Frameshift mutation hotspot identified in Smith-Magenis syndrome: case report and review of literature

Smith-Magenis syndrome (SMS) is a complex syndrome involving intellectual disabilities, sleep disturbance, behavioural problems, and a variety of craniofacial, skeletal, and visceral anomalies. While the majority of SMS cases harbor an ~3.5 Mb common deletion on 17p11.2 that encompasses the retinoic acid induced-1 (RAI1) gene, some patients carry small intragenic deletions or point mutations in RAI1. We present data on two cases of Smith-Magenis syndrome with mutation of RAI1. Both cases are phenotypically consistent with SMS and RAI1 mutation but also have other anomalies not previously reported in SMS, including spontaneous pneumothoraces. These cases also illustrate variability in the SMS phenotype not previously shown for RAI1 mutation cases, including hearing loss, absence of self-abusive behaviours, and mild global delays. Sequencing of RAI1 revealed mutation of the same heptameric C-tract (CCCCCCC) in exon 3 in both cases (c.3103delC one case and and c.3103insC in the other), resulting in frameshift mutations. Of the seven reported frameshift mutations occurring in poly C-tracts in RAI1, four cases (~57%) occur at this heptameric C-tract. Collectively, these results indicate that this heptameric C-tract is a preferential hotspot for single nucleotide insertion/deletions (SNindels) and therefore, should be considered a primary target for analysis in patients suspected for mutations in RAI1. We expect that as more patients are sequenced for mutations in RAI1, the incidence of frameshift mutations in this hotspot will become more evident

Alternative splicing enriched cDNA libraries identify breast cancer-associated transcripts

<p>Abstract</p> <p>Background</p> <p>Alternative splicing (AS) is a central mechanism in the generation of genomic complexity and is a major contributor to transcriptome and proteome diversity. Alterations of the splicing process can lead to deregulation of crucial cellular processes and have been associated with a large spectrum of human diseases. Cancer-associated transcripts are potential molecular markers and may contribute to the development of more accurate diagnostic and prognostic methods and also serve as therapeutic targets. Alternative splicing-enriched cDNA libraries have been used to explore the variability generated by alternative splicing. In this study, by combining the use of trapping heteroduplexes and RNA amplification, we developed a powerful approach that enables transcriptome-wide exploration of the AS repertoire for identifying AS variants associated with breast tumor cells modulated by <it>ERBB2</it> (<it>HER-2/neu</it>) oncogene expression.</p> <p>Results</p> <p>The human breast cell line (C5.2) and a pool of 5 ERBB2 over-expressing breast tumor samples were used independently for the construction of two AS-enriched libraries. In total, 2,048 partial cDNA sequences were obtained, revealing 214 alternative splicing sequence-enriched tags (ASSETs). A subset with 79 multiple exon ASSETs was compared to public databases and reported 138 different AS events. A high success rate of RT-PCR validation (94.5%) was obtained, and 2 novel AS events were identified. The influence of <it>ERBB2</it>-mediated expression on AS regulation was evaluated by capillary electrophoresis and probe-ligation approaches in two mammary cell lines (Hb4a and C5.2) expressing different levels of <it>ERBB2</it>. The relative expression balance between AS variants from 3 genes was differentially modulated by <it>ERBB2</it> in this model system.</p> <p>Conclusions</p> <p>In this study, we presented a method for exploring AS from any RNA source in a transcriptome-wide format, which can be directly easily adapted to next generation sequencers. We identified AS transcripts that were differently modulated by <it>ERBB2</it>-mediated expression and that can be tested as molecular markers for breast cancer. Such a methodology will be useful for completely deciphering the cancer cell transcriptome diversity resulting from AS and for finding more precise molecular markers.</p

Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes

The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11–q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3×10−5). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3×10−4). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3×10−39), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts

Sustainability centres and fit: how centres work to integrate sustainability within business schools

For nearly as long as the topic of sustainable business has been taught and researched in business schools, proponents have warned about barriers to genuine integration in business school practices. This article examines how academic sustainability centres try to overcome barriers to integration by achieving technical, cultural and political fit with their environment (Ansari, Fiss, & Zajac, 2010). Based on survey and interview data, we theorise that technical, cultural and political fit are intricately related, and that these interrelations involve legitimacy, resources and collaboration effects. Our findings about sustainability centres offer novel insights on integrating sustainable business education given the interrelated nature of different types of fit and misfit. We further contribute to the literature on fit by highlighting that incompatibility between strategies to achieve different types of fit may act as a source of dynamism

Somatic retrotransposition alters the genetic landscape of the human brain

Retrotransposons are mobile genetic elements that use a germline 'copy-and-paste' mechanism to spread throughout metazoan genomes. At least 50 per cent of the human genome is derived from retrotransposons, with three active families (L1, Alu and SVA) associated with insertional mutagenesis and disease. Epigenetic and post-transcriptional suppression block retrotransposition in somatic cells, excluding early embryo development and some malignancies. Recent reports of L1 expression and copy number variation in the human brain suggest that L1 mobilization may also occur during later development. However, the corresponding integration sites have not been mapped. Here we apply a high-throughput method to identify numerous L1, Alu and SVA germline mutations, as well as 7,743 putative somatic L1 insertions, in the hippocampus and caudate nucleus of three individuals. Surprisingly, we also found 13,692 somatic Alu insertions and 1,350 SVA insertions. Our results demonstrate that retrotransposons mobilize to protein-coding genes differentially expressed and active in the brain. Thus, somatic genome mosaicism driven by retrotransposition may reshape the genetic circuitry that underpins normal and abnormal neurobiological processes

EFEKTIVITAS PENGAWASAN UNIT KERJA ANTI FRAUD PADA BANK MUAMALAT INDONESIA

Perkembangan perbankan syari‟ah di Indonesia demikian pesat yang ditandai dengan berdirinya Bank Muamalat Indonesia. Perkembangan ini berimplikasi pada besarnya tantangan perbankan syari‟ah di Indonesia terutama dalam mempertahankan identitasnya sebagai perusahaan yang bergerak berlandaskan prinsip-prinsip syari‟ah. Sejak berdirinya perbankan syariah,berbagai kontroversi muncul dari masyarakat, masalah yang paling banyak disorot adalah pelekatan label syariah pada institusi keuangan Islam yang masih dianggap belum layak. Keraguan masyarakat tersebut seolah terjawab dengan munculnya kasus yang cukup menggemparkan yakni kasus fraud (tindak kecurangan) yang terjadi di lembaga syariah. Bank Muamalat Indonesia merupakan bank syari‟ah pertama yang muncul dengan gagasan bank murni syari‟ah. Akan tetapi, bank Muamalat Indonesia juga tak luput dari kasus fraud yang dilakukan oleh karyawan bank tersebut. Berdasarkan Laporan Tahunan BMI menyebutkan bahwa telah terjadi peningkatan kasus fraud dari tahun sebelumnya yang berjumlah 18 kasus menjadi 82 kasus pada tahun 2016. Padahal perusahaan yang menggunakan identitas syariah seharusnya dapat lebih meminimalisir bahkan meniadakan resiko terjadinya kasus fraud dengan adanya internal control perusahaan. Dari latar belakang tersebut, peneliti berusaha mendalami peran pengawasan Unit Kerja Anti Fraud dalam fraud preventive pada Bank Muamalat Indonesia. Penelitian ini merupakan penelitin pustaka yang bersifat deskriptif analisis dengan pendekatan kualitatif. Adapun sumber bahan hukum primer yang dipakai yaitu berdasarkan Laporan Tahunan Bank Muamalat Indonesia Tahun 2016. Sedangkan sumber bahan hukum sekunder berupa buku-buku, jurnal,karya ilmiah, artikel, terkait dengan strategi anti fraud perbankan syariah. Dari hasil penelitian dikemukakan bahwa peningkatan kasus fraud yang terjadi pada Bank Muamalat Indonesia disebabkan kurang efektifnya pengawasan Unit Kerja Anti Fraud. Hal ini dikarenakan kegiatan yang dilakukan selama tahun 2016 belum menujukkan adanya usaha preventif terhadap kasus fraud. Sedangkan pencegahan merupakan pilar penting dalam keefektivan sebuah pengawasan. Tujuan perusahaan dalam mencegah fraud dapat tercapai, jika fungsi pengawasan dilakukan sebelum terjadinya penyimpangan-penyimpangan sehingga lebih bersifat mencegah (prefentive control). Oleh karena itu, keefektivan pengawasan Unit Kerja Anti Fraud diharapkan dapat meminimalisir tindak kecurangan demi mewujudkan perusahaan yang patuh terhadap ketentuan syariah sesuai dengan identitas perusahaan. vii Usaha pencegahan terjadinya kasus pada Bank Muamalat Indonesia diharapkan dapat menjadi bukti terlaksananya tatakelola perusahaan (Good Corporate Governance) pada Bank Syari‟ah dengan baik. Hal ini berdasarkan dalam dalam perbankan syariah dikenal adanya prinsip-prinsip syariah yang mendukung bagi terlaksananya prinsip GCG yakni keharusan bagi subjek hukum termasuk bank untuk menerapkan prinsip kejujuran (shiddiq), edukasi kepada masyarakat (tabligh), kepercayaan (amanah), dan pengelolaan secara profesional (fathanah)

Self-reported race/ethnicity in the age of genomic research: its potential impact on understanding health disparities

This review explores the limitations of self-reported race, ethnicity, and genetic ancestry in biomedical research. Various terminologies are used to classify human differences in genomic research including race, ethnicity, and ancestry. Although race and ethnicity are related, race refers to a person’s physical appearance, such as skin color and eye color. Ethnicity, on the other hand, refers to communality in cultural heritage, language, social practice, traditions, and geopolitical factors. Genetic ancestry inferred using ancestry informative markers (AIMs) is based on genetic/genomic data. Phenotype-based race/ethnicity information and data computed using AIMs often disagree. For example, self-reporting African Americans can have drastically different levels of African or European ancestry. Genetic analysis of individual ancestry shows that some self-identified African Americans have up to 99% of European ancestry, whereas some self-identified European Americans have substantial admixture from African ancestry. Similarly, African ancestry in the Latino population varies between 3% in Mexican Americans to 16% in Puerto Ricans. The implication of this is that, in African American or Latino populations, self-reported ancestry may not be as accurate as direct assessment of individual genomic information in predicting treatment outcomes. To better understand human genetic variation in the context of health disparities, we suggest using “ancestry” (or biogeographical ancestry) to describe actual genetic variation, “race” to describe health disparity in societies characterized by racial categories, and “ethnicity” to describe traditions, lifestyle, diet, and values. We also suggest using ancestry informative markers for precise characterization of individuals’ biological ancestry. Understanding the sources of human genetic variation and the causes of health disparities could lead to interventions that would improve the health of all individuals

An indirect examination of the function of problem behaviour associated with Fragile X Syndrome and Smith-Magenis Syndrome

Fragile X syndrome (FXS) and Smith-Magenis syndrome (SMS) are associated with a number of specific topographies of problem behavior. Very few studies have examined the function served by problem behavior in these groups. Using the Questions About Behavioral Function scale Matson and Vollmer (User’s guide: questions about behavioral function (QABF). Scientific Publishers Inc., Baton Rouge, LA, 1995) the current study examined group differences in the function of problem behavior displayed by children with FXS and SMS, in comparison to a control group of children with non-specific intellectual and developmental disabilities. Between-group analyses showed children with SMS were more likely to display problem behavior related to physical discomfort. Both within- and between-group analyses showed children with FXS were less likely to display attention-maintained problem behavior. These findings hold implications for the assessment, treatment and prevention of problem behavior associated with both FXS and SMS