The brain processes information by transmitting signals at synapses, which connect neurons into vast networks of communicating cells. In these networks, synapses not only transmit signals but also transform and refine them. Neurexins and neuroligins are synaptic cell-adhesion molecules that connect presynaptic and postsynaptic neurons at synapses, mediate signalling across the synapse, and shape the properties of neural networks by specifying synaptic functions. In humans, alterations in genes encoding neurexins or neuroligins have recently been implicated in autism and other cognitive diseases, linking synaptic cell adhesion to cognition and its disorders.

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Neuroligins and Neurexins Link Synaptic Function to Cognitive Disease

BACKGROUND Autism spectrum disorder is a heritable developmental disorder in which chromosomal abnormalities are thought to play a role. METHODS As a first component of a genomewide association study of families from the Autism Genetic Resource Exchange (AGRE), we used two novel algorithms to search for recurrent copy-number variations in genotype data from 751 multiplex families with autism. Specific recurrent de novo events were further evaluated in clinical-testing data from Children's Hospital Boston and in a large population study in Iceland. RESULTS Among the AGRE families, we observed five instances of a de novo deletion of 593 kb on chromosome 16p11.2. Using comparative genomic hybridization, we observed the identical deletion in 5 of 512 children referred to Children's Hospital Boston for developmental delay, mental retardation, or suspected autism spectrum disorder, as well as in 3 of 299 persons with autism in an Icelandic population; the deletion was also carried by 2 of 18,834 unscreened Icelandic control subjects. The reciprocal duplication of this region occurred in 7 affected persons in AGRE families and 4 of the 512 children from Children's Hospital Boston. The duplication also appeared to be a high-penetrance risk factor. CONCLUSIONS We have identified a novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases. We did not identify other regions with similar aggregations of large de novo mutations.

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Association between Microdeletion and Microduplication at 16p11.2 and Autism

Several lines of evidence point to genetic involvement in autism spectrum disorders (ASDs), neurodevelopmental and neuropsychiatric disorders characterized by impaired verbal communication and social interaction. The clinical and genetic complexities of the condition make it difficult to identify susceptibility factors, but two related studies now present robust evidence for a genetic involvement. The first, a genome-wide association study, identifies six single-nucleotide polymorphisms strongly associated with autism. These variants lie between two genes encoding neuronal cell-adhesion molecules (cadherins 9 and 10), suggesting possible involvement in ASD pathogenesis. The second study used copy number variation screens to identify genetic variants in two major gene pathways in children with ASDs. The changes are in the ubiquitin pathway, which has previously been associated with neurological disease, and in genes for neuronal cell-adhesion molecules.

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Autism genome-wide copy number variation reveals ubiquitin and neuronal genes

Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterized by widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitive behaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. SHANK3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for the development of 22q13 deletion syndrome (Phelan–McDermid syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular, electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for SHANK3 in the normal development of neuronal connectivity and establish causality between a disruption in the Shank3 gene and the genesis of autistic-like behaviours in mice. Autism and autism spectrum disorders (ASDs) are neurodevelopmental disorders diagnosed based on a triad of criteria: deficits in communication, impaired social interaction, and repetitive or restricted interests and behaviours 1 . ASDs are highly heritable disorders with concordance rates as high as 90% for monozygotic twins 2 . Recent genetic and genomic studies have identified a large number of candidate genes for ASDs 3 , many of which encode synaptic proteins 4–6 , indicating synaptic dysfunction may have a critical role in ASDs 7,8 . One of the most promising ASD candidate genes is Shank3, which codes for a key postsynaptic density (PSD) protein at glutamatergic synapses. Disruption of Shank3 is thought to be the cause of core neurodevelopmental and neurobehavioural deficits in the 22q13 deletion syndrome (Phelan–McDermid syndrome), an autism spectrum disorder 9–11 . Furthermore, recent genetic screens have identified several mutations/rare variants of the Shank3 gene in ASD patients outside of diagnosed 22q13 deletion syndrome 12,13 . The Shank family of proteins (SHANK1–3) directly bind SAPAP (also known as DLGAP) to form the PSD-95–SAPAP–SHANK complex 14,15 (PSD-95 is also known as DLG4). This core of proteins is thought to function as a scaffold, orchestrating the assembly of the macromolecular postsynaptic signalling complex at glutamatergic synapses. Currently, however, little is known about the in vivo function of SHANK3 at the synapse and how a disruption of Shank3 may contribute to ASDs. Here we demonstrate that genetic disruption of Shank3 in mice leads to compulsive/repetitive behaviour and impaired social interaction, resembling two of the cardinal features of ASDs. Biochemical, morphological and electrophysiological studies revealed synaptic dysfunction at corticostriatal synapses, part of the neural circuits strongly implicated as dysfunctional in ASDs. Our studies provide a synaptic and circuitry mechanism underlying Shank3 disruption and ASD-like behaviours. Shank3B 2/2 mice display repetitive grooming

/pdf/shank3-mutant-mice-display-autistic-like-behaviours-and-kc224hjlsp.pdf

Shank3 mutant mice display autistic-like behaviours and striatal dysfunction

During the last quarter of the twentieth century, our knowledge about human genetic variation was limited mainly to the heterochromatin polymorphisms, large enough to be visible in the light microscope, and the single nucleotide polymorphisms (SNPs) identified by traditional PCR-based DNA sequencing. In the past five years, the rapid development and expanded use of microarray technologies, including oligonucleotide array comparative genomic hybridization and SNP genotyping arrays, as well as next-generation sequencing with “paired-end” methods, has enabled a whole-genome analysis with essentially unlimited resolution. The discovery of submicroscopic copy-number variations (CNVs) present in our genomes has changed dramatically our perspective on DNA structural variation and disease. It is now thought that CNVs encompass more total nucleotides and arise more frequently than SNPs. CNVs, to a larger extent than SNPs, have been shown to be responsible for human evolution, genetic diversity between individuals,...

Structural Variation in the Human Genome and its Role in Disease

Autism is a neurodevelopmental disorder of complex etiology in which genetic factors play a major role. We have implicated the neurexin 1 (NRXN1) gene in two independent subjects who display an autism spectrum disorder (ASD) in association with a balanced chromosomal abnormality involving 2p16.3. In the first, with karyotype 46,XX,ins(16;2)(q22.1;p16.1p16.3)pat, NRXN1 is directly disrupted within intron 5. Importantly, the father possesses the same chromosomal abnormality in the absence of ASD, indicating that the interruption of α-NRXN1 is not fully penetrant and must interact with other factors to produce ASD. The breakpoint in the second subject, with 46,XY,t(1;2)(q31.3;p16.3)dn, occurs ∼750 kb 5′ to NRXN1 within a 2.6 Mb genomic segment that harbors no currently annotated genes. A scan of the NRXN1 coding sequence in a cohort of ASD subjects, relative to non-ASD controls, revealed that amino acid alterations in neurexin 1 are not present at high frequency in ASD. However, a number of rare sequence variants in the coding region, including two missense changes in conserved residues of the α-neurexin 1 leader sequence and of an epidermal growth factor (EGF)-like domain, respectively, suggest that even subtle changes in NRXN1 might contribute to susceptibility to ASD.

Disruption of Neurexin 1 Associated with Autism Spectrum Disorder

Introduction Stargardt macular degeneration (STGD) is the most common form of inherited early/juvenile onset maculopathy in which the peripheral region usually remains free of lesions. STGD has an estimated incidence of 1 : 8000 to 1 : 10 000 and is characterized by decreased central vision, atrophy of the macula, and underlying retinal pigment epithelium. The disease can be recognized by the presence of yellow flecks that cover the entire fundus (fundus flavimaculatus) and hyperfluorescent macular lesions (bull’s eye) (Fingert et al., 2006).

A new syndrome with Stargardt macular degeneration, abnormalities of the corpus callosum, mental retardation, and dysmorphic features: a case report of two siblings.

AsktheGeneticistSM: five years of online experience

Preimplantation genetic diagnosis.

Genetic thrombophilic disorders are variably common and primary care clinicians must be aware of them because of the increased risk of VTE. A physical examination will not be able to determine if a given VTE resulted from a genetic predisposition or not. In some instances, a patient's personal and family history will alert a clinician to the existence of a thrombophilic disorder, but diagnosis of the specific thrombophilia will require laboratory evaluation and referral to a specialist. The acute management of VTE is the same regardless of the presence of a genetic thrombophilia; therefore, laboratory testing or evaluation by a specialist is not cause to delay treatment of the acute thrombotic event. After the initial treatment and stabilization of the patient, ample time exists to perform a thrombophilia workup. Long-term management of thrombophilia disorders is complicated and needs to be individualized, so referral to specialists is necessary. Primary care clinicians need to keep abreast of the studies being conducted on thrombophilia because numerous families continue to be plagued by VTEs without a recognizable cause. Undoubtedly, new causes of inherited thrombophilias are yet to be unveiled.

Lynn Holt

Papers

Disruption of Neurexin 1 Associated with Autism Spectrum Disorder

A new syndrome with Stargardt macular degeneration, abnormalities of the corpus callosum, mental retardation, and dysmorphic features: a case report of two siblings.

AsktheGeneticistSM: five years of online experience

Preimplantation genetic diagnosis.

Genetic susceptibility to VTE: a primary care approach.