1. Crespi BJ, Thiselton DL. {{Comparative immunogenetics of autism and schizophrenia}}. {Genes Brain Behav};2011 (Jun 7)
Autism and schizophrenia are highly-heritable neurodevelopmental disorders, each mediated by a diverse suite of genetic and environmental risk factors. Comorbidity and familial aggregation of such neurodevelopmental disorders with other disease-related conditions can provide important insights into their etiology. Epidemiological studies have documented reduced rates of rheumatoid arthritis, a systemic autoimmune condition, in schizophrenia, and recent work has demonstrated increased rates of rheumatoid arthritis in first-degree relatives of autistic individuals, especially mothers. Advances in understanding the genetic basis of rheumatoid arthritis have demonstrated that much of the genetic liability to this condition is due to risk and protective alleles at the HLA DRB1 locus. These data allow robust testing of the hypotheses that allelic variation at DRB1 pleiotropically modulates risk of rheumatoid arthritis, autism, and schizophrenia. Systematic review of the literature indicates that reported associations of DRB1 variants with these three conditions are congruent with a pleiotropic model: DRB1*04 alleles have been associated with increased risk of rheumatoid arthritis and autism but decreased risk of schizophrenia, and DRB1*13 alleles have been associated with protection from rheumatoid arthritis and autism but higher risk of schizophrenia. These convergent findings from genetics and epidemiology imply that a subset of autism and schizophrenia cases may be underlain by genetically-based neuroimmune alterations, and that analyses of the causes of risk and protective effects from DRB1 variants may provide new approaches to therapy.
2. Dodig-Curkovic K, Curkovic M, Radic J, Radic M. {{The treatment of autistic children with risperidone}}. {Coll Antropol};2011 (Jan);35 Suppl 1:297-301.
Autism is a pervasive developmental disorder characterised by impairment in social interaction and communication, with unusual behavior. In some cases the pharmacotherapy is prescribed and the most studied antipshychotic drugs include haloperidol and risperidone. In this paper we displayed the treatment of two cases of autism in boy and girl with risperidone. With the use of risperidone in girl, we have achieved reduction of psychomotor symptoms and reduction of hetero-aggressive and self-destructive behavior, and in boy we have also achieved reduction of psychomotoric symptoms, with improvement in contact with his surrounding, he had less learning problems and he has felt familiar not only with his mother, but with other persons. Research on the use of risperidone in the treatment of autistic disorders among children in Croatia are rare, given the limited use of risperidone in children younger than 15years, the question arises about the need to expand the scope of application of risperidone in younger age groups.
3. Gilman SR, Iossifov I, Levy D, Ronemus M, Wigler M, Vitkup D. {{Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses}}. {Neuron};2011 (Jun 9);70(5):898-907.
Identification of complex molecular networks underlying common human phenotypes is a major challenge of modern genetics. In this study, we develop a method for network-based analysis of genetic associations (NETBAG). We use NETBAG to identify a large biological network of genes affected by rare de novo CNVs in autism. The genes forming the network are primarily related to synapse development, axon targeting, and neuron motility. The identified network is strongly related to genes previously implicated in autism and intellectual disability phenotypes. Our results are also consistent with the hypothesis that significantly stronger functional perturbations are required to trigger the autistic phenotype in females compared to males. Overall, the presented analysis of de novo variants supports the hypothesis that perturbed synaptogenesis is at the heart of autism. More generally, our study provides proof of the principle that networks underlying complex human phenotypes can be identified by a network-based functional analysis of rare genetic variants.
4. Levy D, Ronemus M, Yamrom B, Lee YH, Leotta A, Kendall J, Marks S, Lakshmi B, Pai D, Ye K, Buja A, Krieger A, Yoon S, Troge J, Rodgers L, Iossifov I, Wigler M. {{Rare de novo and transmitted copy-number variation in autistic spectrum disorders}}. {Neuron};2011 (Jun 9);70(5):886-897.
To explore the genetic contribution to autistic spectrum disorders (ASDs), we have studied genomic copy-number variation in a large cohort of families with a single affected child and at least one unaffected sibling. We confirm a major contribution from de novo deletions and duplications but also find evidence of a role for inherited « ultrarare » duplications. Our results show that, relative to males, females have greater resistance to autism from genetic causes, which raises the question of the fate of female carriers. By analysis of the proportion and number of recurrent loci, we set a lower bound for distinct target loci at several hundred. We find many new candidate regions, adding substantially to the list of potential gene targets, and confirm several loci previously observed. The functions of the genes in the regions of de novo variation point to a great diversity of genetic causes but also suggest functional convergence.
5. Luyster RJ, Kuban KC, O’Shea TM, Paneth N, Allred EN, Leviton A. {{The Modified Checklist for Autism in Toddlers in extremely low gestational age newborns: individual items associated with motor, cognitive, vision and hearing limitations}}. {Paediatr Perinat Epidemiol};2011 (Jul);25(4):366-376.
Luyster RJ, Kuban KCK, O’Shea TM, Paneth N, Allred EN, Leviton A for ELGAN Study investigators. The Modified Checklist for Autism in Toddlers in extremely low gestational age newborns: Individual items associated with motor, cognitive, vision and hearing limitations. Paediatric and Perinatal Epidemiology 2011; 25: 366-376. The Modified Checklist for Autism in Toddlers (M-CHAT) has yielded elevated rates of screening failure for children born preterm or with low birthweight. We extended these findings with a detailed examination of M-CHAT items in a large sample of children born at extremely low gestational age. The sample was grouped according to children’s current limitations and degree of impairment. The aim was to better understand how disabilities might influence M-CHAT scores. Fourteen participating institutions of the Extremely Low Gestational Age Newborns (ELGAN) Study prospectively collected information about 1086 infants who were born before the 28th week of gestation and had an assessment at age 24-months. The 24-month visit included a neurological assessment, the Bayley Scales of Infant Development, Second edition (BSID-II), M-CHAT and a medical history form. Outcome measures included the distribution of failed M-CHAT items among groups classified according to cerebral palsy diagnosis, gross motor function, BSID-II scores and vision or hearing impairments. M-CHAT items were failed more frequently by children with concurrently identified impairments (motor, cognitive, vision and hearing). In addition, the frequency of item failure increased with the severity of impairment. The failed M-CHAT items were often, but not consistently, related to children’s specific impairments. Importantly, four of the six M-CHAT ‘critical items’ were commonly affected by presence and severity of concurrent impairments. The strong association between impaired sensory or motor function and M-CHAT results among extremely low gestational age children suggests that such impairments might give rise to false positive M-CHAT screening.
6. Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, Chu SH, Moreau MP, Gupta AR, Thomson SA, Mason CE, Bilguvar K, Celestino-Soper PB, Choi M, Crawford EL, Davis L, Davis Wright NR, Dhodapkar RM, Dicola M, Dilullo NM, Fernandez TV, Fielding-Singh V, Fishman DO, Frahm S, Garagaloyan R, Goh GS, Kammela S, Klei L, Lowe JK, Lund SC, McGrew AD, Meyer KA, Moffat WJ, Murdoch JD, O’Roak BJ, Ober GT, Pottenger RS, Raubeson MJ, Song Y, Wang Q, Yaspan BL, Yu TW, Yurkiewicz IR, Beaudet AL, Cantor RM, Curland M, Grice DE, Gunel M, Lifton RP, Mane SM, Martin DM, Shaw CA, Sheldon M, Tischfield JA, Walsh CA, Morrow EM, Ledbetter DH, Fombonne E, Lord C, Martin CL, Brooks AI, Sutcliffe JS, Cook EH, Jr., Geschwind D, Roeder K, Devlin B, State MW. {{Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism}}. {Neuron};2011 (Jun 9);70(5):863-885.
We have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6-12.0, p = 2.4 x 10(-7)). We estimate there are 130-234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1.
7. Sarac H, Henigsberg N, Markeljevic J, Pavlisa G, Hof PR, Simic G. {{Fragile X-premutation tremor/ataxia syndrome (FXTAS) in a young woman: clinical, genetics, MRI and 1H-MR spectroscopy correlates}}. {Coll Antropol};2011 (Jan);35 Suppl 1:327-332.
It is generally thought that fragile X-associated tremor/ataxia syndrome (FXTAS) represents a late-onset neurodegenerative disorder occuring in male carriers of a premutation expansion (55-200 CGG repeats) in the fragile X mental retardation 1 (FMR 1) gene. However, several female patients with FXTAS have also been reported recently. Here, we describe a 23-year old woman with positive family history of mental retardation and autism who presented clinically with action tremor, ataxia, emotional disturbances and cognitive dysfunction. Magnetic resonance imaging (MRI) of the brain showed diffuse cortical atrophy, while 1H-MR spectroscopy (MRS) revealed decreased levels of N-acetylaspartate (NAA) in the cerebellum, basal ganglia, and pons. Genetic testing confirmed heterozygous FMR 1 gene premutation of 100 CGG repeats in the abnormal allele and 29 CGG repeats in the normal allele. We concluded that FXTAS may be an under-recognized disorder, particularly in women.
8. Schaaf CP, Zoghbi HY. {{Solving the autism puzzle a few pieces at a time}}. {Neuron};2011 (Jun 9);70(5):806-808.
In this issue, a pair of studies (Levy et al. and Sanders et al.) identify several de novo copy-number variants that together account for 5%-8% of cases of simplex autism spectrum disorders. These studies suggest that several hundreds of loci are likely to contribute to the complex genetic heterogeneity of this group of disorders. An accompanying study in this issue (Gilman et al.), presents network analysis implicating these CNVs in neural processes related to synapse development, axon targeting, and neuron motility.
9. Whitman SA, Cover C, Yu L, Nelson DL, Zarnescu DC, Gregorio CC. {{Desmoplakin and Talin2 Are Novel mRNA Targets of Fragile X-Related Protein-1 in Cardiac Muscle Whitman; Dsp and Tln2 Are mRNA Targets of FXR1 in the Heart}}. {Circ Res};2011 (Jun 9)
Rationale: The proper function of cardiac muscle requires the precise assembly and interactions of numerous cytoskeletal and regulatory proteins into specialized structures that orchestrate contraction and force transmission. Evidence suggests that posttranscriptional regulation is critical for muscle function, but the mechanisms involved remain understudied. Objective: To investigate the molecular mechanisms and targets of the muscle-specific fragile X mental retardation, autosomal homolog 1 (FXR1), an RNA binding protein whose loss leads to perinatal lethality in mice and cardiomyopathy in zebrafish. Methods and Results: Using RNA immunoprecipitation approaches we found that desmoplakin and talin2 mRNAs associate with FXR1 in a complex. In vitro assays indicate that FXR1 binds these mRNA targets directly and represses their translation. Fxr1 KO hearts exhibit an up-regulation of desmoplakin and talin2 proteins, which is accompanied by severe disruption of desmosome as well as costamere architecture and composition in the heart, as determined by electron microscopy and deconvolution immunofluorescence analysis. Conclusions: Our findings reveal the first direct mRNA targets of FXR1 in striated muscle and support translational repression as a novel mechanism for regulating heart muscle development and function, in particular the assembly of specialized cytoskeletal structures.
