1. Bartlett CW, Flax JF, Fermano Z, Hare A, Hou L, Petrill SA, Buyske S, Brzustowicz LM. {{Gene x gene interaction in shared etiology of autism and specific language impairment}}. {Biol Psychiatry};2012 (Oct 15);72(8):692-699.
BACKGROUND: To examine the relationship between autism spectrum disorders (ASD) and specific language impairment (SLI), family studies typically take a comparative approach where families with one disease are examined for traits of the other disease. In contrast, the present report is the first study with both disorders required to be present in each family to provide a more direct test of the hypothesis of shared genetic etiology. METHODS: We behaviorally assessed 51 families including at least one person with ASD and at least one person with SLI (without ASD). Pedigree members were tested with 22 standardized measures of language and intelligence. Because these extended families include a nonshared environmental contrast, we calculated heritability, not just familiality, for each measure twice: 1) baseline heritability analysis, compared with; 2) heritability estimates after statistically removing ASD subjects from pedigrees. RESULTS: Significant increases in heritability on four supra-linguistic measures (including Pragmatic Judgment) and a composite language score but not on any other measures were observed when removing ASD subjects from the analysis, indicating differential genetic effects that are unique to ASD. Nongenetic explanations such as effects of ASD severity or measurement error or low score variability in ASD subjects were systematically ruled out, leaving the hypothesis of nonadditive genetics effects as the potential source of the heritability change caused by ASD. CONCLUSIONS: Although the data suggest genetic risk factors common to both SLI and ASD, there are effects that seem unique to ASD, possibly caused by nonadditive gene-gene interactions of shared risk loci.
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2. Heuer LS, Rose M, Ashwood P, Van de Water J. {{Decreased levels of total immunoglobulin in children with autism are not a result of B cell dysfunction}}. {J Neuroimmunol};2012 (Oct 15);251(1-2):94-102.
Autism spectrum disorders are a heterogeneous group of behaviorally defined disorders having complex etiologies. We previously reported a direct correlation between lower plasma levels of the immunoglobulins (Ig) IgG and IgM and increased severity of behavioral symptoms in children with autism. Our current objective was to determine if these reduced plasma levels of IgG and IgM are the result of defective B cell development, activation, or function. Results suggest no differences in the B cell parameters measured, indicating that decreased Ig in autism is not a result of B cell dysfunction and other immune cells might be involved.
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3. Klei L, Sanders SJ, Murtha MT, Hus V, Lowe JK, Willsey AJ, Moreno-De-Luca D, Yu TW, Fombonne E, Geschwind D, Grice DE, Ledbetter DH, Lord C, Mane SM, Lese Martin C, Martin DM, Morrow EM, Walsh CA, Melhem NM, Chaste P, Sutcliffe JS, State MW, Cook EH, Jr., Roeder K, Devlin B. {{Common genetic variants, acting additively, are a major source of risk for autism}}. {Mol Autism};2012 (Oct 15);3(1):9.
ABSTRACT: BACKGROUND: Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. METHODS: By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. RESULTS: By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. CONCLUSIONS: Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability.
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4. Kleinhans NM, Pauley G, Richards T, Neuhaus E, Martin N, Corrigan NM, Shaw DW, Estes A, Dager SR. {{Age-related abnormalities in white matter microstructure in autism spectrum disorders}}. {Brain Res};2012 (Oct 15);1479:1-16.
Abnormalities in structural and functional connectivity have been reported in autism spectrum disorders (ASD) across a wide age range. However, developmental changes in white matter microstructure are poorly understood. We used a cross-sectional design to determine whether white matter abnormalities measured using diffusion tensor imaging (DTI) were present in adolescents and adults with ASD and whether age-related changes in white matter microstructure differed between ASD and typically developing (TD) individuals. Participants included 28 individuals with ASD and 33 TD controls matched on age and IQ and assessed at one time point. Widespread decreased fractional anisotropy (FA), and increased radial diffusivity (RaD) and mean diffusivity (MD) were observed in the ASD group compared to the TD group. In addition, significant group-by-age interactions were observed in FA, RaD, and MD in all major tracts except the brain stem, indicating that age-related changes in white matter microstructure differed between the groups. We propose that white matter microstructural changes in ASD may reflect myelination and/or other structural differences including differences in axonal density/arborization. In addition, we suggest that white matter microstuctural impairments may be normalizing during young adulthood in ASD. Future longitudinal studies that include a wider range of ages and more extensive clinical characterization will be critical for further uncovering the neurodevelopmental processes unfolding during this dynamic time in development.
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5. Madrigal I, Rodriguez-Revenga L, Xuncla M, Mila M. {{15q11.2 microdeletion and FMR1 premutation in a family with intellectual disabilities and autism}}. {Gene};2012 (Oct 15);508(1):92-95.
Genomic rearrangements of chromosome 15q11-q13 are responsible for diverse phenotypes including intellectual disabilities and autism. 15q11.2 deletion, implicating common PWS/AS breakpoints BP1-BP2, has been described in patients with delayed motor and speech development and behavioural problems. Here we report the clinical and molecular characterisation of a maternally inherited BP1-BP2 deletion in two siblings with intellectual, motor and speech delay, autistic syndrome disorder and several dysmorphic features. One of the patients was also a carrier of an FMR1 allele in the low premutation range. The four genes within the deletion were under-expressed in all deletion carriers but FMR1 mRNA levels remained normal. Our results suggest that BP1-BP2 deletion could be considered as a risk factor for neuropsychological phenotypes and that it presents with variable clinical expressivity.
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6. Puffenberger EG, Jinks RN, Wang H, Xin B, Fiorentini C, Sherman EA, Degrazio D, Shaw C, Sougnez C, Cibulskis K, Gabriel S, Kelley RI, Morton DH, Strauss KA. {{A Homozygous Missense Mutation in HERC2 Associated with Global Developmental Delay and Autism Spectrum Disorder}}. {Hum Mutat};2012 (Oct 15)
We studied a unique phenotype of cognitive delay, autistic behavior, and gait instability segregating in three separate sibships. We initiated genome-wide mapping in two sibships using Affymetrix 10K SNP Mapping Arrays and identified a homozygous 8.2 Mb region on chromosome 15 common to five affected children. We used exome sequencing of two affected children to assess coding sequence variants within the mapped interval. Four novel homozygous exome variants were shared between the two patients; however, only two variants localized to the mapped interval on chromosome 15. A third sibship in an Ohio Amish deme narrowed the mapped interval to 2.6 Mb and excluded one of the two novel homozygous exome variants. The remaining variant, a missense change in HERC2 (c.1781C>T, p.Pro594Leu), occurs in a highly conserved proline residue within an RCC1-like functional domain. Functional studies of truncated HERC2 in ARPE cells suggest that the p.Pro594Leu variant induces protein aggregation and leads to decreased HERC2 abundance. The phenotypic correlation with the mouse Herc1 and Herc2 mutants as well as the phenotypic overlap with Angelman syndrome provide further evidence that pathogenic changes in HERC2 are associated with non-syndromic intellectual disability, autism, and gait disturbance.
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7. Yu B. {{Issues in Bilingualism and Heritage Language Maintenance: Perspectives of Minority-Language Mothers of Children with Autism Spectrum Disorders}}. {Am J Speech Lang Pathol};2012 (Oct 15)
PURPOSE: This study investigated the language practices of ten bilingual, Chinese/English-speaking, immigrant mothers with their children with autism spectrum disorders. It aimed to understand (a) the nature of the language practices, (b) their constraints, and (c) their impact. METHOD: In-depth phenomenological interviewing was employed with thematic and narrative analyses to yield themes. RESULTS: Language practices perceived to be advantageous to intervention access and wellness were adopted. Chinese was valued, but not pursued if it was believed to hinder development or English acquisition. All of the mothers believed bilingualism made learning more challenging. Many believed it caused confusion or exacerbated disabilities. These deficit views of bilingualism were commonly reinforced by professionals. All of the mothers were motivated to help their children learn English but had no assistance to do so. Practices that were sustainable aligned with families’ preferred communication patterns. CONCLUSIONS: There is an urgent need for practitioners to be better informed about issues related to bilingualism and second language learning. Professionals should support parents to arrive at language use patterns that are self-enhancing and congruent with families’ needs.
