pubmed: autism and genetics

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[Diagnostics of the genetic causes of autism spectrum disorders - a clinical geneticist's view].

October 16, 2014 - 8:14am

[Diagnostics of the genetic causes of autism spectrum disorders - a clinical geneticist's view].

Psychiatr Pol. 2014 Jul-Aug;48(4):677-88

Authors: Szczaluba K

Abstract
Explanation of the genetic basis of autism spectrum disorders has, for many decades, been a part of interest of researchers and clinicians. In recent years, thanks to modern molecular and cytogenetic techniques, a significant progress has been achieved in the diagnosis of genetic causes of autism. This applies particularly, but not exclusively, to those cases of autism that are accompanied by other clinical signs (i. e. complex phenotypes). The important clinical markers belong to different categories, and include congenital defects/anomalies, dysmorphism and macro-/microcephaly, to name the few. Thus, the choice of the diagnostic strategy depends on the clinical and pedigree information and, under Polish circumstances, the availability of specific diagnostic techniques and the amount of reimbursement under the National Health Service. Overall, the identification of the genetic causes of autism spectrum disorders is possible in about 10-30% of patients. In this paper the practical aspects of the use of different diagnostic techniques are briefly described. Some clinical examples and current recommendations for the diagnosis of patients with autism spectrum disorders are also presented. The point of view of a specialist in clinical genetics, increasingly involved, as part of the multidisciplinary care team, in the diagnostics of an autistic child has been demonstrated.

PMID: 25314796 [PubMed - in process]

Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR.

October 15, 2014 - 7:30am

Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR.

Mol Psychiatry. 2014 Oct 14;

Authors: Oguro-Ando A, Rosensweig C, Herman E, Nishimura Y, Werling D, Bill BR, Berg JM, Gao F, Coppola G, Abrahams BS, Geschwind DH

Abstract
Rare maternally inherited duplications at 15q11-13 are observed in ~1% of individuals with an autism spectrum disorder (ASD), making it among the most common causes of ASD. 15q11-13 comprises a complex region, and as this copy number variation encompasses many genes, it is important to explore individual genotype-phenotype relationships. Cytoplasmic FMR1-interacting protein 1 (CYFIP1) is of particular interest because of its interaction with Fragile X mental retardation protein (FMRP), its upregulation in transformed lymphoblastoid cell lines from patients with duplications at 15q11-13 and ASD and the presence of smaller overlapping deletions of CYFIP1 in patients with schizophrenia and intellectual disability. Here, we confirm that CYFIP1 is upregulated in transformed lymphoblastoid cell lines and demonstrate its upregulation in the post-mortem brain from 15q11-13 duplication patients for the first time. To investigate how increased CYFIP1 dosage might predispose to neurodevelopmental disease, we studied the consequence of its overexpression in multiple systems. We show that overexpression of CYFIP1 results in morphological abnormalities including cellular hypertrophy in SY5Y cells and differentiated mouse neuronal progenitors. We validate these results in vivo by generating a BAC transgenic mouse, which overexpresses Cyfip1 under the endogenous promotor, observing an increase in the proportion of mature dendritic spines and dendritic spine density. Gene expression profiling on embryonic day 15 suggested the dysregulation of mammalian target of rapamycin (mTOR) signaling, which was confirmed at the protein level. Importantly, similar evidence of mTOR-related dysregulation was seen in brains from 15q11-13 duplication patients with ASD. Finally, treatment of differentiated mouse neuronal progenitors with an mTOR inhibitor (rapamycin) rescued the morphological abnormalities resulting from CYFIP1 overexpression. Together, these data show that CYFIP1 overexpression results in specific cellular phenotypes and implicate modulation by mTOR signaling, further emphasizing its role as a potential convergent pathway in some forms of ASD.Molecular Psychiatry advance online publication, 14 October 2014; doi:10.1038/mp.2014.124.

PMID: 25311365 [PubMed - as supplied by publisher]

Generation of Mice Lacking DUF1220 Protein Domains: Effects on Fecundity and Hyperactivity.

October 14, 2014 - 7:12am

Generation of Mice Lacking DUF1220 Protein Domains: Effects on Fecundity and Hyperactivity.

Mamm Genome. 2014 Oct 12;

Authors: Keeney JG, O'Bleness MS, Anderson N, Davis JM, Arevalo N, Busquet N, Chick W, Rozman J, Hölter SM, Garrett L, Horsch M, Beckers J, Wurst W, Klingenspor M, Restrepo D, German Mouse Clinic Consortium, Sikela JM, de Angelis MH

Abstract
Sequences encoding DUF1220 protein domains show the most extreme human lineage-specific copy number increase of any coding region in the genome and have been linked to human brain evolution. In addition, DUF1220 copy number (dosage) has been implicated in influencing brain size within the human species, both in normal populations and in individuals associated with brain size pathologies (1q21-associated microcephaly and macrocephaly). More recently, increasing dosage of a subtype of DUF1220 has been linked with increasing severity of the primary symptoms of autism. Despite these intriguing associations, a function for these domains has not been described. As a first step in addressing this question, we have developed the first transgenic model of DUF1220 function by removing the single DUF1220 domain (the ancestral form) encoded in the mouse genome. In a hypothesis generating exercise, these mice were evaluated by 197 different phenotype measurements. While resulting DUF1220-minus (KO) mice show no obvious anatomical peculiarities, they exhibit a significantly reduced fecundity (χ (2) = 19.1, df = 2, p = 7.0 × 10(-5)). Further extensive phenotypic analyses suggest hyperactivity (p < 0.05) of DUF1220 mice and changes in gene expression levels of brain associated with distinct neurological functions and disease. Other changes that met statistical significance include an increase in plasma glucose concentration (as measured by area under the curve, AUC 0-30 and AUC 30-120) in male mutants, fasting glucose levels, reduce sodium levels in male mutants, increased levels of the liver functional indicator ALAT/GPT in males, levels of alkaline phosphatase (also an indicator of liver function), mean R and SR amplitude by electrocardiography, elevated IgG3 levels, a reduced ratio of CD4:CD8 cells, and a reduced frequency of T cells; though it should be noted that many of these differences are quite small and require further examination. The linking of DUF1220 loss to a hyperactive phenotype is consistent with separate findings in which DUF1220 over expression results in a down-regulation of mitochondrial function, and potentially suggests a role in developmental metabolism. Finally, the substantially reduced fecundity we observe associated with KO mice argues that the ancestral DUF1220 domain provides an important biological functionthat is critical to survivability and reproductive success.

PMID: 25308000 [PubMed - as supplied by publisher]

Autism associated gene, engrailed2, and flanking gene levels are altered in post-mortem cerebellum.

October 14, 2014 - 7:12am
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Autism associated gene, engrailed2, and flanking gene levels are altered in post-mortem cerebellum.

PLoS One. 2014;9(2):e87208

Authors: Choi J, Ababon MR, Soliman M, Lin Y, Brzustowicz LM, Matteson PG, Millonig JH

Abstract
BACKGROUND: Previous genetic studies demonstrated association between the transcription factor engrailed2 (EN2) and Autism Spectrum Disorder (ASD). Subsequent molecular analysis determined that the EN2 ASD-associated haplotype (rs1861972-rs1861973 A-C) functions as a transcriptional activator to increase gene expression. EN2 is flanked by 5 genes, serotonin receptor5a (HTR5A), insulin induced gene1 (INSIG1), canopy1 homolog (CNPY1), RNA binding motif protein33 (RBM33), and sonic hedgehog (SHH). These flanking genes are co-expressed with EN2 during development and coordinate similar developmental processes. To investigate if mRNA levels for these genes are altered in individuals with autism, post-mortem analysis was performed.
METHODS: qRT-PCR quantified mRNA levels for EN2 and the 5 flanking genes in 78 post-mortem cerebellar samples. mRNA levels were correlated with both affection status and rs1861972-rs1861973 genotype. Molecular analysis investigated whether EN2 regulates flanking gene expression.
RESULTS: EN2 levels are increased in affected A-C/G-T individuals (p = .0077). Affected individuals also display a significant increase in SHH and a decrease in INSIG1 levels. Rs1861972-rs1861973 genotype is correlated with significant increases for SHH (A-C/G-T) and CNPY1 (G-T/G-T) levels. Human cell line over-expression and knock-down as well as mouse knock-out analysis are consistent with EN2 and SHH being co-regulated, which provides a possible mechanism for increased SHH post-mortem levels.
CONCLUSIONS: EN2 levels are increased in affected individuals with an A-C/G-T genotype, supporting EN2 as an ASD susceptibility gene. SHH, CNPY1, and INSIG1 levels are also significantly altered depending upon affection status or rs1861972-rs1861973 genotype. Increased EN2 levels likely contribute to elevated SHH expression observed in the post-mortem samples.

PMID: 24520327 [PubMed - indexed for MEDLINE]

Increased placental trophoblast inclusions in placenta accreta.

October 13, 2014 - 6:36am

Increased placental trophoblast inclusions in placenta accreta.

Placenta. 2014 Oct 2;

Authors: Adler E, Madankumar R, Rosner M, Reznik SE

Abstract
INTRODUCTION: Trophoblast inclusions (TIs) are often found in placentas of genetically abnormal gestations. Although best documented in placentas from molar pregnancies and chromosomal aneuploidy, TIs are also associated with more subtle genetic abnormalities, and possibly autism. Less than 3% of non-aneuploid, non-accreta placentas have TIs. We hypothesize that placental genetics may play a role in the development of placenta accreta and aim to study TIs as a potential surrogate indicator of abnormal placental genetics.
METHODS: Forty cases of placenta accreta in the third trimester were identified in a search of the medical records at one institution. Forty two third trimester control placentas were identified by a review of consecutively received single gestation placentas with no known genetic abnormalities and no diagnosis of placenta accreta.
RESULTS: Forty percent of cases with placenta accreta demonstrated TIs compared to 2.4% of controls. More invasive placenta accretas (increta and percreta) were more likely to demonstrate TIs than accreta (47% versus 20%). Prior cesarean delivery was more likely in accreta patients than controls (67% versus 9.5%).
DISCUSSION: Placenta accreta is thought to be the result of damage to the endometrium predisposing to abnormal decidualization and invasive trophoblast growth into the myometrium. However, the etiology of accreta is incompletely understood with accreta frequently occurring in women without predisposing factors and failing to occur in predisposed patients.
CONCLUSION: This study has shown that TIs are present at increased rates in cases of PA. Further studies are needed to discern what underlying pathogenic mechanisms are in common between abnormal placentation and the formation of TIs.

PMID: 25305693 [PubMed - as supplied by publisher]

Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis.

October 12, 2014 - 6:15am

Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis.

Hum Mol Genet. 2014 Oct 9;

Authors: Ramos-Brossier M, Montani C, Lebrun N, Gritti L, Martin C, Seminatore-Nole C, Toussaint A, Moreno S, Poirier K, Dorseuil O, Chelly J, Hackett A, Gecz J, Bieth E, Faudet A, Heron D, Kooy RF, Loeys B, Humeau Y, Sala C, Billuart P

Abstract
Mutations in interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene have been associated with non-syndromic intellectual disability and autism spectrum disorder. This protein interacts with synaptic partners like PSD-95 and PTPδ, regulating the formation and function of excitatory synapses. The aim of this work is to characterize the synaptic consequences of three IL1RAPL1 mutations, two novel causing the deletion of exon 6 (Δex6) and one point mutation (C31R), identified in patients with intellectual disability. Using immunofluorescence and electrophysiological recordings we examined the effects of IL1RAPL1 mutants over-expression on synapse formation and function in cultured rodent hippocampal neurons. Δex6 but not C31R mutation leads to IL1RAPL1 protein instability and mislocalization within dendrites. Analysis of different markers of excitatory synapses and sEPSC recording revealed that both mutants fail to induce pre- and post-synaptic differentiation, contrary to WT IL1RAPL1 protein. Cell aggregation and immunoprecipitation assays in HEK293 cells showed a reduction of the interaction between IL1RAPL1 mutants and PTPδ that could explain the observed synaptogenic defect in neurons. However, these mutants do not affect all cellular signaling since their over-expression still activates JNK pathway. We conclude that both mutations described in this study lead to a partial loss of function of the IL1RAPL1 protein through different mechanisms. Our work highlights the important function of the trans-synaptic PTPδ/ IL1RAPL1 interaction in synaptogenesis and as such, in intellectual disability in the patients.

PMID: 25305082 [PubMed - as supplied by publisher]

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

October 12, 2014 - 6:15am

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

Psychiatr Genet. 2014 Oct 10;

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 - as supplied by publisher]

A direct molecular link between the autism candidate gene RORa and the schizophrenia candidate MIR137.

October 11, 2014 - 8:57am
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A direct molecular link between the autism candidate gene RORa and the schizophrenia candidate MIR137.

Sci Rep. 2014;4:3994

Authors: Devanna P, Vernes SC

Abstract
Retinoic acid-related orphan receptor alpha gene (RORa) and the microRNA MIR137 have both recently been identified as novel candidate genes for neuropsychiatric disorders. RORa encodes a ligand-dependent orphan nuclear receptor that acts as a transcriptional regulator and miR-137 is a brain enriched small non-coding RNA that interacts with gene transcripts to control protein levels. Given the mounting evidence for RORa in autism spectrum disorders (ASD) and MIR137 in schizophrenia and ASD, we investigated if there was a functional biological relationship between these two genes. Herein, we demonstrate that miR-137 targets the 3'UTR of RORa in a site specific manner. We also provide further support for MIR137 as an autism candidate by showing that a large number of previously implicated autism genes are also putatively targeted by miR-137. This work supports the role of MIR137 as an ASD candidate and demonstrates a direct biological link between these previously unrelated autism candidate genes.

PMID: 24500708 [PubMed - indexed for MEDLINE]

Association of the FGA and SLC6A4 genes with autistic spectrum disorder in a Korean population.

October 11, 2014 - 8:57am
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Association of the FGA and SLC6A4 genes with autistic spectrum disorder in a Korean population.

Neuropsychobiology. 2013;68(4):212-20

Authors: Ro M, Won S, Kang H, Kim SY, Lee SK, Nam M, Bang HJ, Yang JW, Choi KS, Kim SK, Chung JH, Kwack K

Abstract
BACKGROUND: Autism spectrum disorder (ASD) is a neurobiological disorder characterized by distinctive impairments in cognitive function, language, and behavior. Linkage and population studies suggest a genetic association between solute carrier family 6 member 4 (SLC6A4) variants and ASD.
METHOD: Logistic regression was used to identify associations between single-nucleotide polymorphisms (SNPs) and ASD with 3 alternative models (additive, dominant, and recessive). Linear regression analysis was performed to determine the influence of SNPs on Childhood Autism Rating Scale (CARS) scores as a quantitative phenotype.
RESULTS: In the present study, we examined the associations of SNPs in the SLC6A4 gene and the fibrinogen alpha chain (FGA) gene. Logistic regression analysis showed a significant association between the risk of ASD and rs2070025 and rs2070011 in the FGA gene. The gene-gene interaction between SLC6A4 and FGA was not significantly associated with ASD susceptibility. However, polymorphisms in both SLC6A4 and the FGA gene significantly affected the symptoms of ASD.
CONCLUSION: Our findings indicate that FGA and SLC6A4 gene interactions may contribute to the phenotypes of ASD rather than the incidence of ASD.

PMID: 24192574 [PubMed - indexed for MEDLINE]

Acetylcholine elevation relieves cognitive rigidity and social deficiency in a mouse model of autism.

October 11, 2014 - 8:57am
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Acetylcholine elevation relieves cognitive rigidity and social deficiency in a mouse model of autism.

Neuropsychopharmacology. 2014 Mar;39(4):831-40

Authors: Karvat G, Kimchi T

Abstract
Autism spectrum disorders (ASD) are defined by behavioral deficits in social interaction and communication, repetitive stereotyped behaviors, and restricted interests/cognitive rigidity. Recent studies in humans and animal-models suggest that dysfunction of the cholinergic system may underlie autism-related behavioral symptoms. Here we tested the hypothesis that augmentation of acetylcholine (ACh) in the synaptic cleft by inhibiting acetylcholinesterase may ameliorate autistic phenotypes. We first administered the acetylcholinesterase inhibitor (AChEI) Donepezil systemically by intraperitoneal (i.p.) injections. Second, the drug was injected directly into the rodent homolog of the caudate nucleus, the dorsomedial striatum (DMS), of the inbred mouse strain BTBR T+tf/J (BTBR), a commonly-used model presenting all core autism-related phenotypes and expressing low brain ACh levels. We found that i.p. injection of AChEI to BTBR mice significantly relieved autism-relevant phenotypes, including decreasing cognitive rigidity, improving social preference, and enhancing social interaction, in a dose-dependent manner. Microinjection of the drug directly into the DMS, but not into the ventromedial striatum, led to significant amelioration of the cognitive-rigidity and social-deficiency phenotypes. Taken together, these findings provide evidence of the key role of the cholinergic system and the DMS in the etiology of ASD, and suggest that elevated cognitive flexibility may result in enhanced social attention. The potential therapeutic effect of AChEIs in ASD patients is discussed.

PMID: 24096295 [PubMed - indexed for MEDLINE]

CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors.

October 9, 2014 - 7:53am

CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors.

Proc Natl Acad Sci U S A. 2014 Oct 7;

Authors: Sugathan A, Biagioli M, Golzio C, Erdin S, Blumenthal I, Manavalan P, Ragavendran A, Brand H, Lucente D, Miles J, Sheridan SD, Stortchevoi A, Kellis M, Haggarty SJ, Katsanis N, Gusella JF, Talkowski ME

Abstract
Truncating mutations of chromodomain helicase DNA-binding protein 8 (CHD8), and of many other genes with diverse functions, are strong-effect risk factors for autism spectrum disorder (ASD), suggesting multiple mechanisms of pathogenesis. We explored the transcriptional networks that CHD8 regulates in neural progenitor cells (NPCs) by reducing its expression and then integrating transcriptome sequencing (RNA sequencing) with genome-wide CHD8 binding (ChIP sequencing). Suppressing CHD8 to levels comparable with the loss of a single allele caused altered expression of 1,756 genes, 64.9% of which were up-regulated. CHD8 showed widespread binding to chromatin, with 7,324 replicated sites that marked 5,658 genes. Integration of these data suggests that a limited array of direct regulatory effects of CHD8 produced a much larger network of secondary expression changes. Genes indirectly down-regulated (i.e., without CHD8-binding sites) reflect pathways involved in brain development, including synapse formation, neuron differentiation, cell adhesion, and axon guidance, whereas CHD8-bound genes are strongly associated with chromatin modification and transcriptional regulation. Genes associated with ASD were strongly enriched among indirectly down-regulated loci (P < 10(-8)) and CHD8-bound genes (P = 0.0043), which align with previously identified coexpression modules during fetal development. We also find an intriguing enrichment of cancer-related gene sets among CHD8-bound genes (P < 10(-10)). In vivo suppression of chd8 in zebrafish produced macrocephaly comparable to that of humans with inactivating mutations. These data indicate that heterozygous disruption of CHD8 precipitates a network of gene-expression changes involved in neurodevelopmental pathways in which many ASD-associated genes may converge on shared mechanisms of pathogenesis.

PMID: 25294932 [PubMed - as supplied by publisher]

Childhood acne in a boy with XYY syndrome.

October 9, 2014 - 7:53am
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Childhood acne in a boy with XYY syndrome.

BMJ Case Rep. 2014;2014

Authors: Kasparis C, Loffeld A

Abstract
A 3-year-old boy was referred to the dermatology department with a 12-month history of facial erythema associated with a papular-pustular facial eruption consistent with childhood acne. He had been diagnosed with XYY syndrome identified during genetic analysis for cardiac anomalies at birth. XYY syndrome is an aneuploidy of the sex chromosomes which affects 1 in 1000 male births. It is often asymptomatic and identified incidentally following genetic analysis for other conditions. The syndrome can be associated with an increased risk of learning difficulties and delayed language skills. Early diagnosis could alert physicians to the possibility of subtle developmental and learning abnormalities and result in prompt management. Our case highlights the fact that the presence of childhood acne could aid in the early detection of XYY syndrome.

PMID: 24395875 [PubMed - indexed for MEDLINE]

Elevated 5-hydroxymethylcytosine in the Engrailed-2 (EN-2) promoter is associated with increased gene expression and decreased MeCP2 binding in autism cerebellum.

October 8, 2014 - 7:42am

Elevated 5-hydroxymethylcytosine in the Engrailed-2 (EN-2) promoter is associated with increased gene expression and decreased MeCP2 binding in autism cerebellum.

Transl Psychiatry. 2014;4:e460

Authors: James SJ, Shpyleva S, Melnyk S, Pavliv O, Pogribny IP

Abstract
Epigenetic mechanisms regulate programmed gene expression during prenatal neurogenesis and serve as a mediator between genetics and environment in postnatal life. The recent discovery of 5-hydroxymethylcytosine (5-hmC), with highest concentration in the brain, has added a new dimension to epigenetic regulation of neurogenesis and the development of complex behavior disorders. Here, we take a candidate gene approach to define the role 5-hmC in Engrailed-2 (EN-2) gene expression in the autism cerebellum. The EN-2 homeobox transcription factor, previously implicated in autism, is essential for normal cerebellar patterning and development. We previously reported EN-2 overexpression associated with promoter DNA hypermethylation in the autism cerebellum but because traditional DNA methylation methodology cannot distinguish 5-methylcytosine (5-mC) from 5-hmC, we now extend our investigation by quantifying global and gene-specific 5-mC and 5-hmC. Globally, 5-hmC was significantly increased in the autism cerebellum and accompanied by increases in the expression of de novo methyltransferases DNMT3A and DNMT3B, ten-eleven translocase genes TET1 and TET3, and in 8-oxo-deoxyguanosine (8-oxo-dG) content, a marker of oxidative DNA damage. Within the EN-2 promoter, there was a significant positive correlation between 5-hmC content and EN-2 gene expression. Based on reports of reduced MeCP2 affinity for 5-hmC, MeCP2 binding studies in the EN-2 promoter revealed a significant decrease in repressive MeCP2 binding that may contribute to the aberrant overexpression of EN-2. Because normal cerebellar development depends on perinatal EN-2 downregulation, the sustained postnatal overexpression suggests that a critical window of cerebellar development may have been missed in some individuals with autism with downstream developmental consequences. Epigenetic regulation of the programmed on-off switches in gene expression that occur at birth and during early brain development warrants further investigation.

PMID: 25290267 [PubMed - as supplied by publisher]

Autism spectrum disorder severity reflects the average contribution of de novo and familial influences.

October 8, 2014 - 7:42am

Autism spectrum disorder severity reflects the average contribution of de novo and familial influences.

Proc Natl Acad Sci U S A. 2014 Oct 6;

Authors: Robinson EB, Samocha KE, Kosmicki JA, McGrath L, Neale BM, Perlis RH, Daly MJ

Abstract
Autism spectrum disorders (ASDs) are a highly heterogeneous group of conditions-phenotypically and genetically-although the link between phenotypic variation and differences in genetic architecture is unclear. This study aimed to determine whether differences in cognitive impairment and symptom severity reflect variation in the degree to which ASD cases reflect de novo or familial influences. Using data from more than 2,000 simplex cases of ASD, we examined the relationship between intelligence quotient (IQ), behavior and language assessments, and rate of de novo loss of function (LOF) mutations and family history of broadly defined psychiatric disease (depressive disorders, bipolar disorder, and schizophrenia; history of psychiatric hospitalization). Proband IQ was negatively associated with de novo LOF rate (P = 0.03) and positively associated with family history of psychiatric disease (P = 0.003). Female cases had a higher frequency of sporadic genetic events across the severity distribution (P = 0.01). High rates of LOF mutation and low frequencies of family history of psychiatric illness were seen in individuals who were unable to complete a traditional IQ test, a group with the greatest degree of language and behavioral impairment. These analyses provide strong evidence that familial risk for neuropsychiatric disease becomes more relevant to ASD etiology as cases become higher functioning. The findings of this study reinforce that there are many routes to the diagnostic category of autism and could lead to genetic studies with more specific insights into individual cases.

PMID: 25288738 [PubMed - as supplied by publisher]

DUF1220 copy number is linearly associated with increased cognitive function as measured by total IQ and mathematical aptitude scores.

October 8, 2014 - 7:42am

DUF1220 copy number is linearly associated with increased cognitive function as measured by total IQ and mathematical aptitude scores.

Hum Genet. 2014 Oct 7;

Authors: Davis JM, Searles VB, Anderson N, Keeney J, Raznahan A, Horwood LJ, Fergusson DM, Kennedy MA, Giedd J, Sikela JM

Abstract
DUF1220 protein domains exhibit the greatest human lineage-specific copy number expansion of any protein-coding sequence in the genome, and variation in DUF1220 copy number has been linked to both brain size in humans and brain evolution among primates. Given these findings, we examined associations between DUF1220 subtypes CON1 and CON2 and cognitive aptitude. We identified a linear association between CON2 copy number and cognitive function in two independent populations of European descent. In North American males, an increase in CON2 copy number corresponded with an increase in WISC IQ (R (2) = 0.13, p = 0.02), which may be driven by males aged 6-11 (R (2) = 0.42, p = 0.003). We utilized ddPCR in a subset as a confirmatory measurement. This group had 26-33 copies of CON2 with a mean of 29, and each copy increase of CON2 was associated with a 3.3-point increase in WISC IQ (R (2) = 0.22, p = 0.045). In individuals from New Zealand, an increase in CON2 copy number was associated with an increase in math aptitude ability (R (2) = 0.10 p = 0.018). These were not confounded by brain size. To our knowledge, this is the first study to report a replicated association between copy number of a gene coding sequence and cognitive aptitude. Remarkably, dosage variations involving DUF1220 sequences have now been linked to human brain expansion, autism severity and cognitive aptitude, suggesting that such processes may be genetically and mechanistically inter-related. The findings presented here warrant expanded investigations in larger, well-characterized cohorts.

PMID: 25287832 [PubMed - as supplied by publisher]

Fragile X Syndrome: A Review of Associated Medical Problems.

October 8, 2014 - 7:42am

Fragile X Syndrome: A Review of Associated Medical Problems.

Pediatrics. 2014 Oct 6;

Authors: Kidd SA, Lachiewicz A, Barbouth D, Blitz RK, Delahunty C, McBrien D, Visootsak J, Berry-Kravis E

Abstract
Fragile X syndrome (FXS) is the most common known genetic cause of inherited intellectual disability and the most common known single-gene cause of autism spectrum disorder. It has been reported that a spectrum of medical problems are commonly experienced by people with FXS, such as otitis media, seizures, and gastrointestinal problems. Previous studies examining the prevalence of medical problems related to FXS have been challenging to interpret because of their marked differences in population, setting, and sampling. Through this comprehensive review, we update the literature by reviewing studies that have reported on prominent medical problems associated with FXS. We then compare prevalence results from those studies with results from a large cross-sectional database consisting of data collected by fragile X clinics that specialize in the care of children with FXS and are part of the Fragile X Clinical and Research Consortium. It is vital for pediatricians and other clinicians to be familiar with the medical problems related to FXS so that affected patients may receive proper diagnosis and treatment; improved care may lead to better quality of life for these patients and their families.

PMID: 25287458 [PubMed - as supplied by publisher]

An unusual clinical severity of 16p11.2 deletion syndrome caused by unmasked recessive mutation of CLN3.

October 8, 2014 - 7:42am
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An unusual clinical severity of 16p11.2 deletion syndrome caused by unmasked recessive mutation of CLN3.

Eur J Hum Genet. 2014 Mar;22(3):369-73

Authors: Pebrel-Richard C, Debost-Legrand A, Eymard-Pierre E, Greze V, Kemeny S, Gay-Bellile M, Gouas L, Tchirkov A, Vago P, Goumy C, Francannet C

Abstract
With the introduction of array comparative genomic hybridization (aCGH) techniques in the diagnostic setting of patients with developmental delay and congenital malformations, many new microdeletion syndromes have been recognized. One of these recently recognized microdeletion syndromes is the 16p11.2 deletion syndrome, associated with variable clinical outcomes including developmental delay, autism spectrum disorder, epilepsy, and obesity, but also apparently normal phenotype. We report on a 16-year-old patient with developmental delay, exhibiting retinis pigmentosa with progressive visual failure from the age of 9 years, ataxia, and peripheral neuropathy. Chromosomal microarray analysis identified a 1.7-Mb 16p11.2 deletion encompassing the 593-kb common deletion (∼29.5 to ∼30.1 Mb; Hg18) and the 220-kb distal deletion (∼28.74 to ∼28.95 Mb; Hg18) that partially included the CLN3 gene. As the patient's clinical findings were different from usual 16p11.2 microdeletion phenotypes and showed some features reminiscent of juvenile neuronal ceroid-lipofuscinosis (JNCL, Batten disease, OMIM 204200), we suspected and confirmed a mutation of the remaining CLN3 allele. This case further illustrates that unmasking of hemizygous recessive mutations by chromosomal deletion represents one explanation for the phenotypic variability observed in chromosomal deletion disorders.

PMID: 23860047 [PubMed - indexed for MEDLINE]

Prostaglandin E2 alters Wnt-dependent migration and proliferation in neuroectodermal stem cells: implications for autism spectrum disorders.

October 7, 2014 - 7:21am
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Prostaglandin E2 alters Wnt-dependent migration and proliferation in neuroectodermal stem cells: implications for autism spectrum disorders.

Cell Commun Signal. 2014;12:19

Authors: Wong CT, Ahmad E, Li H, Crawford DA

Abstract
Prostaglandin E2 (PGE2) is a natural lipid-derived molecule that is involved in important physiological functions. Abnormal PGE2 signalling has been associated with pathologies of the nervous system. Previous studies provide evidence for the interaction of PGE2 and canonical Wnt signalling pathways in non-neuronal cells. Since the Wnt pathway is crucial in the development and organization of the brain, the main goal of this study is to determine whether collaboration between these pathways exists in neuronal cell types. We report that PGE2 interacts with canonical Wnt signalling through PKA and PI-3K in neuroectodermal (NE-4C) stem cells. We used time-lapse microscopy to determine that PGE2 increases the final distance from origin, path length travelled, and the average speed of migration in Wnt-activated cells. Furthermore, PGE2 alters distinct cellular phenotypes that are characteristic of Wnt-induced NE-4C cells, which corresponds to the modified splitting behaviour of the cells. We also found that in Wnt-induced cells the level of β-catenin protein was increased and the expression levels of Wnt-target genes (Ctnnb1, Ptgs2, Ccnd1, Mmp9) was significantly upregulated in response to PGE2 treatment. This confirms that PGE2 activated the canonical Wnt signalling pathway. Furthermore, the upregulated genes have been previously associated with ASD. Our findings show, for the first time, evidence for cross-talk between PGE2 and Wnt signalling in neuronal cells, where PKA and PI-3K might act as mediators between the two pathways. Given the importance of PGE2 and Wnt signalling in prenatal development of the nervous system, our study provides insight into how interaction between these two pathways may influence neurodevelopment.

PMID: 24656144 [PubMed - indexed for MEDLINE]

Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism.

October 7, 2014 - 7:21am
Related Articles

Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism.

FASEB J. 2014 Jun;28(6):2398-413

Authors: Patrick RP, Ames BN

Abstract
Serotonin and vitamin D have been proposed to play a role in autism; however, no causal mechanism has been established. Here, we present evidence that vitamin D hormone (calcitriol) activates the transcription of the serotonin-synthesizing gene tryptophan hydroxylase 2 (TPH2) in the brain at a vitamin D response element (VDRE) and represses the transcription of TPH1 in tissues outside the blood-brain barrier at a distinct VDRE. The proposed mechanism explains 4 major characteristics associated with autism: the low concentrations of serotonin in the brain and its elevated concentrations in tissues outside the blood-brain barrier; the low concentrations of the vitamin D hormone precursor 25-hydroxyvitamin D [25(OH)D3]; the high male prevalence of autism; and the presence of maternal antibodies against fetal brain tissue. Two peptide hormones, oxytocin and vasopressin, are also associated with autism and genes encoding the oxytocin-neurophysin I preproprotein, the oxytocin receptor, and the arginine vasopressin receptor contain VDREs for activation. Supplementation with vitamin D and tryptophan is a practical and affordable solution to help prevent autism and possibly ameliorate some symptoms of the disorder.

PMID: 24558199 [PubMed - indexed for MEDLINE]

The neurobiology of autism spectrum disorders.

October 7, 2014 - 7:21am
Related Articles

The neurobiology of autism spectrum disorders.

Eur Psychiatry. 2014 Jan;29(1):11-9

Authors: Parellada M, Penzol MJ, Pina L, Moreno C, González-Vioque E, Zalsman G, Arango C

Abstract
Data is progressively and robustly accumulating regarding the biological basis of autism. Autism spectrum disorders (ASD) are currently considered a group of neurodevelopmental disorders with onset very early in life and a complex, heterogeneous, multifactorial aetiology. A comprehensive search of the last five years of the Medline database was conducted in order to summarize recent evidence on the neurobiological bases of autism. The main findings on genetic influence, neuropathology, neurostructure and brain networks are summarized. In addition, findings from peripheral samples of subjects with autism and animal models, which show immune, oxidative, mitochondrial dysregulations, are reported. Then, other biomarkers from very different systems associated with autism are reported. Finally, an attempt is made to try and integrate the available evidence, which points to a oligogenetic, multifactorial aetiology that converges in an aberrant micro-organization of the cortex, with abnormal functioning of the synapses and abnormalities in very general physiological pathways (such as inflammatory, immune and redox systems).

PMID: 24275633 [PubMed - indexed for MEDLINE]

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