Publications by authors named "Ruth K Abramson"

40 Publications

Three Brothers With Autism Carry a Stop-Gain Mutation in the HPA-Axis Gene NR3C2.

Autism Res 2020 04 17;13(4):523-531. Epub 2020 Feb 17.

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida.

Whole exome sequencing and copy-number variant analysis was performed on a family with three brothers diagnosed with autism. Each of the siblings shares an alteration in the nuclear receptor subfamily 3 group C member 2 (NR3C2) gene that is predicted to result in a stop-gain mutation (p.Q919X) in the mineralocorticoid receptor (MR) protein. This variant was maternally inherited and provides further evidence for a connection between the NR3C2 and autism. Interestingly, the NR3C2 gene encodes the MR protein, a steroid hormone-regulated transcription factor that acts in the hypothalamic-pituitary-adrenal axis and has been connected to stress and anxiety, both of which are features often seen in individuals with autism. Autism Res 2020, 13: 523-531. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Given the complexity of the genetics underlying autism, each gene contributes to risk in a relatively small number of individuals, typically less than 1% of all autism cases. Whole exome sequencing of three brothers with autism identified a rare variant in the nuclear receptor subfamily 3 group C member 2 gene that is predicted to strongly interfere with its normal function. This gene encodes the mineralocorticoid receptor protein, which plays a role in how the body responds to stress and anxiety, features that are often elevated in people diagnosed with autism. This study adds further support to the relevance of this gene as a risk factor for autism.
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http://dx.doi.org/10.1002/aur.2269DOI Listing
April 2020

Pharmacotherapy of Autism Spectrum Disorder: Results from the Randomized BAART Clinical Trial.

Pharmacotherapy 2019 06 29;39(6):626-635. Epub 2019 May 29.

Department of Neuropsychiatry and Behavioral Sciences, University of South Carolina, Columbia, South Carolina.

The objective of this trial, Biomarkers in Autism of Aripiprazole and Risperidone Treatment (BAART), was to provide support and guidance for an evidence-based approach for the selection and monitoring of initial pharmacotherapy in patients with autism by assessing predictors of efficacy, tolerability, and safety. This randomized double-blind parallel-group study was conducted in three academic medical centers and a single private pediatric practice. Eighty children or adolescents (aged 6-17 yrs) with autistic disorder were enrolled, and 61 patients were randomized to the study drug. Of those patients, 51 completed the 10-week trial, and 31 completed an optional 12-week blinded extension phase. All patients were treated with 2 weeks of placebo before random assignment to receive aripiprazole (31 patients) or risperidone (30 patients) for 10 weeks. Sixteen placebo responders (20%) were excluded from further analysis. Drug dosing followed U.S. Food and Drug Administration (FDA) labeling, and weekly dosage adjustments were allowed until week 4; patients were then maintained on a fixed dose for 6 additional weeks. Safety, physical, and psychological assessments were recorded weekly or every 2 weeks. No significant differences in severity of illness between the aripiprazole and risperidone groups were noted at baseline. All patients significantly improved on the Aberrant Behavior Checklist-Irritability subscale after 1 week and continued for the remaining 9 weeks and the extension phase. Improvement was greatest in the risperidone group at every assessment period and was statistically significantly better than that in the aripiprazole group at weeks 3 and 6 (p<0.05). No dose-limiting adverse events occurred during the dose-titration period. Mean weight gain in the aripiprazole group was significantly less than that in the risperidone group at week 4 (0.62 vs 1.38 kg, p=0.033) and week 10 (1.61 vs 3.31 kg, p<0.001), but the difference became nonsignificant for the 31 patients completing the 3-month extension phase (4.36 vs 5.55 kg, p=0.26). Pharmacotherapy of patients with autism spectrum disorder resulted in behavioral improvement within 1 week and lasted at least 22 weeks. Weight gain occurred to a greater degree with risperidone than aripiprazole initially, but the differences became nonsignificant by the end of the trial. Our trial supports previous results of drug efficacy and safety in patients with autism spectrum disorder from other trials and extends the evidence-based support for choosing an FDA-approved drug for initial pharmacotherapy for autism spectrum disorder.
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http://dx.doi.org/10.1002/phar.2271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555676PMC
June 2019

Comparison of serum carnitine levels and clinical correlates between outpatients and acutely hospitalised individuals with bipolar disorder and schizophrenia: A cross-sectional study.

World J Biol Psychiatry 2016 Sep 1;17(6):475-9. Epub 2016 Jun 1.

e Departments of Mental Health and Psychiatry & Behavioral Science , Medical University of South Carolina , Charleston , SC , USA.

Objectives: We sought to compare serum carnitine levels and clinical correlates between stable outpatients and acutely hospitalised individuals with diagnoses of bipolar disorder and schizophrenia.

Methods: We obtained clinical information as well as serum levels for total and free carnitine, high-density lipoprotein (HDL) and triglycerides in 60 consenting individuals.

Results: We found higher total serum carnitine levels in our outpatient group in comparison to acutely hospitalised psychiatric patients, with a statistically significant P value of 0.045. Metabolic syndrome was more prevalent in the outpatient (37.9%) versus inpatient group (16.1%). We identified significantly higher carnitine levels in patients who met the criteria for metabolic syndrome in comparison to the patients without metabolic syndrome, with respective P values for total and free carnitine of 0.0048 and 0.0029.

Conclusions: This study revealed a complex relationship among carnitine metabolism, metabolic syndrome and behavioural outcomes. Future studies of carnitine metabolism in the context of mental illness as well as metabolic syndrome are warranted.
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http://dx.doi.org/10.1080/15622975.2016.1178803DOI Listing
September 2016

Candidate glutamatergic and dopaminergic pathway gene variants do not influence Huntington's disease motor onset.

Neurogenetics 2013 Nov 4;14(3-4):173-9. Epub 2013 May 4.

Center for Human Genetic Research, Massachusetts General Hospital, Simches Research Building, Room 5414, 185 Cambridge Street, Boston, MA, 02114, USA.

Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. It is caused by the expansion of the HTT CAG repeat, which is the major determinant of age at onset (AO) of motor symptoms. Aberrant function of N-methyl-D-aspartate receptors and/or overexposure to dopamine has been suggested to cause significant neurotoxicity, contributing to HD pathogenesis. We used genetic association analysis in 1,628 HD patients to evaluate candidate polymorphisms in N-methyl-D-aspartate receptor subtype genes (GRIN2A rs4998386 and rs2650427, and GRIN2B rs1806201) and functional polymorphisms in genes in the dopamine pathway (DAT1 3' UTR 40-bp variable number tandem repeat (VNTR), DRD4 exon 3 48-bp VNTR, DRD2 rs1800497, and COMT rs4608) as potential modifiers of the disease process. None of the seven polymorphisms tested was found to be associated with significant modification of motor AO, either in a dominant or additive model, after adjusting for ancestry. The results of this candidate-genetic study therefore do not provide strong evidence to support a modulatory role for these variations within glutamatergic and dopaminergic genes in the AO of HD motor manifestations.
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http://dx.doi.org/10.1007/s10048-013-0364-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3825533PMC
November 2013

Evaluating mitochondrial DNA variation in autism spectrum disorders.

Ann Hum Genet 2013 Jan 6;77(1):9-21. Epub 2012 Nov 6.

John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.

Despite the increasing speculation that oxidative stress and abnormal energy metabolism may play a role in Autism Spectrum Disorders (ASD), and the observation that patients with mitochondrial defects have symptoms consistent with ASD, there are no comprehensive published studies examining the role of mitochondrial variation in autism. Therefore, we have sought to comprehensively examine the role of mitochondrial DNA (mtDNA) variation with regard to ASD risk, employing a multi-phase approach. In phase 1 of our experiment, we examined 132 mtDNA single-nucleotide polymorphisms (SNPs) genotyped as part of our genome-wide association studies of ASD. In phase 2 we genotyped the major European mitochondrial haplogroup-defining variants within an expanded set of autism probands and controls. Finally in phase 3, we resequenced the entire mtDNA in a subset of our Caucasian samples (∼400 proband-father pairs). In each phase we tested whether mitochondrial variation showed evidence of association to ASD. Despite a thorough interrogation of mtDNA variation, we found no evidence to suggest a major role for mtDNA variation in ASD susceptibility. Accordingly, while there may be attractive biological hints suggesting the role of mitochondria in ASD our data indicate that mtDNA variation is not a major contributing factor to the development of ASD.
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http://dx.doi.org/10.1111/j.1469-1809.2012.00736.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535511PMC
January 2013

The expanding role of MBD genes in autism: identification of a MECP2 duplication and novel alterations in MBD5, MBD6, and SETDB1.

Autism Res 2012 Dec 10;5(6):385-97. Epub 2012 Oct 10.

John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL 33136, USA.

The methyl-CpG-binding domain (MBD) gene family was first linked to autism over a decade ago when Rett syndrome, which falls under the umbrella of autism spectrum disorders (ASDs), was revealed to be predominantly caused by MECP2 mutations. Since that time, MECP2 alterations have been recognized in idiopathic ASD patients by us and others. Individuals with deletions across the MBD5 gene also present with ASDs, impaired speech, intellectual difficulties, repetitive behaviors, and epilepsy. These findings suggest that further investigations of the MBD gene family may reveal additional associations related to autism. We now describe the first study evaluating individuals with ASD for rare variants in four autosomal MBD family members, MBD5, MBD6, SETDB1, and SETDB2, and expand our initial screening in the MECP2 gene. Each gene was sequenced over all coding exons and evaluated for copy number variations in 287 patients with ASD and an equal number of ethnically matched control individuals. We identified 186 alterations through sequencing, approximately half of which were novel (96 variants, 51.6%). We identified 17 ASD specific, nonsynonymous variants, four of which were concordant in multiplex families: MBD5 Tyr1269Cys, MBD6 Arg883Trp, MECP2 Thr240Ser, and SETDB1 Pro1067del. Furthermore, a complex duplication spanning of the MECP2 gene was identified in two brothers who presented with developmental delay and intellectual disability. From our studies, we provide the first examples of autistic patients carrying potentially detrimental alterations in MBD6 and SETDB1, thereby demonstrating that the MBD gene family potentially plays a significant role in rare and private genetic causes of autism.
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http://dx.doi.org/10.1002/aur.1251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528798PMC
December 2012

TAA repeat variation in the GRIK2 gene does not influence age at onset in Huntington's disease.

Biochem Biophys Res Commun 2012 Aug 3;424(3):404-8. Epub 2012 Jul 3.

Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.

Huntington's disease is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeat whose length is the major determinant of age at onset but remaining variation appears to be due in part to the effect of genetic modifiers. GRIK2, which encodes GluR6, a mediator of excitatory neurotransmission in the brain, has been suggested in several studies to be a modifier gene based upon a 3' untranslated region TAA trinucleotide repeat polymorphism. Prior to investing in detailed studies of the functional impact of this polymorphism, we sought to confirm its effect on age at onset in a much larger dataset than in previous investigations. We genotyped the HD CAG repeat and the GRIK2 TAA repeat in DNA samples from 2,911 Huntington's disease subjects with known age at onset, and tested for a potential modifier effect of GRIK2 using a variety of statistical approaches. Unlike previous reports, we detected no evidence of an influence of the GRIK2 TAA repeat polymorphism on age at motor onset. Similarly, the GRIK2 polymorphism did not show significant modifier effect on psychiatric and cognitive age at onset in HD. Comprehensive analytical methods applied to a much larger sample than in previous studies do not support a role for GRIK2 as a genetic modifier of age at onset of clinical symptoms in Huntington's disease.
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http://dx.doi.org/10.1016/j.bbrc.2012.06.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3752397PMC
August 2012

Evaluation of copy number variations reveals novel candidate genes in autism spectrum disorder-associated pathways.

Hum Mol Genet 2012 Aug 27;21(15):3513-23. Epub 2012 Apr 27.

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.

Autism spectrum disorders (ASDs) are highly heritable, yet relatively few associated genetic loci have been replicated. Copy number variations (CNVs) have been implicated in autism; however, the majority of loci contribute to <1% of the disease population. Therefore, independent studies are important to refine associated CNV regions and discover novel susceptibility genes. In this study, a genome-wide SNP array was utilized for CNV detection by two distinct algorithms in a European ancestry case-control data set. We identify a significantly higher burden in the number and size of deletions, and disrupting more genes in ASD cases. Moreover, 18 deletions larger than 1 Mb were detected exclusively in cases, implicating novel regions at 2q22.1, 3p26.3, 4q12 and 14q23. Case-specific CNVs provided further evidence for pathways previously implicated in ASDs, revealing new candidate genes within the GABAergic signaling and neural development pathways. These include DBI, an allosteric binder of GABA receptors, GABARAPL1, the GABA receptor-associated protein, and SLC6A11, a postsynaptic GABA transporter. We also identified CNVs in COBL, deletions of which cause defects in neuronal cytoskeleton morphogenesis in model vertebrates, and DNER, a neuron-specific Notch ligand required for cerebellar development. Moreover, we found evidence of genetic overlap between ASDs and other neurodevelopmental and neuropsychiatric diseases. These genes include glutamate receptors (GRID1, GRIK2 and GRIK4), synaptic regulators (NRXN3, SLC6A8 and SYN3), transcription factor (ZNF804A) and RNA-binding protein FMR1. Taken together, these CNVs may be a few of the missing pieces of ASD heritability and lead to discovering novel etiological mechanisms.
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http://dx.doi.org/10.1093/hmg/dds164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392110PMC
August 2012

Common SNP-based haplotype analysis of the 4p16.3 Huntington disease gene region.

Am J Hum Genet 2012 Mar 1;90(3):434-44. Epub 2012 Mar 1.

Center for Human Genetic Research, Massachusetts General Hospital, Boston, 02114, USA.

Age at the onset of motor symptoms in Huntington disease (HD) is determined largely by the length of a CAG repeat expansion in HTT but is also influenced by other genetic factors. We tested whether common genetic variation near the mutation site is associated with differences in the distribution of expanded CAG alleles or age at the onset of motor symptoms. To define disease-associated single-nucleotide polymorphisms (SNPs), we compared 4p16.3 SNPs in HD subjects with population controls in a case:control strategy, which revealed that the strongest signals occurred at a great distance from the HD mutation as a result of "synthetic association" with SNP alleles that are of low frequency in population controls. Detailed analysis delineated a prominent ancestral haplotype that accounted for ∼50% of HD chromosomes and extended to at least 938 kb on about half of these. Together, the seven most abundant haplotypes accounted for ∼83% of HD chromosomes. Neither the extended shared haplotype nor the individual local HTT haplotypes were associated with altered CAG-repeat length distribution or residual age at the onset of motor symptoms, arguing against modification of these disease features by common cis-regulatory elements. Similarly, the 11 most frequent control haplotypes showed no trans-modifier effect on age at the onset of motor symptoms. Our results argue against common local regulatory variation as a factor influencing HD pathogenesis, suggesting that genetic modifiers be sought elsewhere in the genome. They also indicate that genome-wide association analysis with a small number of cases can be effective for regional localization of genetic defects, even when a founder effect accounts for only a fraction of the disorder.
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http://dx.doi.org/10.1016/j.ajhg.2012.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3309179PMC
March 2012

Serum carnitine levels and levocarnitine supplementation in institutionalized Huntington's disease patients.

Neurol Sci 2013 Jan;34(1):93-8

Department of Mental Health, University of South Carolina School of Medicine, Columbia, SC, USA.

Along with antioxidant properties, carnitine is an important regulator of lipid metabolism in humans. While beneficial effects of carnitine have been demonstrated in animal models of Huntington's disease (HD), metabolism of carnitine has not been studied in humans with this illness. In this retrospective database review from 23 patients admitted to a HD-specialized nursing home unit, we found a relatively high prevalence of hypocarnitinemia (6 cases, 26%). Our review suggests that catabolism and chronic valproate use predisposed our patients to develop hypocarnitinemia. The patients with low serum carnitine levels who received levocarnitine supplementation, during a mean period of 7.3 months, showed improvement in motor, cognitive and behavioral measures. We hypothesize that observed improvement related to the resolution of reversible metabolic encephalopathy and myopathy associated with secondary carnitine deficiency. In conclusion, notwithstanding its limitations, this is the first study to report measurements of carnitine levels in HD patients, revealing relatively high prevalence of hypocarnitinemia in our population. Our findings suggest that HD patients with hypocarnitinemia may benefit from low-dose levocarnitine supplementation. Further studies of carnitine metabolism and supplementation in HD patients are warranted.
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http://dx.doi.org/10.1007/s10072-012-0952-xDOI Listing
January 2013

Exploring the relationship between autism spectrum disorder and epilepsy using latent class cluster analysis.

J Autism Dev Disord 2012 Aug;42(8):1630-41

Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL 33136, USA.

Epilepsy co-occurs frequently in autism spectrum disorders (ASD). Understanding this co-occurrence requires a better understanding of the ASD-epilepsy phenotype (or phenotypes). To address this, we conducted latent class cluster analysis (LCCA) on an ASD dataset (N = 577) which included 64 individuals with epilepsy. We identified a 5-cluster solution with one cluster showing a high rate of epilepsy (29%), earlier age at first recognition, and high rates of repetitive object use and unusual sensory interests. We also conducted LCCA on an ASD-epilepsy subset from the overall dataset (N = 64) which yielded three clusters, the largest of which had impairments in language and motor development; the remaining clusters, while not as developmentally impaired were characterized by different levels of repetitive and sensory behaviors.
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http://dx.doi.org/10.1007/s10803-011-1402-yDOI Listing
August 2012

An X chromosome-wide association study in autism families identifies TBL1X as a novel autism spectrum disorder candidate gene in males.

Mol Autism 2011 Nov 4;2(1):18. Epub 2011 Nov 4.

Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, PO Box 019132 (M-860), Miami, FL 33101, USA.

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic component. The skewed prevalence toward males and evidence suggestive of linkage to the X chromosome in some studies suggest the presence of X-linked susceptibility genes in people with ASD.

Methods: We analyzed genome-wide association study (GWAS) data on the X chromosome in three independent autism GWAS data sets: two family data sets and one case-control data set. We performed meta- and joint analyses on the combined family and case-control data sets. In addition to the meta- and joint analyses, we performed replication analysis by using the two family data sets as a discovery data set and the case-control data set as a validation data set.

Results: One SNP, rs17321050, in the transducin β-like 1X-linked (TBL1X) gene [OMIM:300196] showed chromosome-wide significance in the meta-analysis (P value = 4.86 × 10-6) and joint analysis (P value = 4.53 × 10-6) in males. The SNP was also close to the replication threshold of 0.0025 in the discovery data set (P = 5.89 × 10-3) and passed the replication threshold in the validation data set (P = 2.56 × 10-4). Two other SNPs in the same gene in linkage disequilibrium with rs17321050 also showed significance close to the chromosome-wide threshold in the meta-analysis.

Conclusions: TBL1X is in the Wnt signaling pathway, which has previously been implicated as having a role in autism. Deletions in the Xp22.2 to Xp22.3 region containing TBL1X and surrounding genes are associated with several genetic syndromes that include intellectual disability and autistic features. Our results, based on meta-analysis, joint analysis and replication analysis, suggest that TBL1X may play a role in ASD risk.
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http://dx.doi.org/10.1186/2040-2392-2-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3305893PMC
November 2011

Copy number variants in extended autism spectrum disorder families reveal candidates potentially involved in autism risk.

PLoS One 2011 7;6(10):e26049. Epub 2011 Oct 7.

John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, United States of America.

Copy number variations (CNVs) are a major cause of genetic disruption in the human genome with far more nucleotides being altered by duplications and deletions than by single nucleotide polymorphisms (SNPs). In the multifaceted etiology of autism spectrum disorders (ASDs), CNVs appear to contribute significantly to our understanding of the pathogenesis of this complex disease. A unique resource of 42 extended ASD families was genotyped for over 1 million SNPs to detect CNVs that may contribute to ASD susceptibility. Each family has at least one avuncular or cousin pair with ASD. Families were then evaluated for co-segregation of CNVs in ASD patients. We identified a total of five deletions and seven duplications in eleven families that co-segregated with ASD. Two of the CNVs overlap with regions on 7p21.3 and 15q24.1 that have been previously reported in ASD individuals and two additional CNVs on 3p26.3 and 12q24.32 occur near regions associated with schizophrenia. These findings provide further evidence for the involvement of ICA1 and NXPH1 on 7p21.3 in ASD susceptibility and highlight novel ASD candidates, including CHL1, FGFBP3 and POUF41. These studies highlight the power of using extended families for gene discovery in traits with a complex etiology.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0026049PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3189231PMC
February 2012

Microduplications in an autism multiplex family narrow the region of susceptibility for developmental disorders on 15q24 and implicate 7p21.

Am J Med Genet B Neuropsychiatr Genet 2011 Jun 7;156B(4):493-501. Epub 2011 Apr 7.

John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Florida, USA.

Copy number variations (CNVs) play a crucial role in the intricate genetics of autism spectrum disorders. A region on chromosome 15q24 vulnerable to both deletions and duplications has been previously implicated in a range of phenotypes including autism, Asperger's syndrome, delayed development, and mild to severe mental retardation. Prior studies have delineated a minimal critical region of approximately 1.33 Mb. In this study, a multiplex autism family was evaluated for CNVs using genotyping data from the Illumina 1 M BeadChip and analyzed with the PennCNV algorithm. Variants were then identified that co-segregate with autism features in this family. Here, we report autistic first cousins who carry two microduplications concordant with disease. Both duplications were inherited maternally and found to be identical by descent. The first is an approximately 10,000 base pair microduplication within the minimal region on 15q24 that falls across a single gene, ubiquitin-like 7. This is the smallest duplication in the region to result in a neuropsychiatric disorder, potentially narrowing the critical region for susceptibility to developmental and autism spectrum disorders. The second is a novel, 352 kb tandem duplication on 7p21 that replicates part of the neurexophilin 1 and islet cell autoantigen 1 genes. The breakpoint junction falls within the intronic regions of these genes and demonstrates a microhomology of four base pairs. Each of these microduplications may contribute to the complex etiology of autism spectrum disorders.
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http://dx.doi.org/10.1002/ajmg.b.31188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490366PMC
June 2011

A de novo 1.5 Mb microdeletion on chromosome 14q23.2-23.3 in a patient with autism and spherocytosis.

Autism Res 2011 Jun 28;4(3):221-7. Epub 2011 Feb 28.

John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida 33136, USA.

Autism is a neuro-developmental disorder characterized by deficits in social interaction and communication as well as restricted interests or repetitive behaviors. Cytogenetic studies have implicated large chromosomal aberrations in the etiology of approximately 5-7% of autism patients, and the recent advent of array-based techniques allows the exploration of submicroscopic copy number variations (CNVs). We genotyped a 14-year-old boy with autism, spherocytosis and other physical dysmorphia, his parents, and two non-autistic siblings with the Illumina Human 1M Beadchip as part of a study of the molecular genetics of autism and determined copy number variants using the PennCNV algorithm. We identified and validated a de novo 1.5 Mb microdeletion of 14q23.2-23.3 in our autistic patient. This region contains 15 genes, including spectrin beta (SPTB), encoding a cytoskeletal protein previously associated with spherocytosis, methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), a folate metabolizing enzyme previously associated with bipoloar disorder and schizophrenia, pleckstrin homology domain-containing family G member 3 (PLEKHG3), a guanide nucleotide exchange enriched in the brain, and churchill domain containing protein 1 (CHURC1), homologs of which regulate neuronal development in model organisms. While a similar deletion has previously been reported in a family with spherocytosis, severe learning disabilities, and mild mental retardation, this is the first implication of chr14q23.2-23.3 in the etiology of autism and points to MTHFD1, PLEKHG3, and CHURC1 as potential candidate genes contributing to autism risk.
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http://dx.doi.org/10.1002/aur.186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110642PMC
June 2011

Carnitine and metabolic correlates in hospitalized psychiatric patients: a follow-through report.

J Psychiatr Pract 2011 Jan;17(1):35-40

South Carolina Department of Mental Health and University of South Carolina School of Medicine, SC 29203, USA.

Background: Carnitine deficiency may be encountered in the context of chronic psychiatric illness, particularly with the chronic use of valproic acid. Despite the importance of carnitine in lipid metabolism and mitochondrial function, its metabolic effects have not been studied in a psychiatric population.

Objective: To raise awareness regarding the possible metabolic implications of carnitine homeostasis in psychiatric patients.

Method: Retrospective database review in a subgroup of 23 patients with documented hypo carnitinemia.

Results: Statistical analysis revealed a negative correlation between serum carnitine levels and lipid levels. Initial fasting plasma glucose levels correlated positively with acylcarnitine/free carnitine ratios, suggesting unfavorable secondary effects of carnitine insufficiency, which resolved once carnitine was supplemented.

Conclusion: Carnitine is a plausible substrate for future investigations of metabolic status in psychiatric patients. Further studies are needed to evaluate whether serum carnitine levels may be useful as a marker for psychiatric patients at risk for developing metabolic syndrome, and whether carnitine supplementation may reduce that risk. (Journal of Psychiatric Practice 2011;17:35-40).
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http://dx.doi.org/10.1097/01.pra.0000393842.63841.bcDOI Listing
January 2011

Clinical correlates of low serum carnitine levels in hospitalized psychiatric patients.

World J Biol Psychiatry 2011 Feb 29;12(1):73-9. Epub 2010 Jun 29.

South Carolina Department of Mental Health and Department of Neuropsychiatry and Behavioral Science, University of South Carolina School of Medicine, Columbia, SC, USA.

Objective: We sought to evaluate clinical correlates of low serum carnitine levels in hospitalized psychiatric patients.

Methods: We retrospectively reviewed the charts of 40 psychiatric inpatients identified to have low serum carnitine levels.

Results: Cognitive impairment was present in 38 (95%) cases, frequently accompanied by imbalance, agitation and extrapyramidal symptoms. Valproate therapy was encountered in 28 (70%) patients. The dosage of valproate negatively correlated with total and free carnitine levels (P = 0.003 and 0.0136). Polypharmacy also affected carnitine levels, indicating additional modulatory effects on carnitine metabolism. We encountered a disproportionately high prevalence of mental retardation and dementia in association with hypocarnitinemia.

Conclusion: We hypothesize that in the context of mental illness hypocarnitinemia may be associated with metabolic encephalopathy and cognitive impairment. As carnitine deficiency is a potentially treatable condition further studies are warranted.
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http://dx.doi.org/10.3109/15622975.2010.489619DOI Listing
February 2011

Clinical outcomes and low-dose levocarnitine supplementation in psychiatric inpatients with documented hypocarnitinemia: a retrospective chart review.

J Psychiatr Pract 2010 Jan;16(1):5-14

South Carolina Department of Mental Health and University of South Carolina School of Medicine, Columbia, SC,

Background: Metabolic encephalopathy is one of the crucial manifestations of carnitine deficiency. In psychiatric patients, low serum carnitine levels may result from chronic valproate therapy. Despite the widespread use of valproate in psychiatry, neither carnitine deficiency nor supplementation has been studied in a psychiatric population.

Objective: To describe clinical outcomes in hospitalized psychiatric patients with documented hypocarnitinemia who were receiving oral levocarnitine supplementation.

Method: Retrospective chart review.

Results: In 38 patients with hypocarnitinemia, a low-dose oral levocarnitine supplementation, in association with comprehensive psychiatric therapy, did not result in any adverse psychiatric or medical outcomes, and was associated with overall improved behavioral, cognitive, and motor functioning. Initially all patients had some degree of cognitive impairment, but after correction of carnitine serum levels, scores on the Mini-Mental State Examination (MMSE) improved in most of the patients (mean improvement 5.5 points, P <0.0001), and normalized in 11 cases. This allowed a correction of the diagnosis in 8 of 14 patients who had initially been diagnosed with dementia. African-American patients achieved significantly lower serum carnitine levels and MMSE scores than Caucasian patients with comparable therapy.

Conclusion: We hypothesize that correction of carnitine depletion, either by levocarnitine supplementation or by valproate dose reduction, may enhance recovery from hypocarnitinemia-associated encephalopathy in psychiatric patients. Our findings also suggest that ethnic traits may affect carnitine bioavailability as well as cognitive outcomes in this clinical context. Further studies of carnitine metabolism and supplementation in psychiatric patients are warranted.
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http://dx.doi.org/10.1097/01.pra.0000367773.03636.d1DOI Listing
January 2010

Novel variants identified in methyl-CpG-binding domain genes in autistic individuals.

Neurogenetics 2010 Jul 18;11(3):291-303. Epub 2009 Nov 18.

John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL 33136, USA.

Misregulation of the methyl-CpG-binding protein 2 (MECP2) gene has been found to cause a myriad of neurological disorders including autism, mental retardation, seizures, learning disabilities, and Rett syndrome. We hypothesized that mutations in other members of the methyl-CpG-binding domain (MBD) family may also cause autistic features in individuals. We evaluated 226 autistic individuals for alterations in the four genes most homologous to MECP2: MBD1, MBD2, MBD3, and MBD4. A total of 46 alterations were identified in the four genes, including ten missense changes and two deletions that alter coding sequence. Several are either unique to our autistic population or cosegregate with affected individuals within a family, suggesting a possible relation of these variations to disease etiology. Variants include a R23M alteration in two affected half brothers which falls within the MBD domain of the MBD3 protein, as well as a frameshift in MBD4 that is predicted to truncate almost half of the protein. These results suggest that rare cases of autism may be influenced by mutations in members of the dynamic MBD protein family.
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http://dx.doi.org/10.1007/s10048-009-0228-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2941261PMC
July 2010

Genomic and epigenetic evidence for oxytocin receptor deficiency in autism.

BMC Med 2009 Oct 22;7:62. Epub 2009 Oct 22.

Duke Center for Human Genetics, DUMC, Durham, NC, USA.

Background: Autism comprises a spectrum of behavioral and cognitive disturbances of childhood development and is known to be highly heritable. Although numerous approaches have been used to identify genes implicated in the development of autism, less than 10% of autism cases have been attributed to single gene disorders.

Methods: We describe the use of high-resolution genome-wide tilepath microarrays and comparative genomic hybridization to identify copy number variants within 119 probands from multiplex autism families. We next carried out DNA methylation analysis by bisulfite sequencing in a proband and his family, expanding this analysis to methylation analysis of peripheral blood and temporal cortex DNA of autism cases and matched controls from independent datasets. We also assessed oxytocin receptor (OXTR) gene expression within the temporal cortex tissue by quantitative real-time polymerase chain reaction (PCR).

Results: Our analysis revealed a genomic deletion containing the oxytocin receptor gene, OXTR (MIM accession no.: 167055), previously implicated in autism, was present in an autism proband and his mother who exhibits symptoms of obsessive-compulsive disorder. The proband's affected sibling did not harbor this deletion but instead may exhibit epigenetic misregulation of this gene through aberrant gene silencing by DNA methylation. Further DNA methylation analysis of the CpG island known to regulate OXTR expression identified several CpG dinucleotides that show independent statistically significant increases in the DNA methylation status in the peripheral blood cells and temporal cortex in independent datasets of individuals with autism as compared to control samples. Associated with the increase in methylation of these CpG dinucleotides is our finding that OXTR mRNA showed decreased expression in the temporal cortex tissue of autism cases matched for age and sex compared to controls.

Conclusion: Together, these data provide further evidence for the role of OXTR and the oxytocin signaling pathway in the etiology of autism and, for the first time, implicate the epigenetic regulation of OXTR in the development of the disorder.See the related commentary by Gurrieri and Neri: http://www.biomedcentral.com/1741-7015/7/63.
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http://dx.doi.org/10.1186/1741-7015-7-62DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2774338PMC
October 2009

Sleep patterns in patients with Huntington's disease and their unaffected first-degree relatives: a brief report.

Behav Sleep Med 2009 ;7(4):245-54

Department of Neuropsychiatry, University of South Carolina School of Medicine, Columbia, SC 29203, USA.

Polysomnographic sleep patterns in Huntington's disease (HD) have been studied sporadically in small groups of patients, providing variable results. In this study, by comparing the polysomnographic sleep patterns of HD patients and their unaffected relatives, identifying sleep traits more specifically related to the HD gene was attempted. The results corroborated previously reported findings of prolonged sleep latency and the virtual absence of nocturnal respiratory disturbances in early HD. Sleep latency in the HD patients positively correlated with the results of a screening test for frontal lobe dysfunction. Larger, more standardized studies will be needed to correlate genetic markers and sleep patterns in HD.
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http://dx.doi.org/10.1080/15402000903190215DOI Listing
October 2009

A genome-wide association study of autism reveals a common novel risk locus at 5p14.1.

Ann Hum Genet 2009 May;73(Pt 3):263-73

Miami Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA.

Although autism is one of the most heritable neuropsychiatric disorders, its underlying genetic architecture has largely eluded description. To comprehensively examine the hypothesis that common variation is important in autism, we performed a genome-wide association study (GWAS) using a discovery dataset of 438 autistic Caucasian families and the Illumina Human 1M beadchip. 96 single nucleotide polymorphisms (SNPs) demonstrated strong association with autism risk (p-value < 0.0001). The validation of the top 96 SNPs was performed using an independent dataset of 487 Caucasian autism families genotyped on the 550K Illumina BeadChip. A novel region on chromosome 5p14.1 showed significance in both the discovery and validation datasets. Joint analysis of all SNPs in this region identified 8 SNPs having improved p-values (3.24E-04 to 3.40E-06) than in either dataset alone. Our findings demonstrate that in addition to multiple rare variations, part of the complex genetic architecture of autism involves common variation.
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http://dx.doi.org/10.1111/j.1469-1809.2009.00523.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918410PMC
May 2009

Autism in African American families: clinical-phenotypic findings.

Am J Med Genet B Neuropsychiatr Genet 2007 Dec;144B(8):1022-6

Duke University Medical Center, Durham, NC, USA.

Unlike other complex diseases, the study of autism has been almost exclusively limited to Caucasian families. This study represents a first effort to examine clinical and phenotypic findings in individuals with autism from African American families. Drawing from an ongoing genetic study of autism we compared African American (N = 46, mean age = 118 months) and Caucasian (N = 298, mean age = 105 months) groups on autism symptoms and developmental language symptoms. The African American group showed greater delays in language but did not differ from the Caucasian group on core autism symptoms. These findings, while suggestive of a more severe phenotype, may reflect an ascertainment bias. Nonetheless, we believe that more studies of racial-ethnic groups should be conducted with several goals in mind including strengthening recruiting strategies to include more ethnic-racial groups and more thoughtful evaluation of phenotypic traits. Such considerations will aid greatly in the search for genetic variants in autism.
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http://dx.doi.org/10.1002/ajmg.b.30535DOI Listing
December 2007

Investigation of potential gene-gene interactions between APOE and RELN contributing to autism risk.

Psychiatr Genet 2007 Aug;17(4):221-6

Center for Human Genetics, Department of Medicine, Duke University Medical Center, Snyderman Genomic Sciences Building, Durham, NC 27710, USA.

Background: Several candidate gene studies support RELN as susceptibility gene for autism. Given the complex inheritance pattern of autism, it is expected that gene-gene interactions will exist. A logical starting point for examining potential gene-gene interactions is to evaluate the joint effects of genes involved in a common biological pathway. RELN shares a common biological pathway with APOE, and Persico et al. have observed transmission distortion of the APOE-2 allele in autism families.

Objective: We evaluated RELN and APOE for joint effects in autism susceptibility.

Methods: A total of 470 Caucasian autism families were analyzed (265 multiplex; 168 trios with no family history; 37 positive family history but only one sampled affected). These families were genotyped for 11 RELN polymorphisms, including the 5' untranslated region repeat previously associated with autism, as well as for the APOE functional allele. We evaluated single locus allelic and genotypic association with the pedigree disequilibrium test and geno-PDT, respectively. Multilocus effects were evaluated using the extended version of the multifactorial dimensionality reduction method.

Results: For the single locus analyses, there was no evidence for an effect of APOE in our data set. Evidence for association with RELN (rs2,073,559; trio subset P=0.07 PDT; P=0.001 geno-PDT; overall geno-PDT P=0.05), however, was found. For multilocus geno-PDT analysis, the joint genotype of APOE and RELN rs2,073,559 was highly significant (trio subset, global P=0.0001), probably driven by the RELN single locus effect. Using the extended version of the multifactorial dimensionality reduction method to detect multilocus effects, there were no statistically significant associations for any of the n-locus combinations involving RELN or APOE in the overall or multiplex subset. In the trio subset, 1-locus and 2-locus models selected only markers in RELN as best models for predicting autism case status.

Conclusion: Thus, we conclude that there is no main effect of APOE in our autism data set, nor is there any evidence for a joint effect of APOE with RELN. RELN, however, remains a good candidate for autism susceptibility.
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http://dx.doi.org/10.1097/YPG.0b013e32809c2f75DOI Listing
August 2007

A comparison of repetitive behaviors in Aspergers Disorder and high functioning autism.

Child Psychiatry Hum Dev 2007 Apr;37(4):347-60

Duke University Medical Center, Durham, NC, USA.

In this study we compared 33 IQ and age matched pairs of individuals with Aspergers Disorder (ASP) and high functioning autism (HFA) on measures of repetitive behavior. On the Repetitive Behavior Scale-Revised (RBS-R), the ASP and HFA groups showed no differences in RBS-R Intensity score (severity) score or Frequency score (number of problems present). This suggests that the two groups are similar with respect to the intensity or severity of repetitive behaviors and the presence of repetitive behaviors. At the item level there were no differences on scales typically associated with autism (Stereotyped Behavior) and ASP (Restricted Interests). Similarly, there were no differences between the groups on the Aberrant Behavior Checklist Stereotypy scale. These findings add to the body of literature showing that HFA and ASP fail to differ with respect to repetitive behaviors. The implications of the findings for neurobiologic and genetic studies are discussed.
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http://dx.doi.org/10.1007/s10578-007-0052-yDOI Listing
April 2007

Mapping autism risk loci using genetic linkage and chromosomal rearrangements.

Nat Genet 2007 Mar 18;39(3):319-28. Epub 2007 Feb 18.

Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
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http://dx.doi.org/10.1038/ng1985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867008PMC
March 2007

Autism: the difficult hunt for disease genes.

J S C Med Assoc 2006 Oct;102(8):277-9

Department of Neuropsychiatry, University of South Carolina, 3555 Harden Street Ext. Suite 301, Columbia, SC 29203, USA.

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October 2006

Factor analysis of the aberrant behavior checklist in individuals with autism spectrum disorders.

J Autism Dev Disord 2007 Nov 21;37(10):1949-59. Epub 2006 Dec 21.

Center for Human Genetics, Duke University Medical Center, DUMC Box 3445, Durham, NC 27710, USA.

Exploratory factor analysis (varimax and promax rotations) of the aberrant behavior checklist-community version (ABC) in 275 individuals with Autism spectrum disorder (ASD) identified four- and five-factor solutions which accounted for >70% of the variance. Confirmatory factor analysis (Lisrel 8.7) revealed indices of moderate fit for the five-factor solution. Our results suggest that the factor structure of the ABC is robust within an ASD sample. Both solutions yielded a three items self-injury factor. Stratifying on this factor, we identified significant differences between the high- and low-self injury groups on ABC subscales. The emergence of a self-injury factor, while not suggestive of a new subscale, warrants further exploration as a tool that could help dissect relevant neurobiobehavioral groups in ASD.
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http://dx.doi.org/10.1007/s10803-006-0327-3DOI Listing
November 2007

Genome-wide significance for a modifier of age at neurological onset in Huntington's disease at 6q23-24: the HD MAPS study.

BMC Med Genet 2006 Aug 17;7:71. Epub 2006 Aug 17.

Department of Neurology, Boston University School of Medicine, Boston, MA, USA.

Background: Age at onset of Huntington's disease (HD) is correlated with the size of the abnormal CAG repeat expansion in the HD gene; however, several studies have indicated that other genetic factors also contribute to the variability in HD age at onset. To identify modifier genes, we recently reported a whole-genome scan in a sample of 629 affected sibling pairs from 295 pedigrees, in which six genomic regions provided suggestive evidence for quantitative trait loci (QTL), modifying age at onset in HD.

Methods: In order to test the replication of this finding, eighteen microsatellite markers, three from each of the six genomic regions, were genotyped in 102 newly recruited sibling pairs from 69 pedigrees, and data were analyzed, using a multipoint linkage variance component method, in the follow-up sample and the combined sample of 352 pedigrees with 753 sibling pairs.

Results: Suggestive evidence for linkage at 6q23-24 in the follow-up sample (LOD = 1.87, p = 0.002) increased to genome-wide significance for linkage in the combined sample (LOD = 4.05, p = 0.00001), while suggestive evidence for linkage was observed at 18q22, in both the follow-up sample (LOD = 0.79, p = 0.03) and the combined sample (LOD = 1.78, p = 0.002). Epistatic analysis indicated that there is no interaction between 6q23-24 and other loci.

Conclusion: In this replication study, linkage for modifier of age at onset in HD was confirmed at 6q23-24. Evidence for linkage was also found at 18q22. The demonstration of statistically significant linkage to a potential modifier locus opens the path to location cloning of a gene capable of altering HD pathogenesis, which could provide a validated target for therapeutic development in the human patient.
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http://dx.doi.org/10.1186/1471-2350-7-71DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1586197PMC
August 2006

Investigation of autism and GABA receptor subunit genes in multiple ethnic groups.

Neurogenetics 2006 Jul 13;7(3):167-74. Epub 2006 Jun 13.

Center for Human Genetics, Duke University Medical Center, Durham, NC, USA.

Autism is a neurodevelopmental disorder of complex genetics, characterized by impairment in social interaction and communication, as well as repetitive behavior. Multiple lines of evidence, including alterations in levels of GABA and GABA receptors in autistic patients, indicate that the GABAergic system, which is responsible for synaptic inhibition in the adult brain, may be involved in autism. Previous studies in our lab indicated association of noncoding single nucleotide polymorphisms (SNPs) within a GABA receptor subunit gene on chromosome 4, GABRA4, and interaction between SNPs in GABRA4 and GABRB1 (also on chromosome 4), within Caucasian autism patients. Studies of genetic variation in African-American autism families are rare. Analysis of 557 Caucasian and an independent population of 54 African-American families with 35 SNPs within GABRB1 and GABRA4 strengthened the evidence for involvement of GABRA4 in autism risk in Caucasians (rs17599165, p=0.0015; rs1912960, p=0.0073; and rs17599416, p=0.0040) and gave evidence of significant association in African-Americans (rs2280073, p=0.0287 and rs16859788, p=0.0253). The GABRA4 and GABRB1 interaction was also confirmed in the Caucasian dataset (most significant pair, rs1912960 and rs2351299; p=0.004). Analysis of the subset of families with a positive history of seizure activity in at least one autism patient revealed no association to GABRA4; however, three SNPs within GABRB1 showed significant allelic association; rs2351299 (p=0.0163), rs4482737 (p=0.0339), and rs3832300 (p=0.0253). These results confirmed our earlier findings, indicating GABRA4 and GABRB1 as genes contributing to autism susceptibility, extending the effect to multiple ethnic groups and suggesting seizures as a stratifying phenotype.
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http://dx.doi.org/10.1007/s10048-006-0045-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1513515PMC
July 2006
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