during meiosis in this region, leading to deletions, duplications, triplications and supernumerary chromosomes. Most of the reported cases with epilepsy, autism and Prader-Willi/Angelman syndrome are in association with rearrangements of the proximal long arm of chromosome 15.
RESULTS: Here we report the first two unrelated Hungarian patients with the same epileptic and dysmorphic features, who were investigated by array comparative genomic hybridization (array CGH). By G-banded karyotype followed by FISH and array CGH we could detect partial tetrasomy of the 15q11.2q13.3 chromosomal region, supporting proximal 15q duplication syndrome. Findings of the array CGH gave fully explanation of the phenotypic features of these patients, including epileptic seizures, delayed development, hyperactivity and craniofacial dysmorphic signs. Besides the described features of isodicentric (15) (idic(15)) syndrome Patient 1. suffered from bigeminic extrasystoles and had postnatal growth retardation, which had been published only in a few articles.
CONCLUSIONS: Dosage effect of some genes in the concerned genomic region is known, but several genes have no evidence to have dosage dependence. Our results expanded the previous literature data. We assume dosage dependence in the case of CHRNA7 and OTUD7A, which might be involved in growth regulation. On the other hand increased dosage of the KLF13 gene seems to have no direct causal relationship with heart morphology. The genomic environment of the affected genes may be responsible for the observed phenotype.

PMID: 26110020 [PubMed]

Phthalate concentrations in house dust in relation to autism spectrum disorder and developmental delay in the CHildhood Autism Risks from Genetics and the Environment (CHARGE) study.

June 26, 2015 - 6:11am
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Phthalate concentrations in house dust in relation to autism spectrum disorder and developmental delay in the CHildhood Autism Risks from Genetics and the Environment (CHARGE) study.

Environ Health. 2015 Jun 26;14(1):56

Authors: Philippat C, Bennett DH, Krakowiak P, Rose M, Hwang HM, Hertz-Picciotto I

Abstract
BACKGROUND: Phthalates are endocrine-disrupting chemicals that influence thyroid hormones and sex steroids, both critical for brain development.
AIM: We studied phthalate concentrations in house dust in relation to the risks of developing autism spectrum disorder (ASD) or developmental delay (DD).
METHODS: Participants were a subset of children from the CHARGE (CHildhood Autism Risks from Genetics and the Environment) case-control study. ASD and DD cases were identified through the California Department of Developmental Services system or referrals; general population controls were randomly sampled from state birth files and frequency-matched on age, sex, and broad geographic region to ASD cases. All children (50 ASD, 27 DD, 68 typically developing (TD)) were assessed with Mullen Scales of Early Learning, Vineland Adaptive Behavior Scales (VABS) and Aberrant Behavior Checklist. We measured 5 phthalates in dust collected in the child's home using a high volume small surface sampler.
RESULTS: None of the phthalates measured in dust was associated with ASD. After adjustment, we observed greater di(2-ethylhexyl) phthalate (DEHP) and butylbenzyl phthalate (BBzP) concentrations in indoor dust from homes of DD children: Odds ratios (OR) were 2.10 (95 % confidence interval (CI); 1.10; 4.09) and 1.40 (95 % CI; 0.97; 2.04) for a one-unit increase in the ln-transformed DEHP and BBzP concentrations, respectively. Among TD children, VABS communication, daily living, and adaptive composite standard scores were lower, in association with increased diethyl phthalate (DEP) concentrations in dust. Participants with higher dibutyl phthalate (DBP) concentrations in house dust also trended toward reduced performance on these subscales. Among ASD and DD boys, higher indoor dust concentrations of DEP and DBP were associated with greater hyperactivity-impulsivity and inattention.
DISCUSSION AND CONCLUSION: House dust levels of phthalates were not associated with ASD. The inability to distinguish past from recent exposures in house dust and the fact that house dust does not capture exposure from all sources, limit the interpretation of both positive and null findings and further work is needed. However, the associations observed for DEP and DBP with impairments in several adaptive functions and greater hyperactivity, along with evidence for increased risk of DD raise concerns that these chemicals may affect neurodevelopment in children.

PMID: 26108271 [PubMed - as supplied by publisher]

Disruption of DNA-methylation-dependent long gene repression in Rett syndrome.

June 26, 2015 - 6:11am
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Disruption of DNA-methylation-dependent long gene repression in Rett syndrome.

Nature. 2015 Jun 4;522(7554):89-93

Authors: Gabel HW, Kinde B, Stroud H, Gilbert CS, Harmin DA, Kastan NR, Hemberg M, Ebert DH, Greenberg ME

Abstract
Disruption of the MECP2 gene leads to Rett syndrome (RTT), a severe neurological disorder with features of autism. MECP2 encodes a methyl-DNA-binding protein that has been proposed to function as a transcriptional repressor, but despite numerous mouse studies examining neuronal gene expression in Mecp2 mutants, no clear model has emerged for how MeCP2 protein regulates transcription. Here we identify a genome-wide length-dependent increase in gene expression in MeCP2 mutant mouse models and human RTT brains. We present evidence that MeCP2 represses gene expression by binding to methylated CA sites within long genes, and that in neurons lacking MeCP2, decreasing the expression of long genes attenuates RTT-associated cellular deficits. In addition, we find that long genes as a population are enriched for neuronal functions and selectively expressed in the brain. These findings suggest that mutations in MeCP2 may cause neurological dysfunction by specifically disrupting long gene expression in the brain.

PMID: 25762136 [PubMed - indexed for MEDLINE]

MACROD2 gene associated with autistic-like traits in a general population sample.

June 26, 2015 - 6:11am
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MACROD2 gene associated with autistic-like traits in a general population sample.

Psychiatr Genet. 2014 Dec;24(6):241-8

Authors: Jones RM, Cadby G, Blangero J, Abraham LJ, Whitehouse AJ, Moses EK

Abstract
There is now substantial evidence that autistic-like traits in the general population lie on a continuum, with clinical autism spectrum disorders (ASD) representing the extreme end of this distribution. In this study, we sought to evaluate five independently identified genetic associations with ASD with autistic-like traits in the general population. In the study cohort, clinical phenotype and genomewide association genotype data were obtained from the Western Australian Pregnancy Cohort (Raine) Study. The outcome measure used was the Autism Spectrum Quotient (AQ), a quantitative measure of autistic-like traits of individuals in the cohort. Total AQ scores were calculated for each individual, as well as scores for three subscales. Five candidate single nucleotide polymorphism (SNP) associations with ASD, reported in previously published genomewide association studies, were selected using a nominal cutoff value of P less than 1.0×10. We tested whether these five SNPs were associated with total AQ and the subscales, after adjustment for possible confounders. SNP rs4141463 located in the macro domain containing 2 (MACROD2) gene was significantly associated with the Communication/Mindreading subscale. No other SNP was significantly associated with total AQ or the subscales. The MACROD2 gene is a strong positional candidate risk factor for autistic-like traits in the general population.

PMID: 25360606 [PubMed - indexed for MEDLINE]

Association study identifying a new susceptibility gene (AUTS2) for schizophrenia.

June 26, 2015 - 6:11am
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Association study identifying a new susceptibility gene (AUTS2) for schizophrenia.

Int J Mol Sci. 2014;15(11):19406-16

Authors: Zhang B, Xu YH, Wei SG, Zhang HB, Fu DK, Feng ZF, Guan FL, Zhu YS, Li SB

Abstract
Schizophrenia (SCZ) is a severe and debilitating mental disorder, and the specific genetic factors that underlie the risk for SCZ remain elusive. The autism susceptibility candidate 2 (AUTS2) gene has been reported to be associated with autism, suicide, alcohol consumption, and heroin dependence. We hypothesized that AUTS2 might be associated with SCZ. In the present study, three polymorphisms (rs6943555, rs7459368, and rs9886351) in the AUTS2 gene were genotyped in 410 patients with SCZ and 435 controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and forced PCR-RFLP methods. We detected an association between SCZ and the rs6943555 genotype distribution (odds ratio (OR)=1.363, 95% confidence interval (CI): 0.848-2.191, p=0.001). The association remained significant after adjusting for gender, and a significant effect (p=0.001) was observed among the females. In the present study, rs6943555 was determined to be associated with female SCZ. Our results confirm previous reports which have suggested that rs6943555 might elucidate the pathogenesis of schizophrenia and play an important role in its etiology.

PMID: 25347278 [PubMed - indexed for MEDLINE]

Association between autism spectrum disorder in individuals with velocardiofacial (22q11.2 deletion) syndrome and PRODH and COMT genotypes.

June 26, 2015 - 6:11am
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Association between autism spectrum disorder in individuals with velocardiofacial (22q11.2 deletion) syndrome and PRODH and COMT genotypes.

Psychiatr Genet. 2014 Dec;24(6):269-72

Authors: Radoeva PD, Coman IL, Salazar CA, Gentile KL, Higgins AM, Middleton FA, Antshel KM, Fremont W, Shprintzen RJ, Morrow BE, Kates WR

Abstract
Velocardiofacial (VCFS; 22q11.2 deletion) syndrome is a genetic disorder that results from a hemizygous deletion of the q11.2 region on chromosome 22, and is associated with greatly increased risk for psychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia. There is emerging evidence for the involvement of catechol-O-methyltransferase (COMT) and proline dehydrogenase (oxidase) 1 (PRODH) in the psychiatric phenotype of individuals with VCFS. Here, we tested the hypothesis that PRODH and COMT are associated with ASD in youths with VCFS. We found that individuals with VCFS and the low-activity alleles of both PRODH and COMT (rs4819756A and rs4680A) were more likely to present with ASD as compared with individuals with VCFS and the high-activity alleles of these genes [P<0.05; odds ratio=6.0 (95% confidence interval=1.27-28.26; N=87)]. Our results suggest that PRODH and COMT may interact to contribute to the ASD phenotype in individuals with VCFS.

PMID: 25325218 [PubMed - indexed for MEDLINE]

Common and rare variants of the THBS1 gene associated with the risk for autism.

June 26, 2015 - 6:11am
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Common and rare variants of the THBS1 gene associated with the risk for autism.

Psychiatr Genet. 2014 Dec;24(6):235-40

Authors: Lu L, Guo H, Peng Y, Xun G, Liu Y, Xiong Z, Tian D, Liu Y, Li W, Xu X, Zhao J, Hu Z, Xia K

Abstract
OBJECTIVES: Autism is a severe neurodevelopmental disorder. Many susceptible or causative genes have been identified, and most of them are related to synaptogenesis. The THBS1 gene encodes thrombospondin 1, which plays a critical role in synaptogenesis of the central nervous system in the developing brain. However, no study has been carried out revealing that THBS1 is an autism risk gene.
METHODS: We analyzed the whole coding region and the 5'-untranslated region of the THBS1 gene in 313 autistic patients by Sanger sequencing, which was also used to analyze the identified variants in 350 normal controls. Association analysis was carried out using PLINK or R. Haplotype analysis was carried out using Haploview. Functional prediction and conservation analysis of missense variants were carried out using ANNOVAR.
RESULTS: Twelve variants, including five common variants and seven rare variants, were identified in the THBS1 coding region and the 5'-untranslated region. Among them, one common variant (c.1567A>G:p.T523A) was significantly associated with autism (P<0.05). Two rare variants (c.2429G>A:p.R810Q, c.3496G>C:p.E1166Q) were absent in the 350 controls and were not reported in the single nucleotide polymorphism database (dbSNP). Combined association analysis of the rare variants (minor allele frequency<0.01) in patients and Asian samples in the 1000 genome project revealed a significant association between these rare variants and autism (P=0.039).
CONCLUSION: Our data revealed that both common and rare variants of the THBS1 gene are associated with risk for autism, suggesting that THBS1 is a novel susceptible gene for autism.

PMID: 25304225 [PubMed - indexed for MEDLINE]

The clinical impact of chromosomal microarray on paediatric care in Hong Kong.

June 25, 2015 - 9:56am
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The clinical impact of chromosomal microarray on paediatric care in Hong Kong.

PLoS One. 2014;9(10):e109629

Authors: Tao VQ, Chan KY, Chu YW, Mok GT, Tan TY, Yang W, Lee SL, Tang WF, Tso WW, Lau ET, Kan AS, Tang MH, Lau YL, Chung BH

Abstract
OBJECTIVE: To evaluate the clinical impact of chromosomal microarray (CMA) on the management of paediatric patients in Hong Kong.
METHODS: We performed NimbleGen 135k oligonucleotide array on 327 children with intellectual disability (ID)/developmental delay (DD), autism spectrum disorders (ASD), and/or multiple congenital anomalies (MCAs) in a university-affiliated paediatric unit from January 2011 to May 2013. The medical records of patients were reviewed in September 2013, focusing on the pathogenic/likely pathogenic CMA findings and their "clinical actionability" based on established criteria.
RESULTS: Thirty-seven patients were reported to have pathogenic/likely pathogenic results, while 40 had findings of unknown significance. This gives a detection rate of 11% for clinically significant (pathogenic/likely pathogenic) findings. The significant findings have prompted clinical actions in 28 out of 37 patients (75.7%), while the findings with unknown significance have led to further management recommendation in only 1 patient (p < 0.001). Nineteen out of the 28 management recommendations are "evidence-based" on either practice guidelines endorsed by a professional society (n = 9, Level 1) or peer-reviewed publications making medical management recommendation (n = 10, Level 2). CMA results impact medical management by precipitating referral to a specialist (n = 24); diagnostic testing (n = 25), surveillance of complications (n = 19), interventional procedure (n = 7), medication (n = 15) or lifestyle modification (n = 12).
CONCLUSION: The application of CMA in children with ID/DD, ASD, and/or MCAs in Hong Kong results in a diagnostic yield of ∼ 11% for pathogenic/likely pathogenic results. Importantly the yield for clinically actionable results is 8.6%. We advocate using diagnostic yield of clinically actionable results to evaluate CMA as it provides information of both clinical validity and clinical utility. Furthermore, it incorporates evidence-based medicine into the practice of genomic medicine. The same framework can be applied to other genomic testing strategies enabled by next-generation sequencing.

PMID: 25333781 [PubMed - indexed for MEDLINE]

The dwarf phenotype in GH240B mice, haploinsufficient for the autism candidate gene Neurobeachin, is caused by ectopic expression of recombinant human growth hormone.

June 25, 2015 - 9:56am
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The dwarf phenotype in GH240B mice, haploinsufficient for the autism candidate gene Neurobeachin, is caused by ectopic expression of recombinant human growth hormone.

PLoS One. 2014;9(10):e109598

Authors: Nuytens K, Tuand K, Fu Q, Stijnen P, Pruniau V, Meulemans S, Vankelecom H, Creemers JW

Abstract
Two knockout mouse models for the autism candidate gene Neurobeachin (Nbea) have been generated independently. Although both models have similar phenotypes, one striking difference is the dwarf phenotype observed in the heterozygous configuration of the GH240B model that is generated by the serendipitous insertion of a promoterless human growth hormone (hGH) genomic fragment in the Nbea gene. In order to elucidate this discrepancy, the dwarfism present in this Nbea mouse model was investigated in detail. The growth deficiency in Nbea+/- mice coincided with an increased percentage of fat mass and a decrease in bone mineral density. Low but detectable levels of hGH were detected in the pituitary and hypothalamus of Nbea+/- mice but not in liver, hippocampus nor in serum. As a consequence, several members of the mouse growth hormone (mGH) signaling cascade showed altered mRNA levels, including a reduction in growth hormone-releasing hormone mRNA in the hypothalamus. Moreover, somatotrope cells were less numerous in the pituitary of Nbea+/- mice and both contained and secreted significantly less mGH resulting in reduced levels of circulating insulin-like growth factor 1. These findings demonstrate that the random integration of the hGH transgene in this mouse model has not only inactivated Nbea but has also resulted in the tissue-specific expression of hGH causing a negative feedback loop, mGH hyposecretion and dwarfism.

PMID: 25333629 [PubMed - indexed for MEDLINE]

Female Autism Phenotypes Investigated at Different Levels of Language and Developmental Abilities.

June 24, 2015 - 8:59am
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Female Autism Phenotypes Investigated at Different Levels of Language and Developmental Abilities.

J Autism Dev Disord. 2015 Jun 23;

Authors: Howe YJ, O'Rourke JA, Yatchmink Y, Viscidi EW, Jones RN, Morrow EM

Abstract
This study investigated the differences in clinical symptoms between females and males with autism spectrum disorder (ASD) across three verbal ability groups (nonverbal, phrase and fluent speech), based on which Autism Diagnostic Observation Schedule module was administered to 5723 individuals in four research datasets. In the Simons Simplex Collection and Autism Treatment Network, females with ASD and phrase or fluent speech had lower cognitive, adaptive, and social abilities than males. In the Autism Genetics Resource Exchange and the Autism Consortium, females with phrase or fluent speech had similar or better adaptive and social abilities than males. Females who were nonverbal had similar cognitive, adaptive, and social abilities as males. Population-based longitudinal studies of verbally fluent females with ASD are needed.

PMID: 26100851 [PubMed - as supplied by publisher]

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