Neurite outgrowth mediated by the heat shock protein Hsp90α: a novel target for the antipsychotic drug aripiprazole.

Transl Psychiatry. 2012;2:e170

Authors: Ishima T, Iyo M, Hashimoto K

Abstract
Aripiprazole is an atypical antipsychotic drug approved for the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, major depressive disorder and autism. The drug shows partial agonistic activity at dopamine D(2) receptors and 5-hydroxytryptamine (5-HT) 5-HT(1A) receptors, and antagonistic activity at 5-HT(2A) receptors. However, the precise mechanistic pathways remain unclear. In this study, we examined the effects of aripiprazole on neurite outgrowth. Aripiprazole significantly potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells, in a concentration-dependent manner. The 5-HT(1A) receptor antagonist WAY-100635, but not the dopamine D(2) receptor antagonist sulpiride, blocked the effects of aripiprazole, although, only partially. Specific inhibitors of inositol 1,4,5-triphosphate (IP(3)) receptors and BAPTA-AM, a chelator of intracellular Ca(2+), blocked the effects of aripiprazole. Moreover, specific inhibitors of several common signaling pathways phospholipase C-γ (PLC-γ), phosphatidylinositol-3 kinase (PI3K), mammalian target of rapamycin, p38 MAPK, c-Jun N-terminal kinase, Akt, Ras, Raf, ERK, MAPK) also blocked the effects of aripiprazole. Using proteomic analysis, we found that aripiprazole significantly increased levels of the heat shock protein Hsp90α in cultured cells. The effects of aripiprazole on NGF-induced neurite outgrowth were significantly attenuated by treatment with Hsp90α RNA interference, but not by the negative control of Hsp90α. These findings suggest that both 5-HT(1A) receptor activation and Ca(2+) signaling via IP(3) receptors, as well as their downstream cellular signaling pathways play a role in the promotion of aripiprazole-induced neurite outgrowth. Furthermore, aripiprazole-induced increases in Hsp90α protein expression may form part of the therapeutic mechanism for this drug.

PMID: 23047241 [PubMed - indexed for MEDLINE]

Npas4: a neuronal transcription factor with a key role in social and cognitive functions relevant to developmental disorders.

PLoS One. 2012;7(9):e46604

Authors: Coutellier L, Beraki S, Ardestani PM, Saw NL, Shamloo M

Abstract
Npas4 is a transcription factor, which is highly expressed in the brain and regulates the formation and maintenance of inhibitory synapses in response to excitatory synaptic activity. A deregulation of the inhibitory-excitatory balance has been associated with a variety of human developmental disorders such as schizophrenia and autism. However, not much is known about the role played by inhibitory synapses and inhibitory pathways in the development of nervous system disorders. We hypothesized that alterations in the inhibitory pathways induced by the absence of Npas4 play a major role in the expression of the symptoms observed in psychiatric disorders. To test this hypothesis we tested mice lacking the transcription factor (Npas4 knock-out mice (Npas4-KO)) in a battery of behavioral assays focusing on general activity, social behaviors, and cognitive functions. Npas4-KO mice are hyperactive in a novel environment, spend less time exploring an unfamiliar ovariectomized female, spend more time avoiding an unfamiliar male during a first encounter, show higher social dominance than their WT littermates, and display pre-pulse inhibition, working memory, long-term memory, and cognitive flexibility deficits. These behavioral deficits may replicate schizophrenia-related symptomatology such as social anxiety, hyperactivity, and cognitive and sensorimotor gating deficits. Immunohistochemistry analyses revealed that Npas4 expression is induced in the hippocampus after a social encounter and that Npas4 regulates the expression of c-Fos in the CA1 and CA3 regions of the hippocampus after a cognitive task. Our results suggest that Npas4 may play a major role in the regulation of cognitive and social functions in the brain with possible implications for developmental disorders such as schizophrenia and autism.

PMID: 23029555 [PubMed - indexed for MEDLINE]

Interstitial deletion of 11q-implicating the KIRREL3 gene in the neurocognitive delay associated with Jacobsen syndrome.

Am J Med Genet A. 2012 Oct;158A(10):2551-6

Authors: Guerin A, Stavropoulos DJ, Diab Y, Chénier S, Christensen H, Kahr WH, Babul-Hirji R, Chitayat D

Abstract
Jacobsen syndrome (JS) is a rare contiguous gene disorder characterized by a deletion within the distal part of the long arm of chromosome 11 ranging in size from 7 to 20 Mb. The clinical findings include characteristic dysmorphic features, growth and psychomotor delays and developmental anomalies involving the brain, eyes, heart, kidneys, immune, hematologic, endocrine, and gastrointestinal systems. The majority of cases are due to a terminal deletion of 11q; however interstitial deletions have also been reported. We report on a child with clinical manifestations consistent with JS who had a 2.899 Mb interstitial deletion at 11q24.2-q24.3 which is the smallest interstitial deletion reported so far to our knowledge. This deletion includes the KIRREL3 gene, and given our patient's history of neurocognitive delay and autism spectrum disorder, it raises the possibility that this gene is a candidate for the social and expressive language delay observed in our patient.

PMID: 22965935 [PubMed - indexed for MEDLINE]

Duplication of OCRL and adjacent genes associated with autism but not Lowe syndrome.

Am J Med Genet A. 2012 Oct;158A(10):2602-5

Authors: Schroer RJ, Beaudet AL, Shinawi M, Sahoo T, Patel A, Sun Q, Skinner C, Stevenson RE

Abstract
Disturbances in the form of microduplications and microdeletions have been found throughout the genome and have been associated with autism, intellectual disability, and recognizable malformation syndromes. In our study of 187 probands with autism, we have identified a duplication in Xq25 including full gene duplication of OCRL and six flanking genes. Activity of the enzyme gene product in fibroblasts was elevated to over twice the level in control fibroblasts. The boy had no somatic or neurological findings reminiscent of Lowe syndrome.

PMID: 22965764 [PubMed - indexed for MEDLINE]

Allele-biased expression in differentiating human neurons: implications for neuropsychiatric disorders.

PLoS One. 2012;7(8):e44017

Authors: Lin M, Hrabovsky A, Pedrosa E, Wang T, Zheng D, Lachman HM

Abstract
Stochastic processes and imprinting, along with genetic factors, lead to monoallelic or allele-biased gene expression. Stochastic monoallelic expression fine-tunes information processing in immune cells and the olfactory system, and imprinting plays an important role in development. Recent studies suggest that both stochastic events and imprinting may be more widespread than previously considered. We are interested in allele-biased gene expression occurring in the brain because parent-of-origin effects suggestive of imprinting appear to play a role in the transmission of schizophrenia (SZ) and autism spectrum disorders (ASD) in some families. In addition, allele-biased expression could help explain monozygotic (MZ) twin discordance and reduced penetrance. The ability to study allele-biased expression in human neurons has been transformed with the advent of induced pluripotent stem cell (iPSC) technology and next generation sequencing. Using transcriptome sequencing (RNA-Seq) we identified 801 genes in differentiating neurons that were expressed in an allele-biased manner. These included a number of putative SZ and ASD candidates, such as A2BP1 (RBFOX1), ERBB4, NLGN4X, NRG1, NRG3, NRXN1, and NLGN1. Overall, there was a modest enrichment for SZ and ASD candidate genes among those that showed evidence for allele-biased expression (chi-square, p = 0.02). In addition to helping explain MZ twin discordance and reduced penetrance, the capacity to group many candidate genes affecting a variety of molecular and cellular pathways under a common regulatory process - allele-biased expression - could have therapeutic implications.

PMID: 22952857 [PubMed - indexed for MEDLINE]

De novo interstitial duplication of 15q11.2-q13.1 with complex maternal uniparental trisomy for the 15q11-q13 region in a patient with Prader-Willi syndrome.

Am J Med Genet A. 2012 Oct;158A(10):2557-63

Authors: Burrage LC, Person RE, Flores A, Villanos MT, Bi W, Wiszniewska J, Bacino CA

Abstract
Prader-Willi syndrome is caused by the lack of paternal contribution for the imprinted 15q11-q13 region that originates through a number of mechanisms such as paternal deletion of 15q11-q13, maternal uniparental disomy, or by an imprinting defect due to epimutations in the paternal imprinting center. In the present report, we describe a female patient with complex maternal uniparental trisomy for the 15q11-q13 Prader-Willi syndrome critical region due to a de novo interstitial duplication of 15q11-q13 region that is present in one of the maternal homologs. As a result, the patient has three maternally derived copies of the Prader-Willi syndrome critical region and absence of paternal 15 contribution and thus, presents with a Prader-Willi syndrome phenotype with risk for developing additional phenotypes (e.g., autism and psychiatric phenotypes) characteristic of maternally derived duplications of this region. We suggest that this is a rather unique mechanism leading to Prader-Willi syndrome that has not been previously reported.

PMID: 22903639 [PubMed - indexed for MEDLINE]

Bipolar affective disorder and early dementia onset in a male patient with SHANK3 deletion.

Eur J Med Genet. 2012 Nov;55(11):625-9

Authors: Vucurovic K, Landais E, Delahaigue C, Eutrope J, Schneider A, Leroy C, Kabbaj H, Motte J, Gaillard D, Rolland AC, Doco-Fenzy M

Abstract
The SHANK3 protein is a scaffold protein known to stabilize metabotropic glutamate receptor mGluR5 in the post-synaptic membrane of neurons. It is associated with genetic vulnerability in autism and schizophrenia. Here we report the case of an 18 year-old male patient who displayed psychiatric features of bipolar affective disorder associated with early setting of dementia. This mental status is related to sporadic occurrence of SHANK3 gene complex multiple deletions. A low beta amyloid protein rate (479 mg/L) found in cerebrospinal fluid suggests a possible link between SHANK3 deletion syndrome-associated regression and dementia of Alzheimers's type. In addition, we propose an overview of the phenotype related to SHANK3 deletion.

PMID: 22922660 [PubMed - indexed for MEDLINE]

The Disruption of Celf6, a Gene Identified by Translational Profiling of Serotonergic Neurons, Results in Autism-Related Behaviors.

J Neurosci. 2013 Feb 13;33(7):2732-2753

Authors: Dougherty JD, Maloney SE, Wozniak DF, Rieger MA, Sonnenblick L, Coppola G, Mahieu NG, Zhang J, Cai J, Patti GJ, Abrahams BS, Geschwind DH, Heintz N

Abstract
The immense molecular diversity of neurons challenges our ability to understand the genetic and cellular etiology of neuropsychiatric disorders. Leveraging knowledge from neurobiology may help parse the genetic complexity: identifying genes important for a circuit that mediates a particular symptom of a disease may help identify polymorphisms that contribute to risk for the disease as a whole. The serotonergic system has long been suspected in disorders that have symptoms of repetitive behaviors and resistance to change, including autism. We generated a bacTRAP mouse line to permit translational profiling of serotonergic neurons. From this, we identified several thousand serotonergic-cell expressed transcripts, of which 174 were highly enriched, including all known markers of these cells. Analysis of common variants near the corresponding genes in the AGRE collection implicated the RNA binding protein CELF6 in autism risk. Screening for rare variants in CELF6 identified an inherited premature stop codon in one of the probands. Subsequent disruption of Celf6 in mice resulted in animals exhibiting resistance to change and decreased ultrasonic vocalization as well as abnormal levels of serotonin in the brain. This work provides a reproducible and accurate method to profile serotonergic neurons under a variety of conditions and suggests a novel paradigm for gaining information on the etiology of psychiatric disorders.

PMID: 23407934 [PubMed - as supplied by publisher]

Sex differences in autism spectrum disorders.

Curr Opin Neurol. 2013 Feb 13;

Authors: Werling DM, Geschwind DH

Abstract
PURPOSE OF REVIEW: A strong male bias in autism spectrum disorder (ASD) prevalence has been observed with striking consistency, but no mechanism has yet to definitively account for this sex difference. This review explores the current status of epidemiological, genetic, and neuroendocrinological work addressing ASD prevalence and liability in males and females, so as to frame the major issues necessary to pursue a more complete understanding of the biological basis for sex-differential risk. RECENT FINDINGS: Recent studies continue to report a male bias in ASD prevalence, but also suggest that sex differences in phenotypic presentation, including fewer restricted and repetitive behaviors and externalizing behavioral problems in females, may contribute to this bias. Genetic studies demonstrate that females are protected from the effects of heritable and de-novo ASD risk variants, and compelling work suggests that sex chromosomal genes and/or sex hormones, especially testosterone, may modulate the effects of genetic variation on the presentation of an autistic phenotype. SUMMARY: ASDs affect females less frequently than males, and several sex-differential genetic and hormonal factors may contribute. Future work to determine the mechanisms by which these factors confer risk and protection to males and females is essential.

PMID: 23406909 [PubMed - as supplied by publisher]

Chromosomal microarray (CMA) analysis in infants with congenital anomalies: when is it really helpful?

J Matern Fetal Neonatal Med. 2012 Oct;25 Suppl 4:124-6

Authors: Resta N, Memo L

Abstract
BACKGROUND: Birth defects are very common, affecting two to three infants in every 100 births, and often represent a diagnostic and management challenge. The birth of a child with multiple malformations is the beginning of a complex diagnostic process, where the primary purpose is to determine a precise nosological definition. An accurate diagnosis is a key prerequisite in providing a care plan, a prognosis and genetic counselling. The poor specificity of birth defects, the aetiology and course of which can vary despite similar phenotypic patterns, often makes the diagnostic path problematic. The advent and application of high-resolution chromosomal microarray, encompassing array-based comparative genome hybridization and single-nucleotide polymorphism arrays, has led to the detection of genomic copy-number abnormalities in patients affected by multiple congenital anomalies, dysmorphisms, developmental delay and mental retardation, but who have a normal karyotype.
AIM: We discuss current guidelines and recommendations for chromosomal microarray use and how its application can help clinicians make accurate diagnoses in order to appropriately manage and treat affected newborns.
CONCLUSIONS: Current guidelines strongly support the application of chromosomal microarray analysis as a first-tier cytogenetic diagnostic test alternative to karyotyping for patients with multiple congenital anomalies, or developmental delay, intellectual disability and autism spectrum disorders.

PMID: 22958042 [PubMed - indexed for MEDLINE]

Traffic-related air pollution, particulate matter, and autism.

JAMA Psychiatry. 2013 Jan 1;70(1):71-7

Authors: Volk HE, Lurmann F, Penfold B, Hertz-Picciotto I, McConnell R

Abstract
CONTEXT Autism is a heterogeneous disorder with genetic and environmental factors likely contributing to its origins. Examination of hazardous pollutants has suggested the importance of air toxics in the etiology of autism, yet little research has examined its association with local levels of air pollution using residence-specific exposure assignments. OBJECTIVE To examine the relationship between traffic-related air pollution, air quality, and autism. DESIGN This population-based case-control study includes data obtained from children with autism and control children with typical development who were enrolled in the Childhood Autism Risks from Genetics and the Environment study in California. The mother's address from the birth certificate and addresses reported from a residential history questionnaire were used to estimate exposure for each trimester of pregnancy and first year of life. Traffic-related air pollution was assigned to each location using a line-source air-quality dispersion model. Regional air pollutant measures were based on the Environmental Protection Agency's Air Quality System data. Logistic regression models compared estimated and measured pollutant levels for children with autism and for control children with typical development. SETTING Case-control study from California. PARTICIPANTS A total of 279 children with autism and a total of 245 control children with typical development. MAIN OUTCOME MEASURES Crude and multivariable adjusted odds ratios (AORs) for autism. RESULTS Children with autism were more likely to live at residences that had the highest quartile of exposure to traffic-related air pollution, during gestation (AOR, 1.98 [95% CI, 1.20-3.31]) and during the first year of life (AOR, 3.10 [95% CI, 1.76-5.57]), compared with control children. Regional exposure measures of nitrogen dioxide and particulate matter less than 2.5 and 10 μm in diameter (PM2.5 and PM10) were also associated with autism during gestation (exposure to nitrogen dioxide: AOR, 1.81 [95% CI, 1.37-3.09]; exposure to PM2.5: AOR, 2.08 [95% CI, 1.93-2.25]; exposure to PM10: AOR, 2.17 [95% CI, 1.49-3.16) and during the first year of life (exposure to nitrogen dioxide: AOR, 2.06 [95% CI, 1.37-3.09]; exposure to PM2.5: AOR, 2.12 [95% CI, 1.45-3.10]; exposure to PM10: AOR, 2.14 [95% CI, 1.46-3.12]). All regional pollutant estimates were scaled to twice the standard deviation of the distribution for all pregnancy estimates. CONCLUSIONS Exposure to traffic-related air pollution, nitrogen dioxide, PM2.5, and PM10 during pregnancy and during the first year of life was associated with autism. Further epidemiological and toxicological examinations of likely biological pathways will help determine whether these associations are causal.

PMID: 23404082 [PubMed - in process]

Expression profiling of mouse subplate reveals a dynamic gene network and disease association with autism and schizophrenia.

Proc Natl Acad Sci U S A. 2013 Feb 11;

Authors: Hoerder-Suabedissen A, Oeschger FM, Krishnan ML, Belgard TG, Wang WZ, Lee S, Webber C, Petretto E, Edwards AD, Molnár Z

Abstract
The subplate zone is a highly dynamic transient sector of the developing cerebral cortex that contains some of the earliest generated neurons and the first functional synapses of the cerebral cortex. Subplate cells have important functions in early establishment and maturation of thalamocortical connections, as well as in the development of inhibitory cortical circuits in sensory areas. So far no role has been identified for cells in the subplate in the mature brain and disease association of the subplate-specific genes has not been analyzed systematically. Here we present gene expression evidence for distinct roles of the mouse subplate across development as well as unique molecular markers to extend the repertoire of subplate labels. Performing systematic comparisons between different ages (embryonic days 15 and 18, postnatal day 8, and adult), we reveal the dynamic and constant features of the markers labeling subplate cells during embryonic and early postnatal development and in the adult. This can be visualized using the online database of subplate gene expression at https://molnar.dpag.ox.ac.uk/subplate/. We also identify embryonic similarities in gene expression between the ventricular zones, intermediate zone, and subplate, and distinct postnatal similarities between subplate, layer 5, and layers 2/3. The genes expressed in a subplate-specific manner at some point during development show a statistically significant enrichment for association with autism spectrum disorders and schizophrenia. Our report emphasizes the importance of the study of transient features of the developing brain to better understand neurodevelopmental disorders.

PMID: 23401504 [PubMed - as supplied by publisher]

Contributions of a specialty clinic for children and adolescents with Down syndrome.

Am J Med Genet A. 2013 Feb 7;

Authors: Skotko BG, Davidson EJ, Weintraub GS

Abstract
We investigated what added value, if any, a Down syndrome specialty clinic brings to the healthcare needs of children and adolescents with Down syndrome. For this quality improvement study, we performed a retrospective chart review of 105 new patients with Down syndrome, ages 3 and older, seen during the inaugural year of our specialty clinic. We asked how many of our patients were already up-to-date on the healthcare screenings recommended for people with Down syndrome. We further analyzed what tests we ordered, which referrals we suggested, and, ultimately, what new diagnoses of co-occurring medical conditions were made. Only 9.8% of our patients were current on all of the recommended Down syndrome healthcare screenings. Parents came to clinic with a variety of concerns, and after laboratory tests, radiologic studies, and subspecialty referrals, we made many new diagnoses of gastrointestinal conditions (e.g., constipation and celiac disease), seasonal allergies, dermatologic conditions (e.g., xerosis), behavioral diagnoses (e.g., autism spectrum disorder and disruptive behavior not otherwise specified), and clarifications of neurologic conditions. A Down syndrome specialty clinic can identify and address many healthcare needs of children and adolescents with Down syndrome beyond that which is provided in primary care settings. © 2013 Wiley Periodicals, Inc.

PMID: 23401090 [PubMed - as supplied by publisher]

Disease genetics: Rare inherited mutations in autism.

Nat Rev Genet. 2013 Feb 12;

Authors: Flintoft L

PMID: 23400092 [PubMed - as supplied by publisher]

Homozygosity for piebaldism with a proven KIT mutation resulting in depigmentation of the skin and hair, deafness, developmental delay and autism spectrum disorder.

Clin Dysmorphol. 2013 Feb 7;

Authors: Kilsby AJ, Cruwys M, Kukendrajah C, Russell-Eggitt I, Raglan E, Rajput K, Loshe P, Brady AF

PMID: 23399981 [PubMed - as supplied by publisher]

FMRP targets distinct mRNA sequence elements to regulate protein expression.

Nature. 2012 Dec 20;492(7429):382-6

Authors: Ascano M, Mukherjee N, Bandaru P, Miller JB, Nusbaum JD, Corcoran DL, Langlois C, Munschauer M, Dewell S, Hafner M, Williams Z, Ohler U, Tuschl T

Abstract
Fragile X syndrome (FXS) is a multi-organ disease that leads to mental retardation, macro-orchidism in males and premature ovarian insufficiency in female carriers. FXS is also a prominent monogenic disease associated with autism spectrum disorders (ASDs). FXS is typically caused by the loss of fragile X mental retardation 1 (FMR1) expression, which codes for the RNA-binding protein FMRP. Here we report the discovery of distinct RNA-recognition elements that correspond to the two independent RNA-binding domains of FMRP, in addition to the binding sites within the messenger RNA targets for wild-type and I304N mutant FMRP isoforms and the FMRP paralogues FXR1P and FXR2P (also known as FXR1 and FXR2). RNA-recognition-element frequency, ratio and distribution determine target mRNA association with FMRP. Among highly enriched targets, we identify many genes involved in ASD and show that FMRP affects their protein levels in human cell culture, mouse ovaries and human brain. Notably, we discovered that these targets are also dysregulated in Fmr1(-/-) mouse ovaries showing signs of premature follicular overdevelopment. These results indicate that FMRP targets share signalling pathways across different cellular contexts. As the importance of signalling pathways in both FXS and ASD is becoming increasingly apparent, our results provide a ranked list of genes as basis for the pursuit of new therapeutic targets for these neurological disorders.

PMID: 23235829 [PubMed - indexed for MEDLINE]

Trialing targeted therapies for autism.

Nat Med. 2012 Dec;18(12):1746-7

Authors:

PMID: 23223062 [PubMed - indexed for MEDLINE]

Human maternal behaviour is associated with arginine vasopressin receptor 1A gene.

Biol Lett. 2012 Oct 23;8(5):894-6

Authors: Avinun R, Ebstein RP, Knafo A

Abstract
Parenting is one of the main influences on children's early development, and yet its underlying genetic mechanisms have only recently begun to be explored, with many studies neglecting to control for possible child effects. This study focuses on maternal behaviour and on an allele at the RS3 promoter region of the arginine vasopressin receptor 1A (AVPR1A) gene, previously associated with autism and with higher amygdala activation in a face-matching task. Mothers were observed during a free-play session with each of their 3.5-year-old twins. Multilevel regression analyses revealed that mothers who are carriers of the AVPR1A RS3 allele tend to show less structuring and support throughout the interaction independent of the child's sex and RS3 genotype. This finding advances our understanding of the genetic influences on human maternal behaviour.

PMID: 22764113 [PubMed - indexed for MEDLINE]

Novel 9q34.11 gene deletions encompassing combinations of four Mendelian disease genes: STXBP1, SPTAN1, ENG, and TOR1A.

Genet Med. 2012 Oct;14(10):868-76

Authors: Campbell IM, Yatsenko SA, Hixson P, Reimschisel T, Thomas M, Wilson W, Dayal U, Wheless JW, Crunk A, Curry C, Parkinson N, Fishman L, Riviello JJ, Nowaczyk MJ, Zeesman S, Rosenfeld JA, Bejjani BA, Shaffer LG, Cheung SW, Lupski JR, Stankiewicz P, Scaglia F

Abstract
PURPOSE: A number of genes in the 9q34.11 region may be haploinsufficient. However, studies analyzing genotype-phenotype correlations of deletions encompassing multiple dosage-sensitive genes in the region are lacking.
METHODS: We mapped breakpoints of 10 patients with 9q34.11 deletions using high-resolution 9q34-specific array comparative genomic hybridization (CGH) to determine deletion size and gene content.
RESULTS: The 9q34.11 deletions range in size from 67 kb to 2.8 Mb. Six patients exhibit intellectual disability and share a common deleted region including STXBP1; four manifest variable epilepsy. In five subjects, deletions include SPTAN1, previously associated with early infantile epileptic encephalopathy, infantile spasms, intellectual disability, and hypomyelination. In four patients, the deletion includes endoglin (ENG), causative of hereditary hemorrhagic telangiectasia. Finally, in four patients, deletions involve TOR1A, of which molecular defects lead to early-onset primary dystonia. Ninety-four other RefSeq genes also map to the genomic intervals investigated.
CONCLUSION: STXBP1 haploinsufficiency results in progressive encephalopathy characterized by intellectual disability and may be accompanied by epilepsy, movement disorders, and autism. We propose that 9q34.11 genomic deletions involving ENG, TOR1A, STXBP1, and SPTAN1 are responsible for multisystemic vascular dysplasia, early-onset primary dystonia, epilepsy, and intellectual disability, therefore revealing cis-genetic effects leading to complex phenotypes.

PMID: 22722545 [PubMed - indexed for MEDLINE]

Traits of ADHD and autism in girls with a twin brother: a Mendelian randomization study.

Eur Child Adolesc Psychiatry. 2012 Sep;21(9):503-9

Authors: Attermann J, Obel C, Bilenberg N, Nordenbæk CM, Skytthe A, Olsen J

Abstract
It has been hypothesized that prenatal exposure to testosterone may be associated with traits of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD). We conducted a population-based study of dizygotic female twins to elucidate this hypothesis, assuming that the sex of the co-twin influences the level of prenatal exposure to testosterone. We invited parents of 24,552 3- to 15-year-old twins to answer questionnaires on traits of ADHD and ASD. We analysed the data using a proportional odds model with sex of the co-twin as an instrumental variable for prenatal exposure to testosterone of female twins. We received responses for 6,339 girls from dizygotic twin pairs. Odds ratios for male versus female co-twin were 0.71 (95 % confidence interval 0.61-0.81) for ADHD traits and 0.74 (0.66-0.83) for ASD traits, indicating that a twin brother reduces traits of ADHD and ASD in females. In conclusion, we found that female twins with a twin brother scored significantly lower in parent-reported traits of ADHD and ASD than those with a twin sister. The reason for this may be parental reporting bias, or confounding by unmeasured variables, or a causal effect of an intrauterine environment modified by the sex of the co-twin in the opposite direction of what we expected.

PMID: 22643885 [PubMed - indexed for MEDLINE]