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Single-Gene Determinants of Epilepsy Comorbidity.

August 24, 2016 - 6:10am
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Single-Gene Determinants of Epilepsy Comorbidity.

Cold Spring Harb Perspect Med. 2015 Nov;5(11)

Authors: Noebels JL

Abstract
Common somatic conditions are bound to occur by chance in individuals with neurological disorders as prevalent as epilepsy, but when biological links underlying the comorbidity can be uncovered, the relationship may provide clues into the origin and mechanisms of both. The expanding list of monogenic epilepsies and their associated clinical features offer a remarkable opportunity to mine the epilepsy genome for coordinate neurodevelopmental phenotypes and examine their pathogenic mechanisms. Defined single-gene-linked epilepsy syndromes identified to date include all of the most frequently cited comorbidities, such as cognitive disorders, autism, migraine, mood disorders, late-onset dementia, and even premature lethality. Gene-linked comorbidities may be aggravated by, or independent of, seizure history. Mutations in these genes establish clear biological links between abnormal neuronal synchronization and a variety of neurobehavioral disorders, and critically substantiate the definition of epilepsy as a complex spectrum disorder. Mapping the neural circuitry of epilepsy comorbidities and understanding their single-gene risk should substantially clarify this challenging aspect of clinical epilepsy management.

PMID: 26525453 [PubMed - indexed for MEDLINE]

Persistent astrocyte activation in the fragile X mouse cerebellum.

August 24, 2016 - 6:10am
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Persistent astrocyte activation in the fragile X mouse cerebellum.

Brain Behav. 2015 Oct;5(10):e00400

Authors: Pacey LK, Guan S, Tharmalingam S, Thomsen C, Hampson DR

Abstract
BACKGROUND: Fragile X Syndrome, the most common single gene cause of autism, results from loss of the RNA-binding protein FMRP. Although FMRP is highly expressed in neurons, it has also recently been identified in glia. It has been postulated that in the absence of FMRP, abnormal function of non-neuronal cells may contribute to the pathogenesis of the disorder. We previously demonstrated reduced numbers of oligodendrocyte precursor cells and delayed myelination in the cerebellum of fragile X (Fmr1) knockout mice.
METHODS: We used quantitative western blotting and immunocytochemistry to examine the status of astrocytes and microglia in the cerebellum of Fmr1 mice during development and in adulthood.
RESULTS: We report increased expression of the astrocyte marker GFAP in the cerebellum of Fmr1 mice starting in the second postnatal week and persisting in to adulthood. At 2 weeks postnatal, expression of Tumor Necrosis Factor Receptor 2 (TNFR2) and Leukemia Inhibitory Factor (LIF) were elevated in the Fmr1 KO cerebellum. In adults, expression of TNFR2 and the glial marker S100β were also elevated in Fmr1 knockouts, but LIF expression was not different from wild-type mice. We found no evidence of microglial activation or neuroinflammation at any age examined.
CONCLUSIONS: These findings demonstrate an atypical pattern of astrogliosis in the absence of microglial activation in Fmr1 knockout mouse cerebellum. Enhanced TNFR2 and LIF expression in young mice suggests that changes in the expression of astrocytic proteins may be an attempt to compensate for delayed myelination in the developing cerebellum of Fmr1 mice.

PMID: 26516618 [PubMed - indexed for MEDLINE]

Variants in HNRNPH2 on the X Chromosome Are Associated with a Neurodevelopmental Disorder in Females.

August 23, 2016 - 6:08am

Variants in HNRNPH2 on the X Chromosome Are Associated with a Neurodevelopmental Disorder in Females.

Am J Hum Genet. 2016 Aug 17;

Authors: Bain JM, Cho MT, Telegrafi A, Wilson A, Brooks S, Botti C, Gowans G, Autullo LA, Krishnamurthy V, Willing MC, Toler TL, Ben-Zev B, Elpeleg O, Shen Y, Retterer K, Monaghan KG, Chung WK

Abstract
Via whole-exome sequencing, we identified six females from independent families with a common neurodevelopmental phenotype including developmental delay, intellectual disability, autism, hypotonia, and seizures, all with de novo predicted deleterious variants in the nuclear localization signal of Heterogeneous Nuclear Ribonucleoprotein H2, encoded by HNRNPH2, a gene located on the X chromosome. Many of the females also have seizures, psychiatric co-morbidities, and orthopedic, gastrointestinal, and growth problems as well as common dysmorphic facial features. HNRNPs are a large group of ubiquitous proteins that associate with pre-mRNAs in eukaryotic cells to produce a multitude of alternatively spliced mRNA products during development and play an important role in controlling gene expression. The failure to identify affected males, the severity of the neurodevelopmental phenotype in females, and the essential role of this gene suggests that male conceptuses with these variants may not be viable.

PMID: 27545675 [PubMed - as supplied by publisher]

Patterns of Nonrandom Mating Within and Across 11 Major Psychiatric Disorders.

August 23, 2016 - 6:08am
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Patterns of Nonrandom Mating Within and Across 11 Major Psychiatric Disorders.

JAMA Psychiatry. 2016 Apr;73(4):354-61

Authors: Nordsletten AE, Larsson H, Crowley JJ, Almqvist C, Lichtenstein P, Mataix-Cols D

Abstract
IMPORTANCE: Psychiatric disorders are heritable, polygenic traits, which often share risk alleles and for which nonrandom mating has been suggested. However, despite the potential etiological implications, the scale of nonrandom mating within and across major psychiatric conditions remains unclear.
OBJECTIVE: To quantify the nature and extent of nonrandom mating within and across a broad range of psychiatric conditions at the population level.
DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort using Swedish population registers. Participants were all Swedish residents with a psychiatric diagnosis of interest (attention-deficit/hyperactivity disorder, autism spectrum disorder, schizophrenia, bipolar disorder, major depression, generalized anxiety disorder, agoraphobia, social phobia, obsessive-compulsive disorder, anorexia, or substance abuse), along with their mates. Individuals with select nonpsychiatric disorders (Crohn's disease, type 1 and type 2 diabetes mellitus, multiple sclerosis, or rheumatoid arthritis) were included for comparison. General population samples were also derived and matched 1:5 with each case proband. Inpatient and outpatient diagnostic data were derived from the Swedish National Patient Register (1973-2009), with analyses conducted between June 2014 and May 2015.
MAIN OUTCOMES AND MEASURES: Correlation in the diagnostic status of mates both within and across disorders. Conditional logistic regression was used to quantify the odds of each diagnosis in the mates of cases relative to matched population controls.
RESULTS: Across cohorts, data corresponded to 707 263 unique case individuals, with women constituting 45.7% of the full population. Positive correlations in diagnostic status were evident between mates. Within-disorder correlations were marginally higher (range, 0.11-0.48) than cross-disorder correlations (range, 0.01-0.42). Relative to matched populations, the odds of psychiatric case probands having an affected mate were significantly elevated. Differences in the magnitude of observed relationships were apparent by disorder (odds ratio range, 0.8-11.4). The number of comorbidities in a case proband was associated with the proportion of affected mates. These relationships were not apparent or weaker in magnitude among nonpsychiatric conditions (correlation range, -0.03 to 0.17).
CONCLUSIONS AND RELEVANCE: Nonrandom mating is evident in psychiatric populations both within specific disorders and across the spectrum of psychiatric conditions. This phenomenon may hold important implications for how we understand the familial transmission of these disorders and for psychiatric genetic research.

PMID: 26913486 [PubMed - indexed for MEDLINE]

A network of autism linked genes stabilizes two pools of synaptic GABA(A) receptors.

August 23, 2016 - 6:08am
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A network of autism linked genes stabilizes two pools of synaptic GABA(A) receptors.

Elife. 2015;4:e09648

Authors: Tong XJ, Hu Z, Liu Y, Anderson D, Kaplan JM

Abstract
Changing receptor abundance at synapses is an important mechanism for regulating synaptic strength. Synapses contain two pools of receptors, immobilized and diffusing receptors, both of which are confined to post-synaptic elements. Here we show that immobile and diffusing GABA(A) receptors are stabilized by distinct synaptic scaffolds at C. elegans neuromuscular junctions. Immobilized GABA(A) receptors are stabilized by binding to FRM-3/EPB4.1 and LIN-2A/CASK. Diffusing GABA(A) receptors are stabilized by the synaptic adhesion molecules Neurexin and Neuroligin. Inhibitory post-synaptic currents are eliminated in double mutants lacking both scaffolds. Neurexin, Neuroligin, and CASK mutations are all linked to Autism Spectrum Disorders (ASD). Our results suggest that these mutations may directly alter inhibitory transmission, which could contribute to the developmental and cognitive deficits observed in ASD.

PMID: 26575289 [PubMed - indexed for MEDLINE]

Tuberous sclerosis complex.

August 23, 2016 - 6:08am
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Tuberous sclerosis complex.

Handb Clin Neurol. 2015;132:97-109

Authors: Islam MP, Roach ES

Abstract
Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome that can affect the brain, skin, eyes, kidneys, heart, and lungs. TSC alters cellular proliferation and differentiation, resulting in hamartomas of various organs, tumor formation, and altered neuronal migration. The phenotype is highly variable. Most individuals have seizures, commonly including infantile spasms, and there is variable intellectual disability and autism. Neonates can present with cardiac failure due to intracardiac rhabdomyomas. The likelihood of renal angiomyolipomas increases with age, and renal disease is the most common cause of death in adults with TSC. Pulmonary involvement occurs predominantly in women and carries a high morbidity and mortality. TSC is inherited as an autosomal dominant trait, but spontaneous mutations are common. A mutation of either TSC1 on chromosome 9 or TSC2 on chromosome 16 leads to dysfunction of hamartin or tuberin, respectively. These two proteins form a functional complex that modulates the mammalian target of rapamycin (mTOR) pathway. Medications that inhibit mTOR are being used to treat TSC-related tumors, and current studies are investigating whether these agents could alleviate other TSC complications. Consensus statements guide identification and optimal management of many of the TSC-related complications at diagnosis and throughout the lifespan. A multidisciplinary approach is necessary for optimal management of individuals with TSC.

PMID: 26564073 [PubMed - indexed for MEDLINE]

Hyperactivity and lack of social discrimination in the adolescent Fmr1 knockout mouse.

August 23, 2016 - 6:08am
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Hyperactivity and lack of social discrimination in the adolescent Fmr1 knockout mouse.

Behav Pharmacol. 2015 Dec;26(8 Spec No):733-40

Authors: Sørensen EM, Bertelsen F, Weikop P, Skovborg MM, Banke T, Drasbek KR, Scheel-Krüger J

Abstract
The aims of this study were to investigate behaviour relevant to human autism spectrum disorder (ASD) and the fragile X syndrome in adolescent Fmr1 knockout (KO) mice and to evaluate the tissue levels of striatal monoamines. Fmr1 KO mice were evaluated in the open field, marble burying and three-chamber test for the presence of hyperactivity, anxiety, repetitive behaviour, sociability and observation of social novelty compared with wild-type (WT) mice. The Fmr1 KO mice expressed anxiety and hyperactivity in the open field compared with WT mice. This increased level of hyperactivity was confirmed in the three-chamber test. Fmr1 KO mice spent more time with stranger mice compared with the WT. However, after a correction for hyperactivity, their apparent increase in sociability became identical to that of the WT. Furthermore, the Fmr1 KO mice could not differentiate between a familiar or a novel mouse. Monoamines were measured by HPLC: Fmr1 KO mice showed an increase in the striatal dopamine level. We conclude that the fragile X syndrome model seems to be useful for understanding certain aspects of ASD and may have translational interest for studies of social behaviour when hyperactivity coexists in ASD patients.

PMID: 26110222 [PubMed - indexed for MEDLINE]

ADNP: A major autism mutated gene is differentially distributed (age and gender) in the songbird brain.

August 23, 2016 - 6:08am
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ADNP: A major autism mutated gene is differentially distributed (age and gender) in the songbird brain.

Peptides. 2015 Oct;72:75-9

Authors: Kleiman GH, Barnea A, Gozes I

Abstract
ADNP is a protein necessary for brain development, important for brain plasticity, cognitive and social functioning, characteristics that are all impaired in autism and in the Adnp(+/-) mouse model, in a sex-dependent manner. ADNP was originally discovered as a protein that is secreted from glial cells in response to vasoactive intestinal peptide (VIP). VIP is a major neuroprotective peptide in the CNS and PNS and was also associated with social recognition in rodents and aggression, pair-bonding and parental behaviors in birds. Comparative sequence alignment revealed high evolutionary conservation of ADNP in Chordata. Despite its importance in brain function, ADNP has never been studied in birds. Zebra finches (Taeniopygia guttata) are highly social songbirds that have a sexually dichotomous anatomical brain structure, with males demonstrating a developed song system, presenting a model to study behavior and potential sexually dependent fundamental differences. Here, using quantitative real time polymerase chain reaction (qRT-PCR), we discovered sexually dichotomous and age related differences in ADNP mRNA expression in three different regions of the song bird brain-cerebellum, cerebrum, and brain stem. Higher levels of ADNP mRNA were specifically found in young male compared to the female cerebrum, while aging caused a significant 2 and 3-fold decrease in the female and male cerebrum, respectively. Furthermore, a comparison between the three tested brain regions revealed unique sex-dependent ADNP mRNA distribution patterns, affected by aging. Future studies are aimed at deciphering the function of ADNP in birds, toward a better molecular understanding of sexual dichotomy in singing behavior in birds.

PMID: 25895853 [PubMed - indexed for MEDLINE]

Enhancing inhibitory synaptic function reverses spatial memory deficits in Shank2 mutant mice.

August 22, 2016 - 8:59am

Enhancing inhibitory synaptic function reverses spatial memory deficits in Shank2 mutant mice.

Neuropharmacology. 2016 Aug 17;

Authors: Lim CS, Kim H, Yu NK, Kang SJ, Kim T, Ko HG, Lee J, Yang JE, Ryu HH, Park T, Gim J, Nam HJ, Baek SH, Wegener S, Schmitz D, Boeckers TM, Lee MG, Kim E, Lee JH, Lee YS, Kaang BK

Abstract
Autism spectrum disorders (ASDs) are a group of developmental disorders that cause variable and heterogeneous phenotypes across three behavioral domains such as atypical social behavior, disrupted communications, and highly restricted and repetitive behaviors. In addition to these core symptoms, other neurological abnormalities are associated with ASD, including intellectual disability (ID). However, the molecular etiology underlying these behavioral heterogeneities in ASD is unclear. Mutations in SHANK2 genes are associated with ASD and ID. Interestingly, two lines of Shank2 knockout mice (e6-7 KO and e7 KO) showed shared and distinct phenotypes. Here, we found that the expression levels of Gabra2, as well as of GABAA receptor-mediated inhibitory neurotransmission, are reduced in Shank2 e6-7, but not in e7 KO mice compared with their own wild type littermates. Furthermore, treatment of Shank2 e6-7 KO mice with an allosteric modulator for the GABAA receptor reverses spatial memory deficits, indicating that reduced inhibitory neurotransmission may cause memory deficits in Shank2 e6-7 KO mice.

PMID: 27544825 [PubMed - as supplied by publisher]

Genetic testing and counseling in the case of an autism diagnosis: A caregivers perspective.

August 22, 2016 - 8:59am

Genetic testing and counseling in the case of an autism diagnosis: A caregivers perspective.

Eur J Med Genet. 2016 Aug 17;

Authors: Hens K, Peeters H, Dierickx K

Abstract
The search for genes that can explain the development of autism is ongoing. At the same time, genetic counselling and genetic testing can be offered to families with a child diagnosed with autism. However, given the complexity of autism, both with respect to its aetiology as well as with respect to its heterogeneity, such genetic counselling and testing raises specific ethical questions regarding the aim and scope. In order to map these questions and opinions we interviewed 15 Belgian autism professionals. We found that they believed that genetic counselling and genetic testing have certain benefits for families confronted with an autism diagnosis, but also that direct benefit to the child is limited to those cases where a genetic finding offers a certain prognosis and intervention plan. In cases where autism is the result of a syndrome or a known genetic variant that is associated with other health problems, detection can also enable prevention of these health issues. Benefits of genetic testing, such as relief of guilt and reproductive choice, are primarily benefits to the parents, although indirectly they may affect the wellbeing of the person diagnosed. These benefits are associated with ethical questions.

PMID: 27544064 [PubMed - as supplied by publisher]

STAMS: STRING-Assisted Module Search for Genome Wide Association Studies and Application to Autism.

August 21, 2016 - 8:56am

STAMS: STRING-Assisted Module Search for Genome Wide Association Studies and Application to Autism.

Bioinformatics. 2016 Aug 19;

Authors: Hillenmeyer S, Davis LK, Gamazon ER, Cook EH, Cox NJ, Altman RB

Abstract
MOTIVATION: Analyzing genome wide association data in the context of biological pathways helps us understand how genetic variation influences phenotype and increases power to find associations. However, the utility of pathway-based analysis tools is hampered by undercuration and reliance on a distribution of signal across all of the genes in a pathway. Methods that combine genome wide association results with genetic networks to infer the key phenotype-modulating subnetworks combat these issues, but have primarily been limited to network definitions with yes/no labels for gene-gene interactions. A recent method (EW_dmGWAS) incorporates a biological network with weighted edge probability by requiring a secondary phenotype-specific expression dataset. In this paper, we combine an algorithm for weighted-edge module searching and a probabilistic interaction network in order to develop a method, STAMS, for recovering modules of genes with strong associations to the phenotype and probable biologic coherence. Our method builds on EW_dmGWAS but does not require a secondary expression dataset and performs better in six test cases.
RESULTS: We show that our algorithm improves over EW_dmGWAS and standard gene-based analysis by measuring precision and recall of each method on separately identified associations. In the Wellcome Trust Rheumatoid Arthritis study, STAMS-identified modules were more enriched for separately identified associations than EW_dmGWAS (STAMS p-value 3.0×10(-4); EW_dmGWAS- p-value=0.8). We demonstrate that the area under the Precision-Recall curve is 5.9 times higher with STAMS than EW_dmGWAS run on the Wellcome Trust Type 1 Diabetes data.
AVAILABILITY: STAMS is implemented as an R package and is freely available at https://simtk.org/projects/stams CONTACT: rbaltman@stanford.edu.

PMID: 27542772 [PubMed - as supplied by publisher]

Altered Effects of Perspective-Taking on Functional Connectivity during Self- and Other-Referential Processing in Adults with Autism Spectrum Disorder.

August 20, 2016 - 8:55am

Altered Effects of Perspective-Taking on Functional Connectivity during Self- and Other-Referential Processing in Adults with Autism Spectrum Disorder.

Soc Neurosci. 2016 Aug 18;

Authors: Hashimoto RI, Itahashi T, Ohta H, Yamada T, Kanai C, Nakamura M, Watanabe H, Kato N

Abstract
In interactive social situations, it is often crucial to be able to take another person's perspective when evaluating one's own or another person's specific trait; individuals with ASD critically lack this social skill. To examine how perspective-dependent self- and other-evaluation processes modulate functional connectivity in ASD, we conducted an fMRI study in which 26 high-functioning adults with ASD and 24 typically developed (TD) controls were asked to decide whether an adjective describing a personality trait correctly described the participant himself/herself ("self") or the participant's mother ("other") by taking either the first (1P) or third person (3P) perspective. We observed that functional connectivity between the left sensorimotor cortex and the left middle cingulate cortex was enhanced in TD taking the 3P perspective, this enhancement was significantly reduced in ASD, and the degree of reduction was significantly correlated with the severity of autistic traits. Furthermore, the self-reference effect on functional connectivity between the left inferior frontal cortex and frontopolar cortices was significantly enhanced in TD taking the 3P perspective, whereas such effect was reversed in ASD. These findings indicate altered effects of perspective on the functional connectivity, which may underlie the deficits in social interaction and communication observed in individuals with ASD.

PMID: 27538473 [PubMed - as supplied by publisher]

Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration.

August 20, 2016 - 8:55am
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Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration.

Nat Commun. 2016;7:11173

Authors: Pearson BL, Simon JM, McCoy ES, Salazar G, Fragola G, Zylka MJ

Abstract
Environmental factors, including pesticides, have been linked to autism and neurodegeneration risk using retrospective epidemiological studies. Here we sought to prospectively identify chemicals that share transcriptomic signatures with neurological disorders, by exposing mouse cortical neuron-enriched cultures to hundreds of chemicals commonly found in the environment and on food. We find that rotenone, a pesticide associated with Parkinson's disease risk, and certain fungicides, including pyraclostrobin, trifloxystrobin, famoxadone and fenamidone, produce transcriptional changes in vitro that are similar to those seen in brain samples from humans with autism, advanced age and neurodegeneration (Alzheimer's disease and Huntington's disease). These chemicals stimulate free radical production and disrupt microtubules in neurons, effects that can be reduced by pretreating with a microtubule stabilizer, an antioxidant, or with sulforaphane. Our study provides an approach to prospectively identify environmental chemicals that transcriptionally mimic autism and other brain disorders.

PMID: 27029645 [PubMed - indexed for MEDLINE]

A Cross-Disorder Method to Identify Novel Candidate Genes for Developmental Brain Disorders.

August 20, 2016 - 8:55am
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A Cross-Disorder Method to Identify Novel Candidate Genes for Developmental Brain Disorders.

JAMA Psychiatry. 2016 Mar;73(3):275-83

Authors: Gonzalez-Mantilla AJ, Moreno-De-Luca A, Ledbetter DH, Martin CL

Abstract
IMPORTANCE: Developmental brain disorders are a group of clinically and genetically heterogeneous disorders characterized by high heritability. Specific highly penetrant genetic causes can often be shared by a subset of individuals with different phenotypic features, and recent advances in genome sequencing have allowed the rapid and cost-effective identification of many of these pathogenic variants.
OBJECTIVES: To identify novel candidate genes for developmental brain disorders and provide additional evidence of previously implicated genes.
DATA SOURCES: The PubMed database was searched for studies published from March 28, 2003, through May 7, 2015, with large cohorts of individuals with developmental brain disorders.
DATA EXTRACTION AND SYNTHESIS: A tiered, multilevel data-integration approach was used, which intersects (1) whole-genome data from structural and sequence pathogenic loss-of-function (pLOF) variants, (2) phenotype data from 6 apparently distinct disorders (intellectual disability, autism, attention-deficit/hyperactivity disorder, schizophrenia, bipolar disorder, and epilepsy), and (3) additional data from large-scale studies, smaller cohorts, and case reports focusing on specific candidate genes. All candidate genes were ranked into 4 tiers based on the strength of evidence as follows: tier 1, genes with 3 or more de novo pathogenic loss-of-function variants; tier 2, genes with 2 de novo pathogenic loss-of-function variants; tier 3, genes with 1 de novo pathogenic loss-of-function variant; and tier 4, genes with only inherited (or unknown inheritance) pathogenic loss-of-function variants.
MAIN OUTCOMES AND MEASURES: Development of a comprehensive knowledge base of candidate genes related to developmental brain disorders. Genes were prioritized based on the inheritance pattern and total number of pathogenic loss-of-function variants identified amongst unrelated individuals with any one of six developmental brain disorders.
STUDY SELECTION: A combination of phenotype-based and genotype-based literature review yielded 384 studies that used whole-genome or exome sequencing, chromosomal microarray analysis, and/or targeted sequencing to evaluate 1960 individuals with developmental brain disorders.
RESULTS: Our initial phenotype-based literature review yielded 1911 individuals with pLOF variants involving 1034 genes from 118 studies. Filtering our results to genes with 2 or more pLOF variants identified in at least 2 unrelated individuals resulted in 241 genes from 1110 individuals. Of the 241 genes involved in brain disorders, 7 were novel high-confidence genes and 10 were novel putative candidate genes. Fifty-nine genes were ranked in tier 1, 44 in tier 2, 68 in tier 3, and 70 in tier 4. By transcending clinical diagnostic boundaries, the evidence level for 18 additional genes that were ranked 1 tier higher because of this cross-disorder approach was increased.
CONCLUSIONS AND RELEVANCE: This approach increased the yield of gene discovery over what would be obtained if each disorder, type of genomic variant, and study design were analyzed independently. These results provide further support for shared genomic causes among apparently different disorders and demonstrate the clinical and genetic heterogeneity of developmental brain disorders.

PMID: 26817790 [PubMed - indexed for MEDLINE]

Five patients with a chromosome 1q21.1 triplication show macrocephaly, increased weight and facial similarities.

August 20, 2016 - 8:55am
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Five patients with a chromosome 1q21.1 triplication show macrocephaly, increased weight and facial similarities.

Eur J Med Genet. 2015 Oct;58(10):503-8

Authors: Van Dijck A, van der Werf IM, Reyniers E, Scheers S, Azage M, Siefkas K, Van der Aa N, Lacroix A, Rosenfeld J, Argiropoulos B, Davis K, Innes AM, Mefford HC, Mortier G, Meuwissen M, Kooy RF

Abstract
Recurrent rearrangements of chromosome 1q21.1 that occur as a consequence of non-allelic homologous recombination (NAHR) show considerable variability in phenotypic expression and penetrance. Chromosome 1q21.1 deletions (OMIM 612474) have been associated with microcephaly, intellectual disability, autism, schizophrenia, cardiac abnormalities and cataracts. Phenotypic features in individuals with 1q21.1 duplications (OMIM 612475) include macrocephaly, learning difficulties, developmental delay, intellectual disability and mild dysmorphic features. Half of these patients show autistic behavior. For the first time, we describe five patients, including monozygotic twins, with a triplication of the 1q21.1 chromosomal segment. Facial features common to all patients include a high, broad forehead; a flat and broad nasal bridge; long, downslanted palpebral fissures and dysplastic, low-set ears. Likely associated features include macrocephaly and increased weight. We observed that the triplications arose through different mechanisms in the patients: it was de novo in one patient, inherited from a triplication carrier in two cases, while the father of the twins is a 1q21.1 duplication carrier. The de novo triplication contained copies of both maternal alleles, suggesting it was generated by a combination of inter- and intrachromosomal recombination.

PMID: 26327614 [PubMed - indexed for MEDLINE]

Drosophila mutants of the autism candidate gene neurobeachin (rugose) exhibit neuro-developmental disorders, aberrant synaptic properties, altered locomotion, and impaired adult social behavior and activity patterns.

August 20, 2016 - 8:55am
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Drosophila mutants of the autism candidate gene neurobeachin (rugose) exhibit neuro-developmental disorders, aberrant synaptic properties, altered locomotion, and impaired adult social behavior and activity patterns.

J Neurogenet. 2015;29(2-3):135-43

Authors: Wise A, Tenezaca L, Fernandez RW, Schatoff E, Flores J, Ueda A, Zhong X, Wu CF, Simon AF, Venkatesh T

Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder in humans characterized by complex behavioral deficits, including intellectual disability, impaired social interactions, and hyperactivity. ASD exhibits a strong genetic component with underlying multigene interactions. Candidate gene studies have shown that the neurobeachin (NBEA) gene is disrupted in human patients with idiopathic autism ( Castermans et al., 2003 ). The NBEA gene spans the common fragile site FRA 13A and encodes a signal scaffold protein ( Savelyeva et al., 2006 ). In mice, NBEA has been shown to be involved in the trafficking and function of a specific subset of synaptic vesicles. ( Medrihan et al., 2009 ; Savelyeva et al., 2006 ). Rugose (rg) is the Drosophila homolog of the mammalian and human NBEA. Our previous genetic and molecular analyses have shown that rg encodes an A kinase anchor protein (DAKAP 550), which interacts with components of the epidermal growth factor receptor or EGFR and Notch-mediated signaling pathways, facilitating cross talk between these and other pathways ( Shamloula et al., 2002 ). We now present functional data from studies on the larval neuromuscular junction that reveal abnormal synaptic architecture and physiology. In addition, adult rg loss-of-function mutants exhibit defective social interactions, impaired habituation, aberrant locomotion, and hyperactivity. These results demonstrate that Drosophila NBEA (rg) mutants exhibit phenotypic characteristics reminiscent of human ASD and thus could serve as a genetic model for studying ASDs.

PMID: 26100104 [PubMed - indexed for MEDLINE]

Using endophenotypes to examine molecules related to candidate genes as novel therapeutics: The "endophenotype-associated surrogate endpoint (EASE)" concept.

August 20, 2016 - 8:55am
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Using endophenotypes to examine molecules related to candidate genes as novel therapeutics: The "endophenotype-associated surrogate endpoint (EASE)" concept.

Neurosci Res. 2015 Oct;99:1-7

Authors: Yamasue H

Abstract
In this article, a new concept of an "endophenotype-associated surrogate endpoint (EASE)" is proposed. To examine effect of a novel therapeutic molecule on a target phenotype of a genotype associated with the molecule, state-dependent aspect of an endophenotype can be used as a surrogate endpoint. Desired characteristics for EASE are (1) a close relationship to the endophenotype associated with therapeutics, (2) longitudinal changes in illness severity, while the original "endophenotype" is primarily state independent, (3) a physical sign or laboratory measurement that occurs in association with a pathological process and has putative diagnostic and/or prognostic utility, and (4) serves as a substitute for a clinically meaningful endpoint. Advantages are expected for both surrogate endpoints in drug development and endophenotypes in uncovering pathogenesis. EASE are closer to molecules than clinically meaningful endpoints and can respond to administration of the molecule in a more direct manner. Therefore, a statistically significant effect is likely to be observed in clinical trials with smaller sample sizes and shorter durations. As with endophenotypes, reduced heterogeneity might be expected especially in heterogeneous syndromes such as psychiatric disorders. Potential interactions (e.g., elucidating biological mechanisms underlying novel treatments) can be further expected.

PMID: 26055442 [PubMed - indexed for MEDLINE]

AUTS2 Syndrome in a 68-year-old female: Natural history and further delineation of the phenotype.

August 18, 2016 - 8:49am

AUTS2 Syndrome in a 68-year-old female: Natural history and further delineation of the phenotype.

Am J Med Genet A. 2016 Aug 17;

Authors: Sengun E, Yararbas K, Kasakyan S, Alanay Y

Abstract
Here we summarize the clinical and molecular findings in a 68-year-old female with dysmorphic features, mild-to-moderate intellectual disability, and behavioral findings suggesting autism spectrum disorder. SNP array analysis demonstrated a 257 kb deletion comprising exon 6 of AUTS2. This clinical report provides the natural history in the eldest patient yet to be reported, and complements the existing evidence suggesting that disruption of the AUTS2 leads to a recently delineated neurodevelopmental phenotype with a wide spectrum, namely "AUTS2 Syndrome." © 2016 Wiley Periodicals, Inc.

PMID: 27531620 [PubMed - as supplied by publisher]

Genetic Epidemiology of Mitochondrial Pathogenic Variants Causing Nonsyndromic Hearing Loss in a Large Cohort of South Indian Hearing Impaired Individuals.

August 18, 2016 - 8:49am

Genetic Epidemiology of Mitochondrial Pathogenic Variants Causing Nonsyndromic Hearing Loss in a Large Cohort of South Indian Hearing Impaired Individuals.

Ann Hum Genet. 2016 Sep;80(5):257-73

Authors: Subathra M, Ramesh A, Selvakumari M, Karthikeyen NP, Srisailapathy CR

Abstract
Mitochondria play a critical role in the generation of metabolic energy in the form of ATP. Tissues and organs that are highly dependent on aerobic metabolism are involved in mitochondrial disorders including nonsyndromic hearing loss (NSHL). Seven pathogenic variants leading to NSHL have so far been reported on two mitochondrial genes: MT-RNR1 encoding 12SrRNA and MT-TS1 encoding tRNA for Ser((UCN)) . We screened 729 prelingual NSHL subjects to determine the prevalence of MT-RNR1 variants at position m.961, m.1555A>G and m.1494C>T, and MT-TS1 m.7445A>G, m.7472insC m.7510T>C and m.7511T>C variants. Mitochondrial pathogenic variants were found in eight probands (1.1%). Five of them were found to have the m.1555A>G variant, two others had m.7472insC and one proband had m.7444G>A. The extended relatives of these probands showed variable degrees of hearing loss and age at onset. This study shows that mitochondrial pathogenic alleles contribute to about 1% prelingual hearing loss. This study will henceforth provide the reference for the prevalence of mitochondrial pathogenic alleles in the South Indian population, which to date has not been estimated. The m.1555A>G variant is a primary predisposing genetic factor for the development of hearing loss. Our study strongly suggests that mitochondrial genotyping should be considered for all hearing impaired individuals and particularly in families where transmission is compatible with maternal inheritance, after ruling out the most common variants.

PMID: 27530448 [PubMed - in process]

Red blood cells in Rett syndrome: oxidative stress, morphological changes and altered membrane organization.

August 18, 2016 - 8:49am
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Red blood cells in Rett syndrome: oxidative stress, morphological changes and altered membrane organization.

Biol Chem. 2015 Nov;396(11):1233-40

Authors: Ciccoli L, De Felice C, Leoncini S, Signorini C, Cortelazzo A, Zollo G, Pecorelli A, Rossi M, Hayek J

Abstract
In this review, we summarize the current evidence on the erythrocyte as a previously unrecognized target cell in Rett syndrome, a rare (1:10 000 females) and devastating neurodevelopmental disorder caused by loss-of-function mutations in a single gene (i.e. MeCP2, CDKL5, or rarely FOXG1). In particular, we focus on morphological changes, membrane oxidative damage, altered membrane fatty acid profile, and aberrant skeletal organization in erythrocytes from patients with typical Rett syndrome and MeCP2 gene mutations. The beneficial effects of ω-3 polyunsaturated fatty acids (PUFAs) are also summarized for this condition to be considered as a 'model' condition for autism spectrum disorders.

PMID: 26040005 [PubMed - indexed for MEDLINE]

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