pubmed: autism and genetics

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A direct molecular link between the autism candidate gene RORa and the schizophrenia candidate MIR137.

February 7, 2014 - 7:40am

A direct molecular link between the autism candidate gene RORa and the schizophrenia candidate MIR137.

Sci Rep. 2014;4:3994

Authors: Devanna P, Vernes SC

Abstract
Retinoic acid-related orphan receptor alpha gene (RORa) and the microRNA MIR137 have both recently been identified as novel candidate genes for neuropsychiatric disorders. RORa encodes a ligand-dependent orphan nuclear receptor that acts as a transcriptional regulator and miR-137 is a brain enriched small non-coding RNA that interacts with gene transcripts to control protein levels. Given the mounting evidence for RORa in autism spectrum disorders (ASD) and MIR137 in schizophrenia and ASD, we investigated if there was a functional biological relationship between these two genes. Herein, we demonstrate that miR-137 targets the 3'UTR of RORa in a site specific manner. We also provide further support for MIR137 as an autism candidate by showing that a large number of previously implicated autism genes are also putatively targeted by miR-137. This work supports the role of MIR137 as an ASD candidate and demonstrates a direct biological link between these previously unrelated autism candidate genes.

PMID: 24500708 [PubMed - in process]

Decreased cerebral spinal fluid neurotransmitter levels in Smith-Lemli-Opitz syndrome.

February 7, 2014 - 7:40am

Decreased cerebral spinal fluid neurotransmitter levels in Smith-Lemli-Opitz syndrome.

J Inherit Metab Dis. 2014 Feb 6;

Authors: Sparks SE, Wassif CA, Goodwin H, Conley SK, Lanham DC, Kratz LE, Hyland K, Gropman A, Tierney E, Porter FD

Abstract
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple congenital anomaly syndrome with cognitive impairment and a distinct behavioral phenotype that includes autistic features. SLOS is caused by a defect in 3β-hydroxysterol Δ(7)-reductase which leads to decreased cholesterol levels and elevated cholesterol precursors, specifically 7- and 8-dehydrocholesterol. However, the pathological processes contributing to the neurological abnormalities in SLOS have not been defined. In view of prior data suggesting defects in SLOS in vesicular release and given the association of altered serotonin metabolism with autism, we were interested in measuring neurotransmitter metabolite levels in SLOS to assess their potential to be used as biomarkers in therapeutic trials. We measured cerebral spinal fluid levels of serotonin and dopamine metabolites, 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) respectively, in 21 SLOS subjects. Results were correlated with the SLOS anatomical severity score, Aberrant Behavior Checklist scores and concurrent sterol biochemistry. Cerebral spinal fluid (CSF) levels of both 5HIAA and HVA were significantly reduced in SLOS subjects. In individual patients, the levels of both 5HIAA and HVA were reduced to a similar degree. CSF neurotransmitter metabolite levels did not correlate with either CSF sterols or behavioral measures. This is the first study demonstrating decreased levels of CSF neurotransmitter metabolites in SLOS. We propose that decreased levels of neurotransmitters in SLOS are caused by a sterol-related defect in synaptic vesicle formation and that CSF 5HIAA and HVA will be useful biomarkers in development of future therapeutic trials.

PMID: 24500076 [PubMed - as supplied by publisher]

[Role of glutamate transporters in the pathophysiology of major mental illnesses].

February 7, 2014 - 7:40am
Related Articles

[Role of glutamate transporters in the pathophysiology of major mental illnesses].

Nihon Yakurigaku Zasshi. 2013 Dec;142(6):291-6

Authors: Tanaka K

PMID: 24334928 [PubMed - indexed for MEDLINE]

Loss of function of KIAA2022 causes mild to severe intellectual disability with an autism spectrum disorder and impairs neurite outgrowth.

February 7, 2014 - 7:40am
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Loss of function of KIAA2022 causes mild to severe intellectual disability with an autism spectrum disorder and impairs neurite outgrowth.

Hum Mol Genet. 2013 Aug 15;22(16):3306-14

Authors: Van Maldergem L, Hou Q, Kalscheuer VM, Rio M, Doco-Fenzy M, Medeira A, de Brouwer AP, Cabrol C, Haas SA, Cacciagli P, Moutton S, Landais E, Motte J, Colleaux L, Bonnet C, Villard L, Dupont J, Man HY

Abstract
Existence of a discrete new X-linked intellectual disability (XLID) syndrome due to KIAA2022 deficiency was questioned by disruption of KIAA2022 by an X-chromosome pericentric inversion in a XLID family we reported in 2004. Three additional families with likely pathogenic KIAA2022 mutations were discovered within the frame of systematic parallel sequencing of familial cases of XLID or in the context of routine array-CGH evaluation of sporadic intellectual deficiency (ID) cases. The c.186delC and c.3597dupA KIAA2022 truncating mutations were identified by X-chromosome exome sequencing, while array CGH discovered a 70 kb microduplication encompassing KIAA2022 exon 1 in the third family. This duplication decreased KIAA2022 mRNA level in patients' lymphocytes by 60%. Detailed clinical examination of all patients, including the two initially reported, indicated moderate-to-severe ID with autistic features, strabismus in all patients, with no specific dysmorphic features other than a round face in infancy and no structural brain abnormalities on magnetic resonance imaging (MRI). Interestingly, the patient with decreased KIAA2022 expression had only mild ID with severe language delay and repetitive behaviors falling in the range of an autism spectrum disorder (ASD). Since little is known about KIAA2022 function, we conducted morphometric studies in cultured rat hippocampal neurons. We found that siRNA-mediated KIAA2022 knockdown resulted in marked impairment in neurite outgrowth including both the dendrites and the axons, suggesting a major role for KIAA2022 in neuron development and brain function.

PMID: 23615299 [PubMed - indexed for MEDLINE]

Prevalence of selected genomic deletions and duplications in a French-Canadian population-based sample of newborns.

February 6, 2014 - 7:14am

Prevalence of selected genomic deletions and duplications in a French-Canadian population-based sample of newborns.

Mol Genet Genomic Med. 2013 Jul;1(2):87-97

Authors: Tucker T, Giroux S, Clément V, Langlois S, Friedman JM, Rousseau F

Abstract
Chromosomal microarray analysis has identified many novel microdeletions or microduplications that produce neurodevelopmental disorders with a recognizable clinical phenotype and that are not observed in normal individuals. However, imbalance of other genomic regions is associated with a variable phenotype with intellectual disability (ID) or autism in some individuals but are also observed in completely normal individuals. Several large studies have reported the prevalence of copy number (CN) variants in people with particular features (e.g., ID, autism, schizophrenia, or epilepsy); few studies have investigated the prevalence of genomic CN changes in the general population. We used a high-throughput method to screen 6813 consecutive cord blood samples from a predominantly French-Canadian population to assess genomic CN in five genomic regions: 1p36, 15q11-q13, 16p11.2, 16p11.2-p12.2, and 22q11.2. We identified one deletion and one duplication within 1p36, two deletions of 15q11-q13, eight deletions of 16p11.2-p12.2, two deletions and five duplications of 16p11.2, and six duplications of 22q11.2. This study provides estimates of the frequency of CN variants in an unselected population. Our findings have important implications for genetic counseling.

PMID: 24498606 [PubMed]

Association of human mtDNA mutations with autism in Iranian patients.

February 6, 2014 - 7:14am

Association of human mtDNA mutations with autism in Iranian patients.

J Res Med Sci. 2013 Oct;18(10):926

Authors: Mousavizadeh K, Askari M, Arian H, Gourjipour F, Nikpour AR, Tavafjadid M, Aryani O, Kamalidehghan B, Maroof HR, Houshmand M

PMID: 24497871 [PubMed]

Large Inverted Duplications in the Human Genome Form via a Fold-Back Mechanism.

February 6, 2014 - 7:14am

Large Inverted Duplications in the Human Genome Form via a Fold-Back Mechanism.

PLoS Genet. 2014 Jan;10(1):e1004139

Authors: Hermetz KE, Newman S, Conneely KN, Martin CL, Ballif BC, Shaffer LG, Cody JD, Rudd MK

Abstract
Inverted duplications are a common type of copy number variation (CNV) in germline and somatic genomes. Large duplications that include many genes can lead to both neurodevelopmental phenotypes in children and gene amplifications in tumors. There are several models for inverted duplication formation, most of which include a dicentric chromosome intermediate followed by breakage-fusion-bridge (BFB) cycles, but the mechanisms that give rise to the inverted dicentric chromosome in most inverted duplications remain unknown. Here we have combined high-resolution array CGH, custom sequence capture, next-generation sequencing, and long-range PCR to analyze the breakpoints of 50 nonrecurrent inverted duplications in patients with intellectual disability, autism, and congenital anomalies. For half of the rearrangements in our study, we sequenced at least one breakpoint junction. Sequence analysis of breakpoint junctions reveals a normal-copy disomic spacer between inverted and non-inverted copies of the duplication. Further, short inverted sequences are present at the boundary of the disomic spacer and the inverted duplication. These data support a mechanism of inverted duplication formation whereby a chromosome with a double-strand break intrastrand pairs with itself to form a "fold-back" intermediate that, after DNA replication, produces a dicentric inverted chromosome with a disomic spacer corresponding to the site of the fold-back loop. This process can lead to inverted duplications adjacent to terminal deletions, inverted duplications juxtaposed to translocations, and inverted duplication ring chromosomes.

PMID: 24497845 [PubMed - in process]

Glutamatergic candidate genes in autism spectrum disorder: an overview.

February 5, 2014 - 8:38am

Glutamatergic candidate genes in autism spectrum disorder: an overview.

J Neural Transm. 2014 Feb 4;

Authors: Chiocchetti AG, Bour HS, Freitag CM

Abstract
Autism spectrum disorders (ASD) are neurodevelopmental disorders with early onset in childhood. Most of the risk for ASD can be explained by genetic variants that act in interaction with biological environmental risk factors. However, the architecture of the genetic components is still unclear. Genetic studies and subsequent systems biological approaches described converging functional effects of identified genes towards pathways relevant for neuronal signalling. Mouse models suggest an aberrant synaptic plasticity at the neuropathological level, which is believed to be conferred by dysregulation of long-term potentiation or depression of neuronal connections. A central pathway regulating these mechanisms is glutamatergic signalling. Here, we hypothesized that susceptibility genes for ASD are enriched for components of this pathway. To further understand the impact of ASD risk genes on the glutamatergic pathway, we performed a systematic review using the literature database "pubmed" and the "AutismKB" knowledgebase. We provide an overview of the glutamatergic system in typical brain function and development, and summarize findings from linkage, association, copy number variants, and sequencing studies in ASD to provide a comprehensive picture of the glutamatergic landscape of ASD genetics. Genetic variants associated with ASD were enriched in glutamatergic pathways, affecting receptor signalling, metabolism and transport. Furthermore, in genetically modified mouse models for ASD, pharmacological compounds acting on ionotropic or metabotropic receptor activity are able to rescue ASD reminscent phenotypes. We conclude that glutamatergic genetic risk factors for ASD show a complex pattern and further studies are needed to fully understand its mechanisms, before translation of findings into clinical applications and individualized treatment approaches will be possible.

PMID: 24493018 [PubMed - as supplied by publisher]

Induction or augmentation of labor and autism-reply.

February 5, 2014 - 8:38am

Induction or augmentation of labor and autism-reply.

JAMA Pediatr. 2014 Feb 1;168(2):191-2

Authors: Miranda ML, Anthopolos R, Gregory SG

PMID: 24492875 [PubMed - in process]

Treating the Whole Person With Autism: The Proceedings of the Autism Speaks National Autism Conference.

February 5, 2014 - 8:38am

Treating the Whole Person With Autism: The Proceedings of the Autism Speaks National Autism Conference.

Curr Probl Pediatr Adolesc Health Care. 2014 Feb;44(2):26-47

Authors: Coury DL, Swedo SE, Thurm AE, Miller DT, Veenstra-Vanderweele JM, Carbone PS, Taylor JL

Abstract
The identification of autism spectrum disorders has increased dramatically over the past decade, with the latest estimates indicating prevalence as high as 1 in 54 boys. There is greater awareness of medical conditions that co-occur with autism and expansion of treatment options. Closer scrutiny has led to refinement of the diagnostic criteria, and there have been advances in genetics examining potential causal factors. Transition to adulthood is an area of growing concern, and professionals and families require guidance on this issue. This article summarizes the proceedings of the Autism Speaks conference on Treating the Whole Person with Autism: Care across the Lifespan. The conference was organized with the intent of providing a forum for both families and professionals to learn about the most current research in the field. Dr. Sue Swedo provides important background information regarding the changes in the diagnostic criteria for autism spectrum disorders. She particularly deals with the concerns of individuals and families that their autism diagnosis may change. Recommendations for genetic testing and its interpretation are provided by Dr. David Miller. His discussion helps make sense of the utility of genetic testing for ASD, along with demonstration of the complexity of determining which genetic factors are doing what and through which pathways. Dr. Jeremy Veenstra-VanderWeele provides useful background information on how medicines are initially identified and for what purpose and goes on to describe the present and future treatments in pharmacology. Medical issues are addressed by Dr. Paul Carbone, especially the coordination of comprehensive services through the medical home model of care. Dr. Julie Lounds Taylor concludes with guidance on preparation for adulthood, a topic of great importance to families as their child matures and for the professionals who will help guide this transition.

PMID: 24491508 [PubMed - as supplied by publisher]

Neuroligins provide molecular links between syndromic and nonsyndromic autism.

February 5, 2014 - 8:38am
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Neuroligins provide molecular links between syndromic and nonsyndromic autism.

Sci Signal. 2013 Jul 9;6(283):re4

Authors: Singh SK, Eroglu C

Abstract
Autism is a common and heritable neuropsychiatric disorder that can be categorized into two types: syndromic and nonsyndromic, the former of which are associated with other neurological disorders or syndromes. Molecular and functional links between syndromic and nonsyndromic autism genes were lacking until studies aimed at understanding the role of trans-synaptic adhesion molecule neuroligin, which is associated with nonsyndromic autism, provided important connections. Here, we integrate data from these studies into a model of how neuroligin functions to control synaptic connectivity in the central nervous system and how neuroligin dysfunction may participate in the pathophysiology of autism. Understanding the complex functional interactions between neuroligins and other autism-associated proteins at the synapse is crucial to understand the pathology of autism. This understanding might bring us closer to development of therapeutic approaches for autism.

PMID: 23838185 [PubMed - indexed for MEDLINE]

The dynamics of autism spectrum disorders: how neurotoxic compounds and neurotransmitters interact.

February 4, 2014 - 8:47am
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The dynamics of autism spectrum disorders: how neurotoxic compounds and neurotransmitters interact.

Int J Environ Res Public Health. 2013 Aug;10(8):3384-408

Authors: Quaak I, Brouns MR, Van de Bor M

Abstract
In recent years concern has risen about the increasing prevalence of Autism Spectrum Disorders (ASD). Accumulating evidence shows that exposure to neurotoxic compounds is related to ASD. Neurotransmitters might play a key role, as research has indicated a connection between neurotoxic compounds, neurotransmitters and ASD. In the current review a literature overview with respect to neurotoxic exposure and the effects on neurotransmitter systems is presented. The aim was to identify mechanisms and related factors which together might result in ASD. The literature reported in the current review supports the hypothesis that exposure to neurotoxic compounds can lead to alterations in the GABAergic, glutamatergic, serotonergic and dopaminergic system which have been related to ASD in previous work. However, in several studies findings were reported that are not supportive of this hypothesis. Other factors also might be related, possibly altering the mechanisms at work, such as time and length of exposure as well as dose of the compound. Future research should focus on identifying the pathway through which these factors interact with exposure to neurotoxic compounds making use of human studies.

PMID: 23924882 [PubMed - indexed for MEDLINE]

Biological mechanisms associated with increased perseveration and hyperactivity in a genetic mouse model of neurodevelopmental disorder.

February 1, 2014 - 8:14am
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Biological mechanisms associated with increased perseveration and hyperactivity in a genetic mouse model of neurodevelopmental disorder.

Psychoneuroendocrinology. 2013 Aug;38(8):1370-80

Authors: Trent S, Dean R, Veit B, Cassano T, Bedse G, Ojarikre OA, Humby T, Davies W

Abstract
Chromosomal deletions at Xp22.3 appear to influence vulnerability to the neurodevelopmental disorders attention deficit hyperactivity disorder (ADHD) and autism. 39,X(Y*)O mice, which lack the murine orthologue of the Xp22.3 ADHD candidate gene STS (encoding steroid sulfatase), exhibit behavioural phenotypes relevant to such disorders (e.g. hyperactivity), elevated hippocampal serotonin (5-HT) levels, and reduced serum levels of dehydroepiandrosterone (DHEA). Here we initially show that 39,X(Y*)O mice are also deficient for the recently-characterised murine orthologue of the Xp22.3 autism candidate gene ASMT (encoding acetylserotonin-O-methyltransferase). Subsequently, to specify potential behavioural correlates of elevated hippocampal 5-HT arising due to the genetic lesion, we compared 39,X(Y*)O MF1 mice to 40,XY MF1 mice on behavioural tasks taxing hippocampal and/or 5-HT function (a 'foraging' task, an object-location task, and the 1-choice serial reaction time task of impulsivity). Although Sts/Asmt deficiency did not influence foraging behaviour, reactivity to familiar objects in novel locations, or 'ability to wait', it did result in markedly increased response rates; these rates correlated with hippocampal 5-HT levels and are likely to index behavioural perseveration, a frequent feature of neurodevelopmental disorders. Additionally, we show that whilst there was no systematic relationship between serum DHEA levels and hippocampal 5-HT levels across 39,X(Y*)O and 40,XY mice, there was a significant inverse linear correlation between serum DHEA levels and activity. Our data suggest that deficiency for genes within Xp22.3 could influence core behavioural features of neurodevelopmental disorders via dissociable effects on hippocampal neurochemistry and steroid hormone levels, and that the mediating neurobiological mechanisms may be investigated in the 39,X(Y*)O model.

PMID: 23276394 [PubMed - indexed for MEDLINE]

[Genetic bases of autism spectrum disorders].

January 31, 2014 - 1:51pm
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[Genetic bases of autism spectrum disorders].

Med Wieku Rozwoj. 2013 Jul-Sep;17(3):207-23

Authors: Wiśniowiecka-Kowalnik B, Kastory-Bronowska M, Stankiewicz P

Abstract
Autism spectrum disorders (ASDs) are an etiologically and clinically heterogeneous group of neurodevelopmental disorders affecting approximately 0.6-1% of the general population. ASDs are characterized by deficits in social communication, impaired language development, and stereotyped repetitive behaviour. The impact of genetic factors in ASDs has been confirmed in the past few years. Numerous studies have shown that among patients with ASDs, approximately 10% have DNA copy number variation and 10-20% point mutations. Most of the deficiencies identified in individuals with ASDs relate to genes encoding proteins involved mainly in the development of neurons and their synapses functioning in various signaling pathways. Due to the large heterogeneity of identified changes in the genome of individuals with ASDs, the newest techniques enabling analysis of the entire genome in one study (microarrays, next-generation sequencing) are the methods of choice in the diagnostics of this pathology.

PMID: 24296445 [PubMed - indexed for MEDLINE]

Nonsense-mediated mRNA decay and loss-of-function of the protein underlie the X-linked epilepsy associated with the W356× mutation in synapsin I.

January 31, 2014 - 1:51pm
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Nonsense-mediated mRNA decay and loss-of-function of the protein underlie the X-linked epilepsy associated with the W356× mutation in synapsin I.

PLoS One. 2013;8(6):e67724

Authors: Giannandrea M, Guarnieri FC, Gehring NH, Monzani E, Benfenati F, Kulozik AE, Valtorta F

Abstract
Synapsins are a family of neuronal phosphoproteins associated with the cytosolic surface of synaptic vesicles. Experimental evidence suggests a role for synapsins in synaptic vesicle clustering and recycling at the presynaptic terminal, as well as in neuronal development and synaptogenesis. Synapsin knock-out (Syn1(-/-) ) mice display an epileptic phenotype and mutations in the SYN1 gene have been identified in individuals affected by epilepsy and/or autism spectrum disorder. We investigated the impact of the c.1067G>A nonsense transition, the first mutation described in a family affected by X-linked syndromic epilepsy, on the expression and functional properties of the synapsin I protein. We found that the presence of a premature termination codon in the human SYN1 transcript renders it susceptible to nonsense-mediated mRNA decay (NMD). Given that the NMD efficiency is highly variable among individuals and cell types, we investigated also the effects of expression of the mutant protein and found that it is expressed at lower levels compared to wild-type synapsin I, forms perinuclear aggregates and is unable to reach presynaptic terminals in mature hippocampal neurons grown in culture. Taken together, these data indicate that in patients carrying the W356× mutation the function of synapsin I is markedly impaired, due to both the strongly decreased translation and the altered function of the NMD-escaped protein, and support the value of Syn1(-/-) mice as an experimental model mimicking the human pathology.

PMID: 23818987 [PubMed - indexed for MEDLINE]

Strong genetic influences on the stability of autistic traits in childhood.

January 30, 2014 - 8:56am

Strong genetic influences on the stability of autistic traits in childhood.

J Am Acad Child Adolesc Psychiatry. 2014 Feb;53(2):221-30

Authors: Holmboe K, Rijsdijk FV, Hallett V, Happé F, Plomin R, Ronald A

Abstract
OBJECTIVE: Disorders on the autism spectrum, as well as autistic traits in the general population, have been found to be both highly stable across age and highly heritable at individual ages. However, little is known about the overlap in genetic and environmental influences on autistic traits across age and the contribution of such influences to trait stability itself. The present study investigated these questions in a general population sample of twins.
METHOD: More than 6,000 twin pairs were rated on an established scale of autistic traits by their parents at 8, 9, and 12 years of age and by their teachers at 9 and 12 years of age. Data were analyzed using structural equation modeling.
RESULTS: The results indicated that, consistently across raters, not only were autistic traits stable, and moderately to highly heritable at individual ages, but there was also a high degree of overlap in genetic influences across age. Furthermore, autistic trait stability could largely be accounted for by genetic factors, with the environment unique to each twin playing a minor role. The environment shared by twins had virtually no effect on the longitudinal stability in autistic traits.
CONCLUSIONS: Autistic traits are highly stable across middle childhood. and this stability is caused primarily by genetic factors.

PMID: 24472256 [PubMed - in process]

Viewing social scenes: a visual scan-path study comparing fragile X syndrome and Williams syndrome.

January 30, 2014 - 8:56am
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Viewing social scenes: a visual scan-path study comparing fragile X syndrome and Williams syndrome.

J Autism Dev Disord. 2013 Aug;43(8):1880-94

Authors: Williams TA, Porter MA, Langdon R

Abstract
Fragile X syndrome (FXS) and Williams syndrome (WS) are both genetic disorders which present with similar cognitive-behavioral problems, but distinct social phenotypes. Despite these social differences both syndromes display poor social relations which may result from abnormal social processing. This study aimed to manipulate the location of socially salient information within scenes to investigate the visual attentional mechanisms of: capture, disengagement, and/or general engagement. Findings revealed that individuals with FXS avoid social information presented centrally, at least initially. The WS findings, on the other hand, provided some evidence that difficulties with attentional disengagement, rather than attentional capture, may play a role in the WS social phenotype. These findings are discussed in relation to the distinct social phenotypes of these two disorders.

PMID: 23224515 [PubMed - indexed for MEDLINE]

Disentangling the heterogeneity of autism spectrum disorder through genetic findings.

January 29, 2014 - 7:49am

Disentangling the heterogeneity of autism spectrum disorder through genetic findings.

Nat Rev Neurol. 2014 Jan 28;

Authors: Jeste SS, Geschwind DH

Abstract
Autism spectrum disorder (ASD) represents a heterogeneous group of disorders, which presents a substantial challenge to diagnosis and treatment. Over the past decade, considerable progress has been made in the identification of genetic risk factors for ASD that define specific mechanisms and pathways underlying the associated behavioural deficits. In this Review, we discuss how some of the latest advances in the genetics of ASD have facilitated parsing of the phenotypic heterogeneity of this disorder. We argue that only through such advances will we begin to define endophenotypes that can benefit from targeted, hypothesis-driven treatments. We review the latest technologies used to identify and characterize the genetics underlying ASD and then consider three themes-single-gene disorders, the gender bias in ASD, and the genetics of neurological comorbidities-that highlight ways in which we can use genetics to define the many phenotypes within the autism spectrum. We also present current clinical guidelines for genetic testing in ASD and their implications for prognosis and treatment.

PMID: 24468882 [PubMed - as supplied by publisher]

Identification of rare DNA sequence variants in high-risk autism families and their prevalence in a large case/control population.

January 29, 2014 - 7:49am

Identification of rare DNA sequence variants in high-risk autism families and their prevalence in a large case/control population.

Mol Autism. 2014 Jan 27;5(1):5

Authors: Matsunami N, Hensel CH, Baird L, Stevens J, Otterud B, Leppert T, Varvil T, Hadley D, Glessner JT, Pellegrino R, Kim C, Thomas K, Wang F, Otieno FG, Ho K, Christensen GB, Li D, Prekeris R, Lambert CG, Hakonarson H, Leppert MF

Abstract
BACKGROUND: Genetics clearly plays a major role in the etiology of autism spectrum disorders (ASDs), but studies to date are only beginning to characterize the causal genetic variants responsible. Until recently, studies using multiple extended multi-generation families to identify ASD risk genes had not been undertaken.
METHODS: We identified haplotypes shared among individuals with ASDs in large multiplex families, followed by targeted DNA capture and sequencing to identify potential causal variants. We also assayed the prevalence of the identified variants in a large ASD case/control population.
RESULTS: We identified 584 non-conservative missense, nonsense, frameshift and splice site variants that might predispose to autism in our high-risk families. Eleven of these variants were observed to have odds ratios greater than 1.5 in a set of 1,541 unrelated children with autism and 5,785 controls. Three variants, in the RAB11FIP5, ABP1, and JMJD7-PLA2G4B genes, each were observed in a single case and not in any controls. These variants also were not seen in public sequence databases, suggesting that they may be rare causal ASD variants. Twenty-eight additional rare variants were observed only in high-risk ASD families. Collectively, these 39 variants identify 36 genes as ASD risk genes. Segregation of sequence variants and of copy number variants previously detected in these families reveals a complex pattern, with only a RAB11FIP5 variant segregating to all affected individuals in one two-generation pedigree. Some affected individuals were found to have multiple potential risk alleles, including sequence variants and copy number variants (CNVs), suggesting that the high incidence of autism in these families could be best explained by variants at multiple loci.
CONCLUSIONS: Our study is the first to use haplotype sharing to identify familial ASD risk loci. In total, we identified 39 variants in 36 genes that may confer a genetic risk of developing autism. The observation of 11 of these variants in unrelated ASD cases further supports their role as ASD risk variants.

PMID: 24467814 [PubMed - as supplied by publisher]

Variable behavioural phenotypes of patients with monosomies of 15q26 and a review of 16 cases.

January 29, 2014 - 7:49am
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Variable behavioural phenotypes of patients with monosomies of 15q26 and a review of 16 cases.

Eur J Med Genet. 2013 Jul;56(7):346-50

Authors: Poot M, Verrijn Stuart AA, van Daalen E, van Iperen A, van Binsbergen E, Hochstenbach R

Abstract
Patients with trisomy or tetrasomy of distal 15q show a recognizable overgrowth syndrome, whereas patients with a monosomy of 15q26 share some degree of pre- and postnatal growth retardation, but differ with respect to facial and skeletal dysmorphisms, congenital heart disease and intellectual development. By reviewing 16 cases with losses of 15q26 we found that the size of the deletion was also not a predictor of the breadth of the phenotypic spectrum, the severity of disease or prognosis of the patient. Although monosomies of 15q26 do not represent a classical contiguous gene syndrome, a few candidate genes for selected features such as proportional growth retardation and cardiac abnormalities have been identified. In 11 out of 16 patients with monosomy of distal 15q variable neurobehavioral phenotypes, including learning difficulties, seizures, attention-deficit-hyperactivity disorder, hearing loss and autism, have been found. We discuss clinical ramifications for cases with a loss of 15q26 detected by prenatal array-CGH.

PMID: 23603061 [PubMed - indexed for MEDLINE]

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