Voice characteristics in adults with neurofibromatosis type 1

Introduction and aims of the study: Change or loss of voice in patients with neurofibromatosis type 1 (NF1) has been associated with head and neck neurofibromas. However, laryngeal involvement in NF1 is rare and voice abnormalities have also been reported in absence of such a tumor. Authors mention the occurrence of deviations in voice quality (such as breathiness, hoarseness, harshness, presence of a creak) and problems in regulating pitch and loudness. These studies are mainly based on perceptual evaluations. Therefore, the purpose of this study was to examine the voice characteristics of adult NF1 patients without laryngeal manifestations using a multiparameter approach. Methods: A total of 22 NF1 patients (age range 17-64 years) and 22 controls (age range 18-67 years) participated in the study. The patient group consisted of 9 males (mean age 39,33 years) and 13 females (mean age 32,69 years). The control group consisted of 12 males (mean age 38,00 years) and 10 females (mean age 32,90 years). Voice characteristics were evaluated using aerodynamic, voice range and acoustic measurements. These measurements allowed us to determine the Dysphonia Severity Index (DSI). Additionally, participants were asked to complete the Voice Handicap Index (VHI), a questionnaire concerning voice-related quality of life. Results: Vital capacity was significantly reduced in NF1 patients compared with controls. Also, the frequency and intensity range were significantly narrower in the patient group compared with controls. The narrower frequency and intensity range were due to a significantly lower highest frequency and a significantly lower highest intensity respectively. Additionally, male NF1 patients showed a significantly higher lowest intensity compared with male controls. Further, during reading, female NF1 patients exhibited a significantly smaller standard deviation of the mean frequency compared with female controls. This trend was also observed in the male NF1 patients compared with male controls. However, a significant difference could not be demonstrated. Finally, DSI scores were significantly lower and VHI values were significantly higher in both sexes of the patient group compared with controls. Conclusion: NF1 patients appear to have a vocal quality that is worse compared with controls. In particular, it seems that NF1 patients have reduced laryngeal possibilities with respect to fundamental frequency and sound intensity compared with controls. They are also more likely to present a more marked psychosocial voice impact compared with controls

Pre- and post-testing counseling considerations for the provision of expanded carrier screening : exploration of European geneticists’ views

Background: Carrier screening is generally performed with the aim of identifying healthy couples at risk of having a child affected with a monogenic disorder to provide them with reproductive options. Expanded carrier screening (ECS), which provides the opportunity for multiple conditions to be screened in one test, offers a more cost-effective and comprehensive option than screening for single disorders. However, implementation of ECS at a population level would have implications for genetic counseling practice. Methods: We conducted semi-structured interviews with sixteen European clinical and molecular geneticists with expertise in carrier screening to explore their views on the implementation of ECS in the clinical setting. Results: Using inductive content analysis, we identified content categories relevant to the pre- and post-test settings. Participants believed ECS would ideally be targeted at couples before pregnancy. There was some disagreement regarding the acceptability of performing ECS in individuals, with several participants actively opposing individual-based screening. In addition, participants discussed the importance of ensuring informed and voluntary participation in ECS, recommending measures to minimize external pressure on prospective parents to undergo testing. A need for adequate counseling to foster informed, autonomous reproductive decision-making and provide support for couples found to be at risk was emphasized. Conclusions: Practical challenges in optimizing pre-test education and post-test counseling should not be underestimated and they should be carefully addressed before implementing ECS in the clinical setting

Implementation of non-invasive prenatal testing by semiconductor sequencing in a genetic laboratory

Objectives: To implement non-invasive prenatal testing (NIPT) for fetal aneuploidies with semiconductor sequencing in an academic cytogenomic laboratory and to evaluate the first 15-month experience on clinical samples. Methods: We validated a NIPT protocol for cell-free fetal DNA sequencing from maternal plasma for the detection of trisomy 13, 18 and 21 on a semiconductor sequencing instrument. Fetal DNA fraction calculation for all samples and several quality parameters were implemented in the workflow. One thousand eighty-one clinical NIPT samples were analysed, following the described protocol. Results: Non-invasive prenatal testing was successfully implemented and validated on 201 normal and 74 aneuploid samples. From 1081 clinical samples, 17 samples showed an abnormal result: 14 trisomy 21 samples, one trisomy 18 and one trisomy 16 were detected. Also a maternal copy number variation on chromosome 13 was observed, which could potentially lead to a false positive trisomy 13 result. One sex discordant result was reported, possibly attributable to a vanishing twin. Moreover, our combined fetal fraction calculation enabled a more reliable risk estimate for trisomy 13, 18 and 21. Conclusions: Non-invasive prenatal testing for trisomy 21, 18 and 13 has a very high specificity and sensitivity. Because of several biological phenomena, diagnostic invasive confirmation of abnormal results remains required

Attitudes of European geneticists regarding expanded carrier screening

Objective: To explore attitudes of clinical and molecular geneticists about the implementation of multi-disease or expanded carrier screening (ECS) for monogenic recessive disorders. Design: Qualitative; semistructured interviews. Setting: In person or via Skype. Interviews were audiorecorded and transcribed verbatim. Participants: European clinical and molecular geneticists with expertise in carrier screening (N = 16). Methods: Inductive content analysis was used to identify common content categories in the data. Results: Participants recognized important benefits of ECS, but they also identified major challenges, including limited benefit of ECS for most couples in the general population, lack of knowledge on carrier screening among nongenetic health care providers and the general public, potential negative implications of ECS for society, and limited economic resources. Participants favored an evidence-based approach to the implementation of population-wide ECS and were reluctant to actively offer ECS in the absence of demonstrable benefits. However, there was a consensus among the participants that ECS should be made available to couples who request the test. In addition, they believed ECS could be routinely offered to all people who use assisted reproduction. Conclusion: Although a limited ECS offer is practical, it also raises concerns over equality in access to screening. A comprehensive risk-benefit analysis is needed to determine the desirability of systematic population-wide ECS

The monotypic Brazilian genus Diacrodon is a synonym of Borreria (Spermacoceae, Rubiaceae): Morphological and molecular evidences

Diacrodon is a monotypic genus of the tribe Spermacoceae (Rubiaceae), endemic to northeastern Brazil. Diacrodon compressus is frequently misidentified with a two lobed calyx species of Borreria, B. verticillata. Traditionally, in Spermacoceae the fruit type was considered a diagnostic character among the genera. In this sense, D. compressus presents a strongly compressed, one seeded and indehiscent fruit (vs. globose, two seeded and dehiscent fruit in B. verticillata). In this work, we address two objectives: evaluate the systematic position and determine the identity of Diacrodon in respect to other taxa. Molecular analyses using ITS and ETS indicate that D. compressus is strongly related to other species of Borreria. The morphological results revealed that D. compressus, despite of its type of fruit, is identical to Borreria in floral and palynological features. As conclusion, the new combination Borreria diacrodonta is made and a lectotype is designated. An updated description of the species and a key to the Borreria species with a two lobed calyx are provided. The distribution of B. diacrodonta is extended to Brazilian states Goiás and Minas Gerais, and Paraguay. By this taxonomical change it has become clear that the dehiscence of the fruits lack taxonomic value in the delimitation of Borreria.Fil: Miguel, Laila Mabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; ArgentinaFil: Sobrado, Sandra Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; ArgentinaFil: Janssens, Steven. Botanic Garden Meise; BélgicaFil: Dessein, Steven. Botanic Garden Meise; BélgicaFil: Cabral, Elsa Leonor. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Botánica del Nordeste. Universidad Nacional del Nordeste. Facultad de Ciencias Agrarias. Instituto de Botánica del Nordeste; Argentina. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas y Naturales y Agrimensura; Argentin

Profiling of conserved non-coding elements upstream of SHOX and functional characterisation of the SHOX cis-regulatory landscape

Genetic defects such as copy number variations (CNVs) in non-coding regions containing conserved non-coding elements (CNEs) outside the transcription unit of their target gene, can underlie genetic disease. An example of this is the short stature homeobox (SHOX) gene, regulated by seven CNEs located downstream and upstream of SHOX, with proven enhancer capacity in chicken limbs. CNVs of the downstream CNEs have been reported in many idiopathic short stature (ISS) cases, however, only recently have a few CNVs of the upstream enhancers been identified. Here, we set out to provide insight into: (i) the cis-regulatory role of these upstream CNEs in human cells, (ii) the prevalence of upstream CNVs in ISS, and (iii) the chromatin architecture of the SHOX cis-regulatory landscape in chicken and human cells. Firstly, luciferase assays in human U2OS cells, and 4C-seq both in chicken limb buds and human U2OS cells, demonstrated cis-regulatory enhancer capacities of the upstream CNEs. Secondly, CNVs of these upstream CNEs were found in three of 501 ISS patients. Finally, our 4C-seq interaction map of the SHOX region reveals a cis-regulatory domain spanning more than 1 Mb and harbouring putative new cis-regulatory elementsThis study is supported by FWO grant G079711N (CIS-CODE). Spanish and Andalusian government grants BFU2010-14839, BFU2013-41322-P, and BIO-396 to J.L.G.S. and SAF2012-30871 to K.E.H. and S.B.S. Andalusian government supports A.F.M. as the scientific manager of the CABD´s Aquatic Vertebrates Platform. CIBERER supports S.B.S

Clinical expression of Menkes disease in females with normal karyotype

<p>Abstract</p> <p>Background</p> <p>Menkes Disease (MD) is a rare X-linked recessive fatal neurodegenerative disorder caused by mutations in the <it>ATP7A </it>gene, and most patients are males. Female carriers are mosaics of wild-type and mutant cells due to the random X inactivation, and they are rarely affected. In the largest cohort of MD patients reported so far which consists of 517 families we identified 9 neurologically affected carriers with normal karyotypes.</p> <p>Methods</p> <p>We investigated at-risk females for mutations in the <it>ATP7A </it>gene by sequencing or by multiplex ligation-dependent probe amplification (MLPA). We analyzed the X-inactivation pattern in affected female carriers, unaffected female carriers and non-carrier females as controls, using the human androgen-receptor gene methylation assay (<it>HUMAR</it>).</p> <p>Results</p> <p>The clinical symptoms of affected females are generally milder than those of affected boys with the same mutations. While a skewed inactivation of the X-chromosome which harbours the mutation was observed in 94% of 49 investigated unaffected carriers, a more varied pattern was observed in the affected carriers. Of 9 investigated affected females, preferential silencing of the normal X-chromosome was observed in 4, preferential X-inactivation of the mutant X chromosome in 2, an even X-inactivation pattern in 1, and an inconclusive pattern in 2. The X-inactivation pattern correlates with the degree of mental retardation in the affected females. Eighty-one percent of 32 investigated females in the control group had moderately skewed or an even X-inactivation pattern.</p> <p>Conclusion</p> <p>The X- inactivation pattern alone cannot be used to predict the phenotypic outcome in female carriers, as even those with skewed X-inactivation of the X-chromosome harbouring the mutation might have neurological symptoms.</p

Responsible implementation of expanded carrier screening.

This document of the European Society of Human Genetics contains recommendations regarding responsible implementation of expanded carrier screening. Carrier screening is defined here as the detection of carrier status of recessive diseases in couples or persons who do not have an a priori increased risk of being a carrier based on their or their partners' personal or family history. Expanded carrier screening offers carrier screening for multiple autosomal and X-linked recessive disorders, facilitated by new genetic testing technologies, and allows testing of individuals regardless of ancestry or geographic origin. Carrier screening aims to identify couples who have an increased risk of having an affected child in order to facilitate informed reproductive decision making. In previous decades, carrier screening was typically performed for one or few relatively common recessive disorders associated with significant morbidity, reduced life-expectancy and often because of a considerable higher carrier frequency in a specific population for certain diseases. New genetic testing technologies enable the expansion of screening to multiple conditions, genes or sequence variants. Expanded carrier screening panels that have been introduced to date have been advertised and offered to health care professionals and the public on a commercial basis. This document discusses the challenges that expanded carrier screening might pose in the context of the lessons learnt from decades of population-based carrier screening and in the context of existing screening criteria. It aims to contribute to the public and professional discussion and to arrive at better clinical and laboratory practice guidelines.European Journal of Human Genetics advance online publication, 16 March 2016; doi:10.1038/ejhg.2015.271

Congenital hydrocephalus : new Mendelian mutations and evidence for oligogenic inheritance

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