pubmed: autism and genetics

Subscribe to pubmed: autism and genetics feed pubmed: autism and genetics
NCBI: db=pubmed; Term=autism AND genetics
Updated: 2 hours 23 min ago

Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort.

July 28, 2016 - 8:03am
Related Articles

Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort.

Int J Epidemiol. 2015 Aug;44(4):1199-210

Authors: Feinberg JI, Bakulski KM, Jaffe AE, Tryggvadottir R, Brown SC, Goldman LR, Croen LA, Hertz-Picciotto I, Newschaffer CJ, Fallin MD, Feinberg AP

Abstract
BACKGROUND: Epigenetic mechanisms such as altered DNA methylation have been suggested to play a role in autism, beginning with the classical association of Prader-Willi syndrome, an imprinting disorder, with autistic features.
OBJECTIVES: Here we tested for the relationship of paternal sperm DNA methylation with autism risk in offspring, examining an enriched-risk cohort of fathers of autistic children.
METHODS: We examined genome-wide DNA methylation (DNAm) in paternal semen biosamples obtained from an autism spectrum disorder (ASD) enriched-risk pregnancy cohort, the Early Autism Risk Longitudinal Investigation (EARLI) cohort, to estimate associations between sperm DNAm and prospective ASD development, using a 12-month ASD symptoms assessment, the Autism Observation Scale for Infants (AOSI). We analysed methylation data from 44 sperm samples run on the CHARM 3.0 array, which contains over 4 million probes (over 7 million CpG sites), including 30 samples also run on the Illumina Infinium HumanMethylation450 (450K) BeadChip platform (∼485 000 CpG sites). We also examined associated regions in an independent sample of post-mortem human brain ASD and control samples for which Illumina 450K DNA methylation data were available.
RESULTS: Using region-based statistical approaches, we identified 193 differentially methylated regions (DMRs) in paternal sperm with a family-wise empirical P-value [family-wise error rate (FWER)] <0.05 associated with performance on the Autism Observational Scale for Infants (AOSI) at 12 months of age in offspring. The DMRs clustered near genes involved in developmental processes, including many genes in the SNORD family, within the Prader-Willi syndrome gene cluster. These results were consistent among the 75 probes on the Illumina 450K array that cover AOSI-associated DMRs from CHARM. Further, 18 of 75 (24%) 450K array probes showed consistent differences in the cerebellums of autistic individuals compared with controls.
CONCLUSIONS: These data suggest that epigenetic differences in paternal sperm may contribute to autism risk in offspring, and provide evidence that directionally consistent, potentially related epigenetic mechanisms may be operating in the cerebellum of individuals with autism.

PMID: 25878217 [PubMed - indexed for MEDLINE]

Novel de novo EEF1A2 missense mutations causing epilepsy and intellectual disability.

July 22, 2016 - 7:52am

Novel de novo EEF1A2 missense mutations causing epilepsy and intellectual disability.

Mol Genet Genomic Med. 2016 Jul;4(4):465-74

Authors: Lam WW, Millichap JJ, Soares DC, Chin R, McLellan A, FitzPatrick DR, Elmslie F, Lees MM, Schaefer GB, DDD study, Abbott CM

Abstract
BACKGROUND: Exome sequencing has led to the discovery of mutations in novel causative genes for epilepsy. One such gene is EEF1A2, encoding a neuromuscular specific translation elongation factor, which has been found to be mutated de novo in five cases of severe epilepsy. We now report on a further seven cases, each with a different mutation, of which five are newly described.
METHODS: New cases were identified and sequenced through the Deciphering Developmental Disabilities project, via direct contact with neurologists or geneticists, or recruited via our website.
RESULTS: All the mutations cause epilepsy and intellectual disability, but with a much wider range of severity than previously identified. All new cases share specific subtle facial dysmorphic features. Each mutation occurs at an evolutionarily highly conserved amino acid position indicating strong structural or functional selective pressure.
CONCLUSIONS: EEF1A2 should be considered as a causative gene not only in cases of epileptic encephalopathy but also in children with less severe epilepsy and intellectual disability. The emergence of a possible discernible phenotype, a broad nasal bridge, tented upper lip, everted lower lip and downturned corners of the mouth may help in identifying patients with mutations in EEF1A2.

PMID: 27441201 [PubMed]

[Research advances in candidate genes for autism spectrum disorder].

July 22, 2016 - 7:52am
Related Articles

[Research advances in candidate genes for autism spectrum disorder].

Zhongguo Dang Dai Er Ke Za Zhi. 2016 Mar;18(3):282-7

Authors: Yang ZL, Sun GL

Abstract
Autism spectrum disorder (ASD) is a kind of neurodevelopmental multigenic disorder. More than one hundred of candidate genes for ASD have been reported. The candidate gene research for ASD involves in chromosome loci and screening of candidate genes and epigenetic abnormalities for candidate genes. The reported genes encode neural adhesion molecules, ion channels, scaffold proteins, protein kinases, receptor protein and carrier protein, signaling modulate molecules and circadian relevant proteins. The research of mutation screening and expression regulation of candidate genes can help to elucidate genetic mechanisms for ASD, and may provide new approaches for the diagnosis and treatment of this disorder. This article reviews the research advance in candidate genes for ASD.

PMID: 26975830 [PubMed - indexed for MEDLINE]

Autism Linked to Increased Oncogene Mutations but Decreased Cancer Rate.

July 22, 2016 - 7:52am
Related Articles

Autism Linked to Increased Oncogene Mutations but Decreased Cancer Rate.

PLoS One. 2016;11(3):e0149041

Authors: Darbro BW, Singh R, Zimmerman MB, Mahajan VB, Bassuk AG

Abstract
Autism spectrum disorder (ASD) is one phenotypic aspect of many monogenic, hereditary cancer syndromes. Pleiotropic effects of cancer genes on the autism phenotype could lead to repurposing of oncology medications to treat this increasingly prevalent neurodevelopmental condition for which there is currently no treatment. To explore this hypothesis we sought to discover whether autistic patients more often have rare coding, single-nucleotide variants within tumor suppressor and oncogenes and whether autistic patients are more often diagnosed with neoplasms. Exome-sequencing data from the ARRA Autism Sequencing Collaboration was compared to that of a control cohort from the Exome Variant Server database revealing that rare, coding variants within oncogenes were enriched for in the ARRA ASD cohort (p<1.0 x 10(-8)). In contrast, variants were not significantly enriched in tumor suppressor genes. Phenotypically, children and adults with ASD exhibited a protective effect against cancer, with a frequency of 1.3% vs. 3.9% (p<0.001), but the protective effect decreased with age. The odds ratio of neoplasm for those with ASD relative to controls was 0.06 (95% CI: 0.02, 0.19; p<0.0001) in the 0 to 14 age group; 0.35 (95% CI: 0.14, 0.87; p = 0.024) in the 15 to 29 age group; 0.41 (95% CI: 0.15, 1.17; p = 0.095) in the 30 to 54 age group; and 0.49 (95% CI: 0.14, 1.74; p = 0.267) in those 55 and older. Both males and females demonstrated the protective effect. These findings suggest that defects in cellular proliferation, and potentially senescence, might influence both autism and neoplasm, and already approved drugs targeting oncogenic pathways might also have therapeutic value for treating autism.

PMID: 26934580 [PubMed - indexed for MEDLINE]

Social Cognition Impairments in Mice Overexpressing Alpha-Synuclein Under the Thy1 Promoter, a Model of Pre-manifest Parkinson's Disease.

July 22, 2016 - 7:52am
Related Articles

Social Cognition Impairments in Mice Overexpressing Alpha-Synuclein Under the Thy1 Promoter, a Model of Pre-manifest Parkinson's Disease.

J Parkinsons Dis. 2015;5(3):669-80

Authors: Magen I, Torres ER, Dinh D, Chung A, Masliah E, Chesselet MF

Abstract
BACKGROUND: Patients with Parkinson's disease (PD) may exhibit deficits in "Theory of Mind", the ability to read others' mental states and react appropriately, a prerequisite for successful social interaction. Alpha-synuclein overexpression is widely distributed in the brain of patients with sporadic PD, suggesting that it may contribute to the non-motor deficits observed in PD patients. Mice over-expressing human wild-type alpha-synuclein under the Thy1 promoter (Thy1-aSyn mice) have synaptic deficits in the frontostriatal pathway, low cortical acetylcholine, and high level of expression of mGluR5 receptors, which have all been implicated in social recognition deficits.
OBJECTIVE: To determine whether Thy1-aSyn mice present alterations in their response to social stimuli.
METHODS: We have submitted Thy1-aSyn mice to tests adapted from autism models.
RESULTS: At 7-8 month of age Thy1-aSyn mice explored their conspecifics significantly less than did wild-type littermates, without differences in exploration of inanimate objects, and pairs of Thy1-aSyn mice were involved in reciprocal interactions for a shorter duration than wild-type mice at this age. These deficits persisted when the test animal was enclosed in a beaker and were not present at 3-4 months of age despite the presence of olfactory deficits at that age, indicating that they were not solely caused by impairment in olfaction.
CONCLUSION: Thy1-aSyn mice present progressive deficits in social recognition, supporting an association between alpha-synuclein overexpression and Theory of Mind deficits in PD and providing a useful model for identifying mechanisms and testing novel treatments for these deficits which impact patients and caretakers quality of life.

PMID: 25588356 [PubMed - indexed for MEDLINE]

De novo nonsense and frameshift variants of TCF20 in individuals with intellectual disability and postnatal overgrowth.

July 21, 2016 - 1:49pm
Related Articles

De novo nonsense and frameshift variants of TCF20 in individuals with intellectual disability and postnatal overgrowth.

Eur J Hum Genet. 2016 Jul 20;

Authors: Schäfgen J, Cremer K, Becker J, Wieland T, Zink AM, Kim S, Windheuser IC, Kreiß M, Aretz S, Strom TM, Wieczorek D, Engels H

Abstract
Recently, germline variants of the transcriptional co-regulator gene TCF20 have been implicated in the aetiology of autism spectrum disorders (ASD). However, the knowledge about the associated clinical picture remains fragmentary. In this study, two individuals with de novo TCF20 sequence variants were identified in a cohort of 313 individuals with intellectual disability of unknown aetiology, which was analysed by whole exome sequencing using a child-parent trio design. Both detected variants - one nonsense and one frameshift variant - were truncating. A comprehensive clinical characterisation of the patients yielded mild intellectual disability, postnatal tall stature and macrocephaly, obesity and muscular hypotonia as common clinical signs while ASD was only present in one proband. The present report begins to establish the clinical picture of individuals with de novo nonsense and frameshift variants of TCF20 which includes features such as proportionate overgrowth and muscular hypotonia. Furthermore, intellectual disability/developmental delay seems to be fully penetrant amongst known individuals with de novo nonsense and frameshift variants of TCF20, whereas ASD is shown to be incompletely penetrant. The transcriptional co-regulator gene TCF20 is hereby added to the growing number of genes implicated in the aetiology of both ASD and intellectual disability. Furthermore, such de novo variants of TCF20 may represent a novel differential diagnosis in the overgrowth syndrome spectrum.European Journal of Human Genetics advance online publication, 20 July 2016; doi:10.1038/ejhg.2016.90.

PMID: 27436265 [PubMed - as supplied by publisher]

Reciprocal Effects on Neurocognitive and Metabolic Phenotypes in Mouse Models of 16p11.2 Deletion and Duplication Syndromes.

July 20, 2016 - 4:47pm
Related Articles

Reciprocal Effects on Neurocognitive and Metabolic Phenotypes in Mouse Models of 16p11.2 Deletion and Duplication Syndromes.

PLoS Genet. 2016 Feb;12(2):e1005709

Authors: Arbogast T, Ouagazzal AM, Chevalier C, Kopanitsa M, Afinowi N, Migliavacca E, Cowling BS, Birling MC, Champy MF, Reymond A, Herault Y

Abstract
The 16p11.2 600 kb BP4-BP5 deletion and duplication syndromes have been associated with developmental delay; autism spectrum disorders; and reciprocal effects on the body mass index, head circumference and brain volumes. Here, we explored these relationships using novel engineered mouse models carrying a deletion (Del/+) or a duplication (Dup/+) of the Sult1a1-Spn region homologous to the human 16p11.2 BP4-BP5 locus. On a C57BL/6N inbred genetic background, Del/+ mice exhibited reduced weight and impaired adipogenesis, hyperactivity, repetitive behaviors, and recognition memory deficits. In contrast, Dup/+ mice showed largely opposite phenotypes. On a F1 C57BL/6N × C3B hybrid genetic background, we also observed alterations in social interaction in the Del/+ and the Dup/+ animals, with other robust phenotypes affecting recognition memory and weight. To explore the dosage effect of the 16p11.2 genes on metabolism, Del/+ and Dup/+ models were challenged with high fat and high sugar diet, which revealed opposite energy imbalance. Transcriptomic analysis revealed that the majority of the genes located in the Sult1a1-Spn region were sensitive to dosage with a major effect on several pathways associated with neurocognitive and metabolic phenotypes. Whereas the behavioral consequence of the 16p11 region genetic dosage was similar in mice and humans with activity and memory alterations, the metabolic defects were opposite: adult Del/+ mice are lean in comparison to the human obese phenotype and the Dup/+ mice are overweight in comparison to the human underweight phenotype. Together, these data indicate that the dosage imbalance at the 16p11.2 locus perturbs the expression of modifiers outside the CNV that can modulate the penetrance, expressivity and direction of effects in both humans and mice.

PMID: 26872257 [PubMed - indexed for MEDLINE]

Deciphering H3K4me3 broad domains associated with gene-regulatory networks and conserved epigenomic landscapes in the human brain.

July 20, 2016 - 4:47pm
Related Articles

Deciphering H3K4me3 broad domains associated with gene-regulatory networks and conserved epigenomic landscapes in the human brain.

Transl Psychiatry. 2015;5:e679

Authors: Dincer A, Gavin DP, Xu K, Zhang B, Dudley JT, Schadt EE, Akbarian S

Abstract
Regulators of the histone H3-trimethyl lysine-4 (H3K4me3) mark are significantly associated with the genetic risk architecture of common neurodevelopmental disease, including schizophrenia and autism. Typical H3K4me3 is primarily localized in the form of sharp peaks, extending in neuronal chromatin on average only across 500-1500 base pairs mostly in close proximity to annotated transcription start sites. Here, through integrative computational analysis of epigenomic and transcriptomic data based on next-generation sequencing, we investigated H3K4me3 landscapes of sorted neuronal and non-neuronal nuclei in human postmortem, non-human primate and mouse prefrontal cortex (PFC), and blood. To explore whether H3K4me3 peak signals could also extend across much broader domains, we examined broadest domain cell-type-specific H3K4me3 peaks in an unbiased manner with an innovative approach on 41+12 ChIP-seq and RNA-seq data sets. In PFC neurons, broadest H3K4me3 distribution ranged from 3.9 to 12 kb, with extremely broad peaks (~10 kb or broader) related to synaptic function and GABAergic signaling (DLX1, ELFN1, GAD1, IGSF9B and LINC00966). Broadest neuronal peaks showed distinct motif signatures and were centrally positioned in prefrontal gene-regulatory Bayesian networks and sensitive to defective neurodevelopment. Approximately 120 of the broadest H3K4me3 peaks in human PFC neurons, including many genes related to glutamatergic and dopaminergic signaling, were fully conserved in chimpanzee, macaque and mouse cortical neurons. Exploration of spread and breadth of lysine methylation markings could provide novel insights into epigenetic mechanism involved in neuropsychiatric disease and neuronal genome evolution.

PMID: 26575220 [PubMed - indexed for MEDLINE]

Functional genomics of human brain development and implications for autism spectrum disorders.

July 20, 2016 - 4:47pm
Related Articles

Functional genomics of human brain development and implications for autism spectrum disorders.

Transl Psychiatry. 2015;5:e665

Authors: Ziats MN, Grosvenor LP, Rennert OM

Abstract
Transcription of the inherited DNA sequence into copies of messenger RNA is the most fundamental process by which the genome functions to guide development. Encoded sequence information, inherited epigenetic marks and environmental influences all converge at the level of mRNA gene expression to allow for cell-type-specific, tissue-specific, spatial and temporal patterns of expression. Thus, the transcriptome represents a complex interplay between inherited genomic structure, dynamic experiential demands and external signals. This property makes transcriptome studies uniquely positioned to provide insight into complex genetic-epigenetic-environmental processes such as human brain development, and disorders with non-Mendelian genetic etiologies such as autism spectrum disorders. In this review, we describe recent studies exploring the unique functional genomics profile of the human brain during neurodevelopment. We then highlight two emerging areas of research with great potential to increase our understanding of functional neurogenomics-non-coding RNA expression and gene interaction networks. Finally, we review previous functional genomics studies of autism spectrum disorder in this context, and discuss how investigations at the level of functional genomics are beginning to identify convergent molecular mechanisms underlying this genetically heterogeneous disorder.

PMID: 26506051 [PubMed - indexed for MEDLINE]

Genetic modulation of oxytocin sensitivity: a pharmacogenetic approach.

July 20, 2016 - 4:47pm
Related Articles

Genetic modulation of oxytocin sensitivity: a pharmacogenetic approach.

Transl Psychiatry. 2015;5:e664

Authors: Chen FS, Kumsta R, Dvorak F, Domes G, Yim OS, Ebstein RP, Heinrichs M

Abstract
Intranasal administration of the neuropeptide oxytocin has been shown to influence a range of complex social cognitions and social behaviors, and it holds therapeutic potential for the treatment of mental disorders characterized by social functioning deficits such as autism, social phobia and borderline personality disorder. However, considerable variability exists in individual responses to oxytocin administration. Here, we undertook a study to investigate the role of genetic variation in sensitivity to exogenous oxytocin using a socioemotional task. In a randomized, double-blind, placebo-controlled experiment with a repeated-measures (crossover) design, we assessed the performance of 203 men on an emotion recognition task under oxytocin and placebo. We took a haplotype-based approach to investigate the association between oxytocin receptor gene variation and oxytocin sensitivity. We identified a six-marker haplotype block spanning the promoter region and intron 3 that was significantly associated with our measure of oxytocin sensitivity. Specifically, the TTCGGG haplotype comprising single-nucleotide polymorphisms rs237917-rs2268498-rs4564970-rs237897-rs2268495-rs53576 is associated with increased emotion recognition performance under oxytocin versus placebo, and the CCGAGA haplotype with the opposite pattern. These results on the genetic modulation of sensitivity to oxytocin document a significant source of individual differences with implications for personalized treatment approaches using oxytocin administration.

PMID: 26506050 [PubMed - indexed for MEDLINE]

Genome-wide differential expression of synaptic long noncoding RNAs in autism spectrum disorder.

July 20, 2016 - 4:47pm
Related Articles

Genome-wide differential expression of synaptic long noncoding RNAs in autism spectrum disorder.

Transl Psychiatry. 2015;5:e660

Authors: Wang Y, Zhao X, Ju W, Flory M, Zhong J, Jiang S, Wang P, Dong X, Tao X, Chen Q, Shen C, Zhong M, Yu Y, Brown WT, Zhong N

Abstract
A genome-wide differential expression of long noncoding RNAs (lncRNAs) was identified in blood specimens of autism spectrum disorder (ASD). A total of 3929 lncRNAs were found to be differentially expressed in ASD peripheral leukocytes, including 2407 that were upregulated and 1522 that were downregulated. Simultaneously, 2591 messenger RNAs (mRNAs), including 1789 upregulated and 821 downregulated, were also identified in ASD leukocytes. Functional pathway analysis of these lncRNAs revealed neurological pathways of the synaptic vesicle cycling, long-term depression and long-term potentiation to be primarily involved. Thirteen synaptic lncRNAs, including nine upregulated and four downregulated, and 19 synaptic mRNAs, including 12 upregulated and seven downregulated, were identified as being differentially expressed in ASD. Our identification of differential expression of synaptic lncRNAs and mRNAs suggested that synaptic vesicle transportation and cycling are important for the delivery of synaptosomal protein(s) between presynaptic and postsynaptic membranes in ASD. Finding of 19 lncRNAs, which are the antisense, bi-directional and intergenic, of HOX genes may lead us to investigate the role of HOX genes involved in the development of ASD. Discovery of the lncRNAs of SHANK2-AS and BDNF-AS, the natural antisense of genes SHANK2 and BDNF, respectively, indicates that in addition to gene mutations, deregulation of lncRNAs on ASD-causing gene loci presents a new approach for exploring possible epigenetic mechanisms underlying ASD. Our study also opened a new avenue for exploring the use of lncRNA(s) as biomarker(s) for the early detection of ASD.

PMID: 26485544 [PubMed - indexed for MEDLINE]

Copy Number Variants Associated with 14 Cases of Self-Injurious Behavior.

July 19, 2016 - 7:45pm
Related Articles

Copy Number Variants Associated with 14 Cases of Self-Injurious Behavior.

PLoS One. 2016;11(3):e0149646

Authors: Shirley MD, Frelin L, López JS, Jedlicka A, Dziedzic A, Frank-Crawford MA, Silverman W, Hagopian L, Pevsner J

Abstract
Copy number variants (CNVs) were detected and analyzed in 14 probands with autism and intellectual disability with self-injurious behavior (SIB) resulting in tissue damage. For each proband we obtained a clinical history and detailed behavioral descriptions. Genetic anomalies were observed in all probands, and likely clinical significance could be established in four cases. This included two cases having novel, de novo copy number variants and two cases having variants likely to have functional significance. These cases included segmental trisomy 14, segmental monosomy 21, and variants predicted to disrupt the function of ZEB2 (encoding a transcription factor) and HTR2C (encoding a serotonin receptor). Our results identify variants in regions previously implicated in intellectual disability and suggest candidate genes that could contribute to the etiology of SIB.

PMID: 26933844 [PubMed - indexed for MEDLINE]

Patient Mutations of the Intellectual Disability Gene KDM5C Downregulate Netrin G2 and Suppress Neurite Growth in Neuro2a Cells.

July 17, 2016 - 7:38am

Patient Mutations of the Intellectual Disability Gene KDM5C Downregulate Netrin G2 and Suppress Neurite Growth in Neuro2a Cells.

J Mol Neurosci. 2016 Jul 16;

Authors: Wei G, Deng X, Agarwal S, Iwase S, Disteche C, Xu J

Abstract
The X-linked lysine (K)-specific demethylase 5C (KDM5C) gene plays an important role in brain development and behavior. It encodes a histone demethylase that is involved in gene regulation in neuronal differentiation and morphogenesis. When mutated, it causes neuropsychiatric symptoms, such as intellectual disability, delayed language development, epilepsy, and impulsivity. To better understand how the patient mutations affect neuronal development, we expressed KDM5C mutants in Neuro2a cells, a mouse neuroblastoma cell line. Retinoic acid (RA)-induced neurite growth was suppressed by the mutation KDM5C (Y751C) , KDM5C (H514A) , and KDM5C (F642L) , but not KDM5C (D87G) or KDM5C (A388P) . RNA-seq analysis indicated an upregulation of genes important for neuronal development, such as Ntng2, Enah, Gas1, Slit2, and Dscam, in response to the RA treatment in control Neuro2a cells transfected with GFP or wild-type KDM5C. In contrast, in cells transfected with KDM5C (Y751C) , these genes were not upregulated by RA. Ntng2 was downregulated in cells with KDM5C mutations, concordant with the lower levels of H3K4 methylation at its promoter. Moreover, knocking down Ntng2 in control Neuro2a cells led to the phenotype of short neurites similar to that of cells with KDM5C (Y751C) , whereas Ntng2 overexpression in the mutant cells rescued the morphological phenotype. These findings provide new insight into the pathogenesis of phenotypes associated with KDM5C mutations.

PMID: 27421841 [PubMed - as supplied by publisher]

17q12 deletion and duplication syndrome in Denmark-A clinical cohort of 38 patients and review of the literature.

July 14, 2016 - 7:33pm

17q12 deletion and duplication syndrome in Denmark-A clinical cohort of 38 patients and review of the literature.

Am J Med Genet A. 2016 Jul 13;

Authors: Rasmussen M, Vestergaard EM, Graakjaer J, Petkov Y, Bache I, Fagerberg C, Kibaek M, Svaneby D, Petersen OB, Brasch-Andersen C, Sunde L

Abstract
17q12 deletions and duplications are two distinct, recurrent chromosomal aberrations usually diagnosed by chromosomal microarray analysis (CMA). The aberrations encompass the genes, HNF1B, LHX1, and ACACA, among others. We here describe a large national cohort of 12 phenotyped patients with 17q12 deletions and 26 phenotyped patients with 17q12 duplications. The total cohort includes 19 index patients and 19 family members. We also reviewed the literature in order to further improve the basis for the counseling. We emphasize that renal disease, learning disability, behavioral abnormalities, epilepsy, autism, schizophrenia, structural brain abnormalities, facial dysmorphism, and joint laxity are features seen in both the 17q12 deletion syndrome and the reciprocal 17q12 duplication syndrome; and we extend the list of features seen in both patient categories to include strabismus, esophageal defects, and duodenal atresia. Delayed language development, learning disability, kidney involvement, and eye dysmorphism and strabismus were the most consistently shared features among patients with 17q12 deletion. Patients with 17q12 duplications were characterized by an extremely wide phenotypic spectrum, including a variable degree of learning disabilities, delayed language development, delayed motor milestones, and a broad range of psychiatric and neurological features. This patient group also included adults achieving an academic degree. Assessing index patients and non-index patients separately, our observations illustrate that an overall milder disease burden is seen, in particular in patients with 17q12 duplications who are ascertained on the duplication rather than the phenotype. This evidence may be useful in prenatal counseling. © 2016 Wiley Periodicals, Inc.

PMID: 27409573 [PubMed - as supplied by publisher]

De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.

July 14, 2016 - 7:33pm
Related Articles

De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.

Neuron. 2016 Mar 2;89(5):940-7

Authors: Takata A, Ionita-Laza I, Gogos JA, Xu B, Karayiorgou M

Abstract
We analyze de novo synonymous mutations identified in autism spectrum disorders (ASDs) and schizophrenia (SCZ) with potential impact on regulatory elements using data from whole-exome sequencing (WESs) studies. Focusing on five types of genetic regulatory functions, we found that de novo near-splice site synonymous mutations changing exonic splicing regulators and those within frontal cortex-derived DNase I hypersensitivity sites are significantly enriched in ASD and SCZ, respectively. These results remained significant, albeit less so, after incorporating two additional ASD datasets. Among the genes identified, several are hit by multiple functional de novo mutations, with RAB2A and SETD1A showing the highest statistical significance in ASD and SCZ, respectively. The estimated contribution of these synonymous mutations to disease liability is comparable to de novo protein-truncating mutations. These findings expand the repertoire of functional de novo mutations to include "functional" synonymous ones and strengthen the role of rare variants in neuropsychiatric disease risk.

PMID: 26938441 [PubMed - indexed for MEDLINE]

Association of Autism Spectrum Disorder with Obsessive-Compulsive and Attention-Deficit/Hyperactivity Traits and Response Inhibition in a Community Sample.

July 13, 2016 - 7:29am

Association of Autism Spectrum Disorder with Obsessive-Compulsive and Attention-Deficit/Hyperactivity Traits and Response Inhibition in a Community Sample.

J Autism Dev Disord. 2016 Jul 11;

Authors: van der Plas E, Dupuis A, Arnold P, Crosbie J, Schachar R

Abstract
We examined co-occurrence of autism spectrum disorder (ASD) with (traits of) attention-deficit/hyperactivity (ADHD), obsessive-compulsive (OCD) and inhibition deficits in a community sample (n = 16,676) and tested whether having a sibling with ASD manifested in increased features of ADHD, OCD or inhibition deficits. Individuals with ASD had increased ADHD and OCD traits compared with individuals without ASD. Individuals with a sibling with ASD exhibited more ADHD traits than did individuals whose sibling did not have ASD. The "sibling effect" on manifestation of ADHD traits was observed in individuals with and without ASD. Having a sibling with ASD did not affect OCD traits. Inhibition was impaired in individuals with ASD who had a sibling with ASD only.

PMID: 27401994 [PubMed - as supplied by publisher]

Identification of novel genetic causes of Rett syndrome-like phenotypes.

July 13, 2016 - 7:29am
Related Articles

Identification of novel genetic causes of Rett syndrome-like phenotypes.

J Med Genet. 2016 Mar;53(3):190-9

Authors: Lopes F, Barbosa M, Ameur A, Soares G, de Sá J, Dias AI, Oliveira G, Cabral P, Temudo T, Calado E, Cruz IF, Vieira JP, Oliveira R, Esteves S, Sauer S, Jonasson I, Syvänen AC, Gyllensten U, Pinto D, Maciel P

Abstract
BACKGROUND: The aim of this work was to identify new genetic causes of Rett-like phenotypes using array comparative genomic hybridisation and a whole exome sequencing approach.
METHODS AND RESULTS: We studied a cohort of 19 Portuguese patients (16 girls, 3 boys) with a clinical presentation significantly overlapping Rett syndrome (RTT). Genetic analysis included filtering of the single nucleotide variants and indels with preference for de novo, homozygous/compound heterozygous, or maternally inherited X linked variants. Examination by MRI and muscle biopsies was also performed. Pathogenic genomic imbalances were found in two patients (10.5%): an 18q21.2 deletion encompassing four exons of the TCF4 gene and a mosaic UPD of chromosome 3. Variants in genes previously implicated in neurodevelopmental disorders (NDD) were identified in six patients (32%): de novo variants in EEF1A2, STXBP1 and ZNF238 were found in three patients, maternally inherited X linked variants in SLC35A2, ZFX and SHROOM4 were detected in two male patients and one homozygous variant in EIF2B2 was detected in one patient. Variants were also detected in five novel NDD candidate genes (26%): we identified de novo variants in the RHOBTB2, SMARCA1 and GABBR2 genes; a homozygous variant in EIF4G1; compound heterozygous variant in HTT.
CONCLUSIONS: Network analysis reveals that these genes interact by means of protein interactions with each other and with the known RTT genes. These findings expand the phenotypical spectrum of previously known NDD genes to encompass RTT-like clinical presentations and identify new candidate genes for RTT-like phenotypes.

PMID: 26740508 [PubMed - indexed for MEDLINE]

Glutamatergic synapse protein composition of wild-type mice is sensitive to in utero MTHFR genotype and the timing of neonatal vigabatrin exposure.

July 13, 2016 - 7:29am
Related Articles

Glutamatergic synapse protein composition of wild-type mice is sensitive to in utero MTHFR genotype and the timing of neonatal vigabatrin exposure.

Eur Neuropsychopharmacol. 2015 Oct;25(10):1787-802

Authors: Zuckerman C, Blumkin E, Melamed O, Golan HM

Abstract
The enzyme methylenetetrahydrofolate-reductase (MTHFR) is part of the homocysteine and folate metabolic pathways. In utero, Mthfr-deficient environment has been reported as a risk factor for neurodevelopmental disorders such as autism and neural tube defects. Neonatal disruption of the GABAergic system is also associated with behavioral outcomes. The interaction between Mthfr deficiency and neonatal exposure to the GABA-potentiating drug vigabatrin (GVG) in mice alters anxiety, memory, and social behavior in a gender-dependent manner. In addition, a gender-dependent enhancement of proteins implicated in excitatory synapse plasticity in the cerebral cortex was shown. Here we show that in utero MTHFR deficiency is sufficient to alter the levels of glutamate receptor subunits GluR1, GluR2, and NR2B in the cerebral cortex and hippocampus of adult offspring with a WT genotype. In addition, FMRP1, CAMKII α and γ, and NLG1 levels in WT offspring were vulnerable to the in utero genotype. These effects depend on brain region and the cellular compartment tested. The effect of in utero MTHFR deficiency varies with the age of neonatal GVG exposure to modify GluR1, NR2A, reelin, CAMKII α, and NLG1 levels. These changes in molecular composition of the glutamatergic synapse were associated with increased anxiety-like behavior. Complex, multifactorial disorders of the nervous system show significant association with several genetic and environmental factors. Our data exemplify the contribution of an in utero MTHFR-deficient environment and early exposure to an antiepileptic drug to the basal composition of the glutamatergic synapses. The robust effect is expected to alter synapse function and plasticity and the cortico-hippocampal circuitry.

PMID: 26235956 [PubMed - indexed for MEDLINE]

Engrailed-2 (En2) deletion produces multiple neurodevelopmental defects in monoamine systems, forebrain structures and neurogenesis and behavior.

July 13, 2016 - 7:29am
Related Articles

Engrailed-2 (En2) deletion produces multiple neurodevelopmental defects in monoamine systems, forebrain structures and neurogenesis and behavior.

Hum Mol Genet. 2015 Oct 15;24(20):5805-27

Authors: Genestine M, Lin L, Durens M, Yan Y, Jiang Y, Prem S, Bailoor K, Kelly B, Sonsalla PK, Matteson PG, Silverman J, Crawley JN, Millonig JH, DiCicco-Bloom E

Abstract
Many genes involved in brain development have been associated with human neurodevelopmental disorders, but underlying pathophysiological mechanisms remain undefined. Human genetic and mouse behavioral analyses suggest that ENGRAILED-2 (EN2) contributes to neurodevelopmental disorders, especially autism spectrum disorder. In mouse, En2 exhibits dynamic spatiotemporal expression in embryonic mid-hindbrain regions where monoamine neurons emerge. Considering their importance in neuropsychiatric disorders, we characterized monoamine systems in relation to forebrain neurogenesis in En2-knockout (En2-KO) mice. Transmitter levels of serotonin, dopamine and norepinephrine (NE) were dysregulated from Postnatal day 7 (P7) to P21 in En2-KO, though NE exhibited the greatest abnormalities. While NE levels were reduced ∼35% in forebrain, they were increased 40 -: 75% in hindbrain and cerebellum, and these patterns paralleled changes in locus coeruleus (LC) fiber innervation, respectively. Although En2 promoter was active in Embryonic day 14.5 -: 15.5 LC neurons, expression diminished thereafter and gene deletion did not alter brainstem NE neuron numbers. Significantly, in parallel with reduced NE levels, En2-KO forebrain regions exhibited reduced growth, particularly hippocampus, where P21 dentate gyrus granule neurons were decreased 16%, suggesting abnormal neurogenesis. Indeed, hippocampal neurogenic regions showed increased cell death (+77%) and unexpectedly, increased proliferation. Excess proliferation was restricted to early Sox2/Tbr2 progenitors whereas increased apoptosis occurred in differentiating (Dcx) neuroblasts, accompanied by reduced newborn neuron survival. Abnormal neurogenesis may reflect NE deficits because intra-hippocampal injections of β-adrenergic agonists reversed cell death. These studies suggest that disruption of hindbrain patterning genes can alter monoamine system development and thereby produce forebrain defects that are relevant to human neurodevelopmental disorders.

PMID: 26220976 [PubMed - indexed for MEDLINE]

Plausible etiology of brain dysconnectivity in autism - Review and prospectus.

July 13, 2016 - 7:29am
Related Articles

Plausible etiology of brain dysconnectivity in autism - Review and prospectus.

Med Hypotheses. 2015 Oct;85(4):405-7

Authors: Steinman G

Abstract
This report summarizes recent findings related to the neuropathology of autism. Combining the relevant observations assessed here, a comprehensive, coherent hypothesis explaining the etiology of juvenile autism may be deduced. This proposed mechanism describes a process initiated by insulin-like growth factor deficiency, resulting in brain dysconnectivity as central to the behavioral manifestations of this disease.

PMID: 26141637 [PubMed - indexed for MEDLINE]

Pages