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CNTNAP2 polymorphisms and structural brain connectivity: a diffusion-tensor imaging study.

April 5, 2014 - 3:51pm
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CNTNAP2 polymorphisms and structural brain connectivity: a diffusion-tensor imaging study.

J Psychiatr Res. 2013 Oct;47(10):1349-56

Authors: Clemm von Hohenberg C, Wigand MC, Kubicki M, Leicht G, Giegling I, Karch S, Hartmann AM, Konte B, Friedl M, Ballinger T, Eckbo R, Bouix S, Jäger L, Shenton ME, Rujescu D, Mulert C

Abstract
CNTNAP2 is a gene on chromosome 7 that has shown associations with autism and schizophrenia, and there is evidence that it plays an important role for neuronal synchronization and brain connectivity. In this study, we assessed the relationship between Diffusion Tensor Imaging (DTI), a putative marker of anatomical brain connectivity, and multiple single nucleotide polymorphisms (SNPs) spread out over this large gene. 81 healthy controls and 44 patients with schizophrenia (all Caucasian) underwent DTI and genotyping of 31 SNPs within CNTNAP2. We employed Tract-based Spatial Statistics (TBSS) for inter-subject brain registration and computed average diffusivity values for six major white matter tracts. Analyses of Covariance (ANCOVAs) were computed to test for possible associations with genotypes. The strongest association, which survived rigorous Bonferroni correction, was between rs2710126 genotype and Fractional Anisotropy (FA) in the uncinate fasciculus (p = .00003). This anatomical location is particularly interesting given the enriched fronto-temporal expression of CNTNAP2 in the developing brain. For this SNP, no phenotype association has been reported before. There were several further genotype-DTI associations that were nominally significant but did not survive Bonferroni correction, including an association between axial diffusivity in the dorsal cingulum bundle and a region in intron 13 (represented by rs2710102, rs759178, rs2538991), which has previously been reported to be associated with anterior-posterior functional connectivity. We present new evidence about the effects of CNTNAP2 on brain connectivity, whose disruption has been hypothesized to be central to schizophrenia pathophysiology.

PMID: 23871450 [PubMed - indexed for MEDLINE]

Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills.

April 4, 2014 - 8:59am
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Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills.

Proc Natl Acad Sci U S A. 2014 Feb 4;111(5):1987-92

Authors: Skuse DH, Lori A, Cubells JF, Lee I, Conneely KN, Puura K, Lehtimäki T, Binder EB, Young LJ

Abstract
The neuropeptides oxytocin and vasopressin are evolutionarily conserved regulators of social perception and behavior. Evidence is building that they are critically involved in the development of social recognition skills within rodent species, primates, and humans. We investigated whether common polymorphisms in the genes encoding the oxytocin and vasopressin 1a receptors influence social memory for faces. Our sample comprised 198 families, from the United Kingdom and Finland, in whom a single child had been diagnosed with high-functioning autism. Previous research has shown that impaired social perception, characteristic of autism, extends to the first-degree relatives of autistic individuals, implying heritable risk. Assessments of face recognition memory, discrimination of facial emotions, and direction of gaze detection were standardized for age (7-60 y) and sex. A common SNP in the oxytocin receptor (rs237887) was strongly associated with recognition memory in combined probands, parents, and siblings after correction for multiple comparisons. Homozygotes for the ancestral A allele had impairments in the range -0.6 to -1.15 SD scores, irrespective of their diagnostic status. Our findings imply that a critical role for the oxytocin system in social recognition has been conserved across perceptual boundaries through evolution, from olfaction in rodents to visual memory in humans.

PMID: 24367110 [PubMed - indexed for MEDLINE]

Attentional switching forms a genetic link between attention problems and autistic traits in adults.

April 4, 2014 - 8:59am
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Attentional switching forms a genetic link between attention problems and autistic traits in adults.

Psychol Med. 2013 Sep;43(9):1985-96

Authors: Polderman TJ, Hoekstra RA, Vinkhuyzen AA, Sullivan PF, van der Sluis S, Posthuma D

Abstract
BACKGROUND: Attention deficit hyperactivity disorder (ADHD) symptoms and autistic traits often occur together. The pattern and etiology of co-occurrence are largely unknown, particularly in adults. This study investigated the co-occurrence between both traits in detail, and subsequently examined the etiology of the co-occurrence, using two independent adult population samples. Method Data on ADHD traits (Inattention and Hyperactivity/Impulsivity) were collected in a population sample (S1, n = 559) of unrelated individuals. Data on Attention Problems (AP) were collected in a population-based family sample of twins and siblings (S2, n = 560). In both samples five dimensions of autistic traits were assessed (social skills, routine, attentional switching, imagination, patterns).
RESULTS: Hyperactive traits (S1) did not correlate substantially with the autistic trait dimensions. For Inattention (S1) and AP (S2), the correlations with the autistic trait dimensions were low, apart from a prominent correlation with the attentional switching scale (0.47 and 0.32 respectively). Analyses in the genetically informative S2 revealed that this association could be explained by a shared genetic factor.
CONCLUSIONS: Our findings suggest that the co-occurrence of ADHD traits and autistic traits in adults is not determined by problems with hyperactivity, social skills, imagination or routine preferences. Instead, the association between those traits is due primarily to shared attention-related problems (inattention and attentional switching capacity). As the etiology of this association is purely genetic, biological pathways involving attentional control could be a promising focus of future studies aimed at unraveling the genetic causes of these disorders.

PMID: 23257114 [PubMed - indexed for MEDLINE]

Associations between single-nucleotide polymorphism in the FNDC3A and autism spectrum disorder in a Korean population.

April 3, 2014 - 8:31am
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Associations between single-nucleotide polymorphism in the FNDC3A and autism spectrum disorder in a Korean population.

Psychiatry Res. 2013 Sep 30;209(2):246-8

Authors: Ro M, Park J, Nam M, Bang HJ, Yang JW, Choi KS, Kim SK, Chung JH, Kwack K

Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental syndrome associated with impairments of reciprocal communication and cognitive function. Associations between single-nucleotide polymorphisms (SNPs) and ASD were analysed by logistic regression. Polymorphisms in fibronectin type III domain-containing 3A (FNDC3A) exhibited significant associations in genotype and diplotype analyses. We conclude that FNDC3A influences the prevalence of ASD.

PMID: 23639254 [PubMed - indexed for MEDLINE]

Chromosomal microarray analysis as a first-tier clinical diagnostic test: Estonian experience.

April 2, 2014 - 8:14am

Chromosomal microarray analysis as a first-tier clinical diagnostic test: Estonian experience.

Mol Genet Genomic Med. 2014 Mar;2(2):166-75

Authors: Zilina O, Teek R, Tammur P, Kuuse K, Yakoreva M, Vaidla E, Mölter-Väär T, Reimand T, Kurg A, Ounap K

Abstract
Chromosomal microarray analysis (CMA) is now established as the first-tier cytogenetic diagnostic test for fast and accurate detection of chromosomal abnormalities in patients with developmental delay/intellectual disability (DD/ID), multiple congenital anomalies (MCA), and autism spectrum disorders (ASD). We present our experience with using CMA for postnatal and prenatal diagnosis in Estonian patients during 2009-2012. Since 2011, CMA is on the official service list of the Estonian Health Insurance Fund and is performed as the first-tier cytogenetic test for patients with DD/ID, MCA or ASD. A total of 1191 patients were analyzed, including postnatal (1072 [90%] patients and 59 [5%] family members) and prenatal referrals (60 [5%] fetuses). Abnormal results were reported in 298 (25%) patients, with a total of 351 findings (1-3 per individual): 147 (42%) deletions, 106 (30%) duplications, 89 (25%) long contiguous stretches of homozygosity (LCSH) events (>5 Mb), and nine (3%) aneuploidies. Of all findings, 143 (41%) were defined as pathogenic or likely pathogenic; for another 143 findings (41%), most of which were LCSH, the clinical significance remained unknown, while 61 (18%) reported findings can now be reclassified as benign or likely benign. Clinically relevant findings were detected in 126 (11%) patients. However, the proportion of variants of unknown clinical significance was quite high (41% of all findings). It seems that our ability to detect chromosomal abnormalities has far outpaced our ability to understand their role in disease. Thus, the interpretation of CMA findings remains a rather difficult task requiring a close collaboration between clinicians and cytogeneticists.

PMID: 24689080 [PubMed]

Incontinentia pigmenti and hypomelanosis of Ito.

April 2, 2014 - 8:14am
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Incontinentia pigmenti and hypomelanosis of Ito.

Handb Clin Neurol. 2013;111:341-7

Authors: Bodemer C

Abstract
Incontinentia pigmenti (IP) is a rare X-linked dominant neurocutaneous disorder affecting ectodermal tissue: skin, eyes, central nervous system, hair, nails, and teeth. It is usually lethal for males in utero. The involved gene is NEMO, an essential component of the nuclear factor-kappa B (NF-κB) signaling pathway. Skin lesions are highly diagnostic, occurring in neonates, with a particular distribution on Blaschko lines. The severity of the disease is related to ocular and neurological impairment. The hallmark of ocular IP is retinal vasculopathy including peripheral retinal vascular nonperfusion, macular infarction and neovascularization, and preretinal neovascularization. CNS involvement consists of seizures, mental retardation, hemiparesis, spasticity, microcephaly, cerebellar ataxia, and coma. It often occurs in neonates. Some patients have persistent pharmacoresistant seizures throughout life. MRI findings consist essentially in: white-matter lesions; scattered cortical neuronal necrosis; multiple cerebral infarctions; cerebral atrophy, hypoplasia of the corpus callosum, encephalomalacia and neuronal heterotopia. A predominant role of vascular occlusive phenomena in small vessels is highly suspected. In fact several intricate mechanisms could be discussed: vascular, inflammatory, developmental mechanisms. Their role and predictive factors of IP CNS involvement in neonatal IP need to be better understood to identify effective innovative therapies. Hypomelanosis of Ito can occur in the neonate, infancy, or childhood, be isolated or diffuse, often following the Blaschko lines, and can fade in childhood or adulthood. It is due to reduced melanin in the epidermis. Eye, central nervous (mental retardation, epilepsy, language disabilities, motor system dysfunction, psychiatric symptoms including autism - with frequent cortical malformations including hemimegalencephaly and white matter involvement), and musculoskeletal systems can also be affected. Mosaicism with various chromosomal rearrangements has been reported.

PMID: 23622185 [PubMed - indexed for MEDLINE]

X-linked mental deficiency.

April 2, 2014 - 8:14am
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X-linked mental deficiency.

Handb Clin Neurol. 2013;111:297-306

Authors: des Portes V

Abstract
Ten percent of cases of intellectual deficiency in boys are caused by genes located on the X chromosome. X-linked mental retardation (XLMR) includes more than 200 syndromes and 80 genes identified to date. The fragile X syndrome is the most frequent syndrome, due to a dynamic mutation with a CGG triplet amplification. Mental retardation is virtually always present. Phonological and syntactic impairments are often combined with pragmatic language impairment and visuospatial reasoning difficulties. A minority fulfill the criteria for autism. In girls, the clinical expression of the complete mutation varies according to the X chromosome inactivation profile. Several XLMR occur as severe early onset encephalopathies: Lowe oculocerebrorenal syndrome, ATR-X syndrome (alpha thalassemia/mental retardation X-linked), Allan-Herdon-Dudley syndrome (MCT8 gene). Two genes, ARX (X-LAG; Partington syndrome) and MECP2 (Rett syndrome in females; mild MR with spastic diplegia/psychotic problems in males) are associated with various phenotypes, according to the mutation involved. Oligophrenine 1 (OPHN-1) gene mutations lead to vermal dysplasia. PQBP1 gene mutations (Renpenning syndrome) are responsible for moderate to severe mental deficiency, microcephaly, and small stature. Although some forms of XLMR are not very specific and the phenotype for each given gene is somewhat heterogeneous, a clinical diagnostic strategy is emerging.

PMID: 23622180 [PubMed - indexed for MEDLINE]

The autistic spectrum.

April 2, 2014 - 8:14am
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The autistic spectrum.

Handb Clin Neurol. 2013;111:263-71

Authors: Mottron L, Dawson M

Abstract
The autistic spectrum currently encompasses common precocious behaviourally identified constellations of social and communication atypicalities associated with restricted interests and repetitive behavior, together with uneven ability profiles. It is associated with multiple but heterogeneous genetic, functional, and structural variations whose established links with an autistic behavioral phenotype are as yet minimal. Strong evidence of high heritability contrasts with limited determination of genes and modes of transmission involved. Adaptation and outcomes vary widely according to opportunities, accommodation, and co-occurring conditions. With current diagnostic practices, multiple genetic conditions overlap with the autistic spectrum, with potential for confusion arising from phenocopies. Recent advances question the often presumed association between autism and intellectual disability and/or epilepsy. Autism is currently understood as a final common phenotypical pathway resulting from an indefinite number of genetic variations, possibly involving the same information processing pathways, and producing a variant in the way humans perceive, memorize, manipulate, and attribute emotional value to available information. Findings plausibly converge on more optional, rather than typically mandatory, hierarchies of information processing as fundamental to autism. Adaptation of education and employment according to individual strengths and needs, as well as attention to co-occurring conditions as necessary, remains today the best way to assist autistic individuals.

PMID: 23622174 [PubMed - indexed for MEDLINE]

De Novo Loss-of-Function Mutations in SETD5, Encoding a Methyltransferase in a 3p25 Microdeletion Syndrome Critical Region, Cause Intellectual Disability.

April 1, 2014 - 7:50am

De Novo Loss-of-Function Mutations in SETD5, Encoding a Methyltransferase in a 3p25 Microdeletion Syndrome Critical Region, Cause Intellectual Disability.

Am J Hum Genet. 2014 Mar 26;

Authors: Grozeva D, Carss K, Spasic-Boskovic O, Parker MJ, Archer H, Firth HV, Park SM, Canham N, Holder SE, Wilson M, Hackett A, Field M, Floyd JA, UK10K Consortium, Hurles M, Raymond FL

Abstract
To identify further Mendelian causes of intellectual disability (ID), we screened a cohort of 996 individuals with ID for variants in 565 known or candidate genes by using a targeted next-generation sequencing approach. Seven loss-of-function (LoF) mutations-four nonsense (c.1195A>T [p.Lys399(∗)], c.1333C>T [p.Arg445(∗)], c.1866C>G [p.Tyr622(∗)], and c.3001C>T [p.Arg1001(∗)]) and three frameshift (c.2177_2178del [p.Thr726Asnfs(∗)39], c.3771dup [p.Ser1258Glufs(∗)65], and c.3856del [p.Ser1286Leufs(∗)84])-were identified in SETD5, a gene predicted to encode a methyltransferase. All mutations were compatible with de novo dominant inheritance. The affected individuals had moderate to severe ID with additional variable features of brachycephaly; a prominent high forehead with synophrys or striking full and broad eyebrows; a long, thin, and tubular nose; long, narrow upslanting palpebral fissures; and large, fleshy low-set ears. Skeletal anomalies, including significant leg-length discrepancy, were a frequent finding in two individuals. Congenital heart defects, inguinal hernia, or hypospadias were also reported. Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features. SETD5 lies within the critical interval for 3p25 microdeletion syndrome. The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in this condition. Our findings add to the growing evidence that mutations in genes encoding methyltransferases regulating histone modification are important causes of ID. This analysis provides sufficient evidence that rare de novo LoF mutations in SETD5 are a relatively frequent (0.7%) cause of ID.

PMID: 24680889 [PubMed - as supplied by publisher]

Sex differences in Attention Deficit Hyperactivity Disorder: candidate genetic and endocrine mechanisms.

April 1, 2014 - 7:50am

Sex differences in Attention Deficit Hyperactivity Disorder: candidate genetic and endocrine mechanisms.

Front Neuroendocrinol. 2014 Mar 25;

Authors: Davies W

Abstract
Attention Deficit Hyperactivity Disorder (ADHD) is a developmental condition characterised by severe inattention, pathological impulsivity and hyperactivity; it is relatively common affecting up to 6% of children, and is associated with a risk of long-term adverse educational and social consequences. Males are considerably more likely to be diagnosed with ADHD than females; the course of the disorder and its associated co-morbidities also appear to be sensitive to sex. Here, I discuss fundamental biological (genetic and endocrine) mechanisms that have been shown to, or could theoretically, contribute towards these sexually dimorphic phenomena. Greater understanding of how and why the sexes differ with respect to ADHD vulnerability should allow us to identify and characterise novel protective and risk factors for the disorder, and should ultimately facilitate improved diagnosis, prognosis and treatment.

PMID: 24680800 [PubMed - as supplied by publisher]

Prevalence, comorbidity and heritability of hoarding symptoms in adolescence: a population based twin study in 15-year olds.

April 1, 2014 - 7:50am
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Prevalence, comorbidity and heritability of hoarding symptoms in adolescence: a population based twin study in 15-year olds.

PLoS One. 2013;8(7):e69140

Authors: Ivanov VZ, Mataix-Cols D, Serlachius E, Lichtenstein P, Anckarsäter H, Chang Z, Gumpert CH, Lundström S, Långström N, Rück C

Abstract
BACKGROUND: Hoarding Disorder (HD) is often assumed to be an 'old age' problem, but many individuals diagnosed with HD retrospectively report first experiencing symptoms in childhood or adolescence. We examined the prevalence, comorbidity and etiology of hoarding symptoms in adolescence.
METHODS: To determine the presence of clinically significant hoarding symptoms, a population-based sample of 15-year old twins (N = 3,974) completed the Hoarding Rating Scale-Self Report. Co-occurring Obsessive Compulsive Disorder (OCD), Autism Spectrum Disorders (ASD) and Attention Deficit Hyperactivity Disorder (ADHD) were estimated from parental report. Model-fitting analyses divided hoarding symptom scores into additive genetic, shared, and non-shared environmental effects.
RESULTS: The prevalence of clinically significant hoarding symptoms was 2% (95% CI 1.6-2.5%), with a significantly higher prevalence in girls than boys. Exclusion of the clutter criterion (as adolescents do not have control over their environment) increased the prevalence rate to 3.7% (95% CI 3.1-4.3%). Excessive acquisition was reported by 30-40% among those with clinically significant hoarding symptoms. The prevalence of co-occurring OCD (2.9%), ASD (2.9%) and ADHD (10.0%) was comparable in hoarding and non-hoarding teenagers. Model-fitting analyses suggested that, in boys, additive genetic (32%; 95% CI 13-44%) and non-shared environmental effects accounted for most of the variance. In contrast, among girls, shared and non-shared environmental effects explained most of the variance, while additive genetic factors played a negligible role.
CONCLUSIONS: Hoarding symptoms are relatively prevalent in adolescents, particularly in girls, and cause distress and/or impairment. Hoarding was rarely associated with other common neurodevelopmental disorders, supporting its DSM-5 status as an independent diagnosis. The relative importance of genetic and shared environmental factors for hoarding differed across sexes. The findings are suggestive of dynamic developmental genetic and environmental effects operating from adolescence onto adulthood.

PMID: 23874893 [PubMed - indexed for MEDLINE]

Genetic Risk for Attention-Deficit/Hyperactivity Disorder Contributes to Neurodevelopmental Traits in the General Population.

March 29, 2014 - 8:25am

Genetic Risk for Attention-Deficit/Hyperactivity Disorder Contributes to Neurodevelopmental Traits in the General Population.

Biol Psychiatry. 2014 Feb 25;

Authors: Martin J, Hamshere ML, Stergiakouli E, O'Donovan MC, Thapar A

Abstract
BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) can be viewed as the extreme end of traits in the general population. Epidemiological and twin studies suggest that ADHD frequently co-occurs with and shares genetic susceptibility with autism spectrum disorder (ASD) and ASD-related traits. The aims of this study were to determine whether a composite of common molecular genetic variants, previously found to be associated with clinically diagnosed ADHD, predicts ADHD and ASD-related traits in the general population.
METHODS: Polygenic risk scores were calculated in the Avon Longitudinal Study of Parents and Children (ALSPAC) population sample (N = 8229) based on a discovery case-control genome-wide association study of childhood ADHD. Regression analyses were used to assess whether polygenic scores predicted ADHD traits and ASD-related measures (pragmatic language abilities and social cognition) in the ALSPAC sample. Polygenic scores were also compared in boys and girls endorsing any (rating ≥1) ADHD item (n = 3623).
RESULTS: Polygenic risk for ADHD showed a positive association with ADHD traits (hyperactive-impulsive, p = .0039; inattentive, p = .037). Polygenic risk for ADHD was also negatively associated with pragmatic language abilities (p = .037) but not with social cognition (p = .43). In children with a rating ≥1 for ADHD traits, girls had a higher polygenic score than boys (p = .003).
CONCLUSIONS: These findings provide molecular genetic evidence that risk alleles for the categorical disorder of ADHD influence hyperactive-impulsive and attentional traits in the general population. The results further suggest that common genetic variation that contributes to ADHD diagnosis may also influence ASD-related traits, which at their extreme are a characteristic feature of ASD.

PMID: 24673882 [PubMed - as supplied by publisher]

Patches of disorganization in the neocortex of children with autism.

March 29, 2014 - 8:25am
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Patches of disorganization in the neocortex of children with autism.

N Engl J Med. 2014 Mar 27;370(13):1209-19

Authors: Stoner R, Chow ML, Boyle MP, Sunkin SM, Mouton PR, Roy S, Wynshaw-Boris A, Colamarino SA, Lein ES, Courchesne E

Abstract
BACKGROUND: Autism involves early brain overgrowth and dysfunction, which is most strongly evident in the prefrontal cortex. As assessed on pathological analysis, an excess of neurons in the prefrontal cortex among children with autism signals a disturbance in prenatal development and may be concomitant with abnormal cell type and laminar development.
METHODS: To systematically examine neocortical architecture during the early years after the onset of autism, we used RNA in situ hybridization with a panel of layer- and cell-type-specific molecular markers to phenotype cortical microstructure. We assayed markers for neurons and glia, along with genes that have been implicated in the risk of autism, in prefrontal, temporal, and occipital neocortical tissue from postmortem samples obtained from children with autism and unaffected children between the ages of 2 and 15 years.
RESULTS: We observed focal patches of abnormal laminar cytoarchitecture and cortical disorganization of neurons, but not glia, in prefrontal and temporal cortical tissue from 10 of 11 children with autism and from 1 of 11 unaffected children. We observed heterogeneity between cases with respect to cell types that were most abnormal in the patches and the layers that were most affected by the pathological features. No cortical layer was uniformly spared, with the clearest signs of abnormal expression in layers 4 and 5. Three-dimensional reconstruction of layer markers confirmed the focal geometry and size of patches.
CONCLUSIONS: In this small, explorative study, we found focal disruption of cortical laminar architecture in the cortexes of a majority of young children with autism. Our data support a probable dysregulation of layer formation and layer-specific neuronal differentiation at prenatal developmental stages. (Funded by the Simons Foundation and others.).

PMID: 24670167 [PubMed - in process]

Establishing a reference group for distal 18q-: clinical description and molecular basis.

March 29, 2014 - 8:25am
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Establishing a reference group for distal 18q-: clinical description and molecular basis.

Hum Genet. 2014 Feb;133(2):199-209

Authors: Cody JD, Hasi M, Soileau B, Heard P, Carter E, Sebold C, O'Donnell L, Perry B, Stratton RF, Hale DE

Abstract
Although constitutional chromosome abnormalities have been recognized since the 1960s, clinical characterization and development of treatment options have been hampered by their obvious genetic complexity and relative rarity. Additionally, deletions of 18q are particularly heterogeneous, with no two people having the same breakpoints. We identified 16 individuals with deletions that, despite unique breakpoints, encompass the same set of genes within a 17.6-Mb region. This group represents the most genotypically similar group yet identified with distal 18q deletions. As the deletion is of average size when compared with other 18q deletions, this group can serve as a reference point for the clinical and molecular description of this condition. We performed a thorough medical record review as well as a series of clinical evaluations on 14 of the 16 individuals. Common functional findings included developmental delays, hypotonia, growth hormone deficiency, and hearing loss. Structural anomalies included foot anomalies, ear canal atresia/stenosis, and hypospadias. The majority of individuals performed within the low normal range of cognitive ability but had more serious deficits in adaptive abilities. Of interest, the hemizygous region contains 38 known genes, 26 of which are sufficiently understood to tentatively determine dosage sensitivity. Published data suggest that 20 are unlikely to cause an abnormal phenotype in the hemizygous state and five are likely to be dosage sensitive: TNX3, NETO1, ZNF407, TSHZ1, and NFATC. A sixth gene, ATP9B, may be conditionally dosage sensitive. Not all distal 18q- phenotypes can be attributed to these six genes; however, this is an important advance in the molecular characterization of 18q deletions.

PMID: 24092497 [PubMed - indexed for MEDLINE]

Cholesterol metabolism deficiency.

March 29, 2014 - 8:25am
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Cholesterol metabolism deficiency.

Handb Clin Neurol. 2013;113:1845-50

Authors: Jira P

Abstract
Genetic defects in enzymes responsible for cholesterol biosynthesis have emerged as important causes of congenital dysmorphology and retardation syndromes. Cholesterol is an important constituent of the cell membrane of most eukaryotic cells, in myelin formation in the brain, spinal cord, and peripheral nervous system, and acts as the precursor for steroid hormones and bile acids. Finally, cholesterol has important interactions with proteins, which control embryonic development. To date, eight distinct inherited disorders have been linked to different defects in cholesterol biosynthesis. Two result from an enzyme defect in the pre-squalene segment of the pathway: the classical form of mevalonic aciduria and the hyperimmunoglobulinemia D syndrome, also known as Dutch-type periodic fever. Six defects in the post-squalene segment of the pathway include: Smith-Lemli-Opitz syndrome, two X-linked dominant inherited and male-lethal disorders, Conradi-Hünermann-Happle syndrome and congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD), and at least three extremely rare autosomal recessive disorders, Greenberg skeletal dysplasia, lathosterolosis, and desmosterolosis. All these inborn errors known to date have been linked to deficiency of specific enzymes on the basis of elevated levels of specific sterol intermediates in tissues of affected patients followed by demonstrating disease-causing mutations in the encoding genes. These cholesterol deficiency multiple malformation-retardation syndromes have clinical overlap. Besides psychomotor retardation, developmental delay, structural brain malformations, multiple congenital anomalies, microcephaly, and cataract, impaired cholesterol biosynthesis is associated with autism and other behavioral disorders.

PMID: 23622407 [PubMed - indexed for MEDLINE]

Creatine deficiency syndromes.

March 29, 2014 - 8:25am
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Creatine deficiency syndromes.

Handb Clin Neurol. 2013;113:1837-43

Authors: Schulze A

Abstract
The lack of creatine in the central nervous system causes a severe but treatable neurological disease. Three inherited defects, AGAT, GAMT, and CrT deficiency, compromising synthesis and transport of creatine have been discovered recently. Together these so-called creatine deficiency syndromes (CDS) might represent the most frequent metabolic disorders with a primarily neurological phenotype. Patients with CDS present with global developmental delays, mental retardation, speech impairment especially affecting active language, seizures, extrapyramidal movement disorder, and autism spectrum disorder. The two defects in the creatine synthesis, AGAT and GAMT, are autosomal recessive disorders. They can be diagnosed by analysis of the creatine, guanidinoacetate, and creatinine in body fluids. Treatment is available and, especially when introduced in infancy, has a good outcome. The defect of creatine transport, CrT, is an X-linked condition and perhaps the most frequent reasons for X-linked mental retardation. Diagnosis is made by an increased ratio of creatine to creatinine in urine, but successful treatment still needs to be explored. CDS are under-diagnosed because easy to miss in standard diagnostic workup. Because CDS represent a frequent cause of cognitive and neurological impairment that is treatable they warrant consideration in the workup for genetic mental retardation syndromes, for intractable seizure disorders, and for neurological diseases with a predominant lack of active speech.

PMID: 23622406 [PubMed - indexed for MEDLINE]

Outfoxed by RBFOX1-A caution about ascertainment bias.

March 26, 2014 - 6:37am

Outfoxed by RBFOX1-A caution about ascertainment bias.

Am J Med Genet A. 2014 Mar 24;

Authors: Kamien B, Lionel AC, Bain N, Scherer SW, Hunter M

Abstract
We report on two patients with intragenic deletions of RBFOX1 and one patient with an intragenic duplication of RBFOX1. These patients, by report, all had autism spectrum disorder and/or developmental delay and had strong family histories of these conditions. We initially hypothesized that RBFOX1 was another susceptibility locus for autism spectrum disorder or developmental delay. However, epidemiological evidence examining large numbers of individuals did not support this hypothesis and the data presented here suggests that RBFOX1 intragenic copy number variants are not pathogenic. This contradicts previous reports that examined smaller numbers of patients and controls. © 2014 Wiley Periodicals, Inc.

PMID: 24664471 [PubMed - as supplied by publisher]

Epigenetic findings in autism: new perspectives for therapy.

March 26, 2014 - 6:37am
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Epigenetic findings in autism: new perspectives for therapy.

Int J Environ Res Public Health. 2013 Sep;10(9):4261-73

Authors: Siniscalco D, Cirillo A, Bradstreet JJ, Antonucci N

Abstract
Autism and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders characterized by dysfunctions in social interactions, communications, restricted interests, and repetitive stereotypic behaviors. Despite extensive genetic and biological research, significant controversy surrounds our understanding of the specific mechanisms of their pathogenesis. However, accumulating evidence points to the involvement of epigenetic modifications as foundational in creating ASD pathophysiology. Epigenetic modifications or the alteration of DNA transcription via variations in DNA methylation and histone modifications but without alterations in the DNA sequence, affect gene regulation. These alterations in gene expression, obtained through DNA methylation and/or histone modifications, result from transcriptional regulatory influences of environmental factors, such as nutritional deficiencies, various toxicants, immunological effects, and pharmaceuticals. As such these effects are epigenetic regulators which determine the final biochemistry and physiology of the individual. In contrast to psychopharmacological interventions, bettering our understanding of how these gene-environmental interactions create autistic symptoms should facilitate the development of therapeutic targeting of gene expression for ASD biomedical care.

PMID: 24030655 [PubMed - indexed for MEDLINE]

Comparative RNA editing in autistic and neurotypical cerebella.

March 26, 2014 - 6:37am
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Comparative RNA editing in autistic and neurotypical cerebella.

Mol Psychiatry. 2013 Sep;18(9):1041-8

Authors: Eran A, Li JB, Vatalaro K, McCarthy J, Rahimov F, Collins C, Markianos K, Margulies DM, Brown EN, Calvo SE, Kohane IS, Kunkel LM

Abstract
Adenosine-to-inosine (A-to-I) RNA editing is a neurodevelopmentally regulated epigenetic modification shown to modulate complex behavior in animals. Little is known about human A-to-I editing, but it is thought to constitute one of many molecular mechanisms connecting environmental stimuli and behavioral outputs. Thus, comprehensive exploration of A-to-I RNA editing in human brains may shed light on gene-environment interactions underlying complex behavior in health and disease. Synaptic function is a main target of A-to-I editing, which can selectively recode key amino acids in synaptic genes, directly altering synaptic strength and duration in response to environmental signals. Here, we performed a high-resolution survey of synaptic A-to-I RNA editing in a human population, and examined how it varies in autism, a neurodevelopmental disorder in which synaptic abnormalities are a common finding. Using ultra-deep (>1000 × ) sequencing, we quantified the levels of A-to-I editing of 10 synaptic genes in postmortem cerebella from 14 neurotypical and 11 autistic individuals. A high dynamic range of editing levels was detected across individuals and editing sites, from 99.6% to below detection limits. In most sites, the extreme ends of the population editing distributions were individuals with autism. Editing was correlated with isoform usage, clusters of correlated sites were identified, and differential editing patterns examined. Finally, a dysfunctional form of the editing enzyme adenosine deaminase acting on RNA B1 was found more commonly in postmortem cerebella from individuals with autism. These results provide a population-level, high-resolution view of A-to-I RNA editing in human cerebella and suggest that A-to-I editing of synaptic genes may be informative for assessing the epigenetic risk for autism.

PMID: 22869036 [PubMed - indexed for MEDLINE]

Allelic expression analysis in the brain suggests a role for heterogeneous insults affecting epigenetic processes in autism spectrum disorders.

March 25, 2014 - 6:02am

Allelic expression analysis in the brain suggests a role for heterogeneous insults affecting epigenetic processes in autism spectrum disorders.

Hum Mol Genet. 2014 Mar 21;

Authors: Ben-David E, Shohat S, Shifman S

Abstract
Monoallelic expression, including genomic imprinting, X-chromosome inactivation and random monoallelic expression of autosomal genes are epigenetic phenomena. Genes that are expressed in a monoallelic way may be more vulnerable to genetic or epigenetic mutations. Thus, comprehensive exploration of monoallelic expression in human brains may shed light on complex brain disorders. Autism-related disorders are known to be associated with imprinted genes on chromosome 15. However, it is not clear if other imprinted regions or other types of monoallelic expression are associated with autism spectrum disorder (ASD). Here, we performed a genome-wide survey of allele expression imbalance (AEI) in the human brain using single nucleotide polymorphisms (SNPs), in 18 individuals with ASD and 15 controls. Individuals with ASD had the most extreme number of monoallelic expressed SNPs in both the autosomes and the X chromosome. In two cases that were studied in detail the monoallelic expression was confined to specific brain region or cell type. Using these data we were also able to define the allelic expression status of known imprinted genes in the human brain, and to identify abnormal imprinting in an individual with ASD. Lastly, we developed an analysis of individual level expression, focusing on the difference of each individual from the mean. We found that individuals with ASD had more genes that were up or down-regulated in an individual-specific manner. We also identified pathways perturbed in specific individuals. These results underline the heterogeneity in gene regulation in ASD, at the level of both allelic and total expression.

PMID: 24659497 [PubMed - as supplied by publisher]

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