Behavioral phenotype in five individuals with de novo mutations within the GRIN2B gene

Background: Intellectual disability (ID) is often associated with behavioral problems or disorders. Mutations in the GRIN2B gene (MRD6, MIM613970) have been identified as a common cause of ID (prevalence of 0.5 – 1% in individuals with ID) associated with EEG and behavioral problems. Methods: We assessed five GRIN2B mutation carriers aged between 3 and 14 years clinically and via standardized questionnaires to delineate a detailed behavioral phenotype. Parents and teachers rated problem behavior of their affected children by completing the Developmental Behavior Checklist (DBC) and the Conners’ Rating Scales Revised (CRS-R:L). Results: All individuals had mild to severe ID and needed guidance in daily routine. They showed characteristic behavior problems with prominent hyperactivity, impulsivity, distractibility and a short attention span. Stereotypies, sleeping problems and a friendly but boundless social behavior were commonly reported. Conclusion: Our observations provide an initial delineation of the behavioral phenotype of GRIN2B mutation carriers

Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Abstract Background Heterozygous copy-number and missense variants in CNTNAP2 and NRXN1 have repeatedly been associated with a wide spectrum of neuropsychiatric disorders such as developmental language and autism spectrum disorders, epilepsy and schizophrenia. Recently, homozygous or compound heterozygous defects in either gene were reported as causative for severe intellectual disability. Methods 99 patients with severe intellectual disability and resemblance to Pitt-Hopkins syndrome and/or suspected recessive inheritance were screened for mutations in CNTNAP2 and NRXN1. Molecular karyotyping was performed in 45 patients. In 8 further patients with variable intellectual disability and heterozygous deletions in either CNTNAP2 or NRXN1, the remaining allele was sequenced. Results By molecular karyotyping and mutational screening of CNTNAP2 and NRXN1 in a group of severely intellectually disabled patients we identified a heterozygous deletion in NRXN1 in one patient and heterozygous splice-site, frameshift and stop mutations in CNTNAP2 in four patients, respectively. Neither in these patients nor in eight further patients with heterozygous deletions within NRXN1 or CNTNAP2 we could identify a defect on the second allele. One deletion in NRXN1 and one deletion in CNTNAP2 occurred de novo, in another family the deletion was also identified in the mother who had learning difficulties, and in all other tested families one parent was shown to be healthy carrier of the respective deletion or mutation. Conclusions We report on patients with heterozygous defects in CNTNAP2 or NRXN1 associated with severe intellectual disability, which has only been reported for recessive defects before. These results expand the spectrum of phenotypic severity in patients with heterozygous defects in either gene. The large variability between severely affected patients and mildly affected or asymptomatic carrier parents might suggest the presence of a second hit, not necessarily located in the same gene.Peer Reviewe

Применение микробиологических методов для повышения нефтеотдачи на примере нефтяного месторождения Мухто (Сахалинская область)

Подбор и применение микробиологического метода увеличения нефтеотдачи на месторождении РН-Сахалинморнефтегаз.Актуальность этого метода заключается в том, что этот метод позволяет извлекать трудноизвлекаемые запасы нефти, которые увеличиваются с каждым годом. В этой работе выбирается наиболее эффективный микробный агент, и рассчитывается рентабельность этого нововведения для компании.Selection and application of the microbiological method of increasing oil recovery at the RN-Sakhalinmorneftegaz.The relevance of this method lies in the fact that this method allows you to extract hard-to-recover oil reserves, which increase every year. In this paper, the most effective microbial agent is selected, and the profitability of this innovation for the company is calculated

Foundations of Collective Cultural Rights in International Human Rights Law

Although collective cultural rights are included in international human rights law, their precise place and their nature and significance are not well-explored or understood. This paper aims to show where collective cultural rights can be found in international human rights law and explore how these rights fit in the general body and framework of international human rights law. The starting point in this chapter is international human rights law, which implies that the analysis of collective cultural rights is framed by positive law and international legal instruments, such as treaties and conventions, as well as by soft law instruments, such as declarations, recommendations and resolutions. In this paper, the two categories of collective rights and cultural rights are defined, drawing a distinction between a) different types of collective rights, including rights for collectivities as such, rights for individuals as members of collectivities, and rights with a collective interest or object; and b) between different types of cultural rights, including rights that explicitly refer to ‘culture’ and rights that relate to culture or have a cultural dimension. This paper furthermore analyses various contentious issues surrounding collective rights and cultural rights in international human rights law, including the lack of clarity on the object and subject of these rights. The paper then outlines the different forms of collective cultural rights in international human rights law, by providing examples of legal provisions in international human rights law that can be classified as collective cultural rights. Finally, the paper elaborates on how collective subjects and collective cultural interests are integrated in international human rights law and analyses how and to what extent collective cultural rights provisions provide answers to the above-noted issues

A mutation screen in patients with Kabuki syndrome

Kabuki syndrome (KS) is one of the classical, clinically well-known multiple anomalies/mental retardation syndromes, mainly characterized by a very distinctive facial appearance in combination with additional clinical signs such as developmental delay, short stature, persistent fingerpads, and urogenital tract anomalies. In our study, we sequenced all 54 coding exons of the recently identified MLL2 gene in 34 patients with Kabuki syndrome. We identified 18 distinct mutations in 19 patients, 11 of 12 tested de novo. Mutations were located all over the gene and included three nonsense mutations, two splice-site mutations, six small deletions or insertions, and seven missense mutations. We compared frequencies of clinical symptoms in MLL2 mutation carriers versus non-carriers. MLL2 mutation carriers significantly more often presented with short stature and renal anomalies (p = 0.026 and 0.031, respectively), and in addition, MLL2 carriers obviously showed more frequently a typical facial gestalt (17/19) compared with non-carriers (9/15), although this result was not statistically significant (p = 0.1). Mutation-negative patients were subsequently tested for mutations in ten functional candidate genes (e.g. MLL, ASC2, ASH2L, and WDR5), but no convincing causative mutations could be found. Our results indicate that MLL2 is the major gene for Kabuki syndrome with a wide spectrum of de novo mutations and strongly suggest further genetic heterogeneity

Targeted next generation sequencing as a diagnostic tool in epileptic disorders

Epilepsies have a highly heterogeneous background with a strong genetic contribution. The variety of unspecific and overlapping syndromic and nonsyndromic phenotypes often hampers a clear clinical diagnosis and prevents straightforward genetic testing. Knowing the genetic basis of a patient's epilepsy can be valuable not only for diagnosis but also for guiding treatment and estimating recurrence risks

Compound Heterozygosity of Low-Frequency Promoter Deletions and Rare Loss-of-Function Mutations in TXNL4A Causes Burn-McKeown Syndrome.

Mutations in components of the major spliceosome have been described in disorders with craniofacial anomalies, e.g., Nager syndrome and mandibulofacial dysostosis type Guion-Almeida. The U5 spliceosomal complex of eight highly conserved proteins is critical for pre-mRNA splicing. We identified biallelic mutations in TXNL4A, a member of this complex, in individuals with Burn-McKeown syndrome (BMKS). This rare condition is characterized by bilateral choanal atresia, hearing loss, cleft lip and/or palate, and other craniofacial dysmorphisms. Mutations were found in 9 of 11 affected families. In 8 families, affected individuals carried a rare loss-of-function mutation (nonsense, frameshift, or microdeletion) on one allele and a low-frequency 34 bp deletion (allele frequency 0.76%) in the core promoter region on the other allele. In a single highly consanguineous family, formerly diagnosed as oculo-oto-facial dysplasia, the four affected individuals were homozygous for a 34 bp promoter deletion, which differed from the promoter deletion in the other families. Reporter gene and in vivo assays showed that the promoter deletions led to reduced expression of TXNL4A. Depletion of TXNL4A (Dib1) in yeast demonstrated reduced assembly of the tri-snRNP complex. Our results indicate that BMKS is an autosomal-recessive condition, which is frequently caused by compound heterozygosity of low-frequency promoter deletions in combination with very rare loss-of-function mutations

Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation

Published online 1 September 2004To define the range of phenotypic expression in Treacher Collins syndrome (TCS; Franceschetti–Klein syndrome), we performed mutation analysis in the TCOF1 gene in 46 patients with tentative diagnosis of TCS and evaluated the clinical data, including a scoring system. A total of 27 coding exons of TCOF1 and adjacent splice junctions were analysed by direct sequencing. In 36 patients with a clinically unequivocal diagnosis of TCS, we detected 28 pathogenic mutations, including 25 novel alterations. No mutation was identified in the remaining eight patients with unequivocal diagnosis of TCS and 10 further patients, in whom the referring diagnosis of TCS was clinically doubtful. There is no overt genotype–phenotype correlation except that conductive deafness is significantly less frequent in patients with mutations in the 3' part of the open reading frame. Inter- and intrafamilial variation is wide. Some mutation carriers, parents of typically affected patients, are so mildly affected that the diagnosis might be overlooked clinically. This suggests that modifying factors are important for phenotypic expression. Based on these findings, minimal diagnostic criteria were defined: downward slanting palpebral fissures and hypoplasia of the zygomatic arch. The difficulties in genetic counselling, especially diagnosis of family members with a mild phenotype, are described.Özge Altug Teber, Gabriele Gillessen-Kaesbach, Sven Fischer, Stefan Böhringer, Beate Albrecht, Angelika Albert, Mine Arslan-Kirchner, Eric Haan, Monika Hagedorn-Greiwe, Christof Hammans, Wolfram Henn, Georg Klaus Hinkel, Rainer König, Erdmute Kunstmann, Jürgen Kunze, Luitgard M Neumann, Eva-Christina Prott, Anita Rauch, Hans-Dieter Rott, Heide Seide, Stephanie Spranger, Martin Sprengel, Barbara Zoll, Dietmar R Lohmann and Dagmar Wieczore