Publications by authors named "André Reis"

385 Publications

Mutations in and Other Panel Genes in Patients With Metastatic Breast Cancer -Association With Patient and Disease Characteristics and Effect on Prognosis.

J Clin Oncol 2021 Mar 29:JCO2001200. Epub 2021 Mar 29.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

Purpose: Among patients with metastatic breast cancer (mBC), the frequency of germline mutations in cancer susceptibility genes and the clinical relevance of these mutations are unclear. In this study, a prospective cohort of patients with mBC was used to determine mutation rates for breast cancer (BC) predisposition genes, to evaluate the clinical characteristics of patients with mutations, and to assess the influence of mutations on patient outcome.

Patients And Methods: Germline DNA from 2,595 patients with mBC enrolled in the prospective PRAEGNANT registry was evaluated for mutations in cancer predisposition genes. The frequencies of mutations in known BC predisposition genes were compared with results from a prospective registry of patients with nonmetastatic BC sequenced using the same QIAseq method and with public reference controls. Associations between mutation status and tumor characteristics, progression-free survival, and overall survival were assessed.

Results: Germline mutations in 12 established BC predisposition genes (including and ) were detected in 271 (10.4%) patients. A mutation in or was seen in 129 patients (5.0%). mutation carriers had a higher proportion of brain metastasis (27.1%) compared with nonmutation carriers (12.8%). Mutations were significantly enriched in PRAEGNANT patients with mBC compared with patients with nonmetastatic BC (10.4% 6.6%, < .01). Mutations did not significantly modify progression-free survival or overall survival for patients with mBC.

Conclusion: Multigene panel testing may be considered in all patients with mBC because of the high frequency of germline mutations in and other BC predisposition genes. Although the prognosis of mutation carriers and nonmutation carriers with mBC was similar, differences observed in tumor characteristics have implications for treatment and for future studies of targeted therapies.
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http://dx.doi.org/10.1200/JCO.20.01200DOI Listing
March 2021

EIF3F-related neurodevelopmental disorder: refining the phenotypic and expanding the molecular spectrum.

Orphanet J Rare Dis 2021 Mar 18;16(1):136. Epub 2021 Mar 18.

Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 10, 91054, Erlangen, Germany.

Background: An identical homozygous missense variant in EIF3F, identified through a large-scale genome-wide sequencing approach, was reported as causative in nine individuals with a neurodevelopmental disorder, characterized by variable intellectual disability, epilepsy, behavioral problems and sensorineural hearing-loss. To refine the phenotypic and molecular spectrum of EIF3F-related neurodevelopmental disorder, we examined independent patients.

Results: 21 patients were homozygous and one compound heterozygous for c.694T>G/p.(Phe232Val) in EIF3F. Haplotype analyses in 15 families suggested that c.694T>G/p.(Phe232Val) was a founder variant. All affected individuals had developmental delays including delayed speech development. About half of the affected individuals had behavioral problems, altered muscular tone, hearing loss, and short stature. Moreover, this study suggests that microcephaly, reduced sensitivity to pain, cleft lip/palate, gastrointestinal symptoms and ophthalmological symptoms are part of the phenotypic spectrum. Minor dysmorphic features were observed, although neither the individuals' facial nor general appearance were obviously distinctive. Symptoms in the compound heterozygous individual with an additional truncating variant were at the severe end of the spectrum in regard to motor milestones, speech delay, organic problems and pre- and postnatal growth of body and head, suggesting some genotype-phenotype correlation.

Conclusions: Our study refines the phenotypic and expands the molecular spectrum of EIF3F-related syndromic neurodevelopmental disorder.
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http://dx.doi.org/10.1186/s13023-021-01744-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977188PMC
March 2021

Agronomic biofortification of cowpea with zinc: Variation in primary metabolism responses and grain nutritional quality among 29 diverse genotypes.

Plant Physiol Biochem 2021 May 21;162:378-387. Epub 2021 Feb 21.

São Paulo State University (UNESP), 14884-900, Jaboticabal, SP, Brazil; São Paulo State University (UNESP), Rua Domingos da Costa Lopes 780, Jd. Itaipu, 17602-496, Tupã, SP, Brazil. Electronic address:

Dietary zinc (Zn) deficiency is widespread globally, and is particularly prevalent in low- and middle-income countries (LMICs). Cowpea (Vigna unguiculata (L.) Walp) is consumed widely in LMICs due to its high protein content, and has potential for use in agronomic biofortification strategies using Zn. This study aimed to evaluate the effect of Zn biofortification on grain nutritional quality of 29 cowpea genotypes. Zn application did not increase cowpea yield. In 11 genotypes sucrose concentration, in 12 genotypes total sugar concentration, and in 27 genotypes storage protein concentration increased in response to Zn supply. Fifteen genotypes had lower concentrations of amino acids under Zn application, which are likely to have been converted into storage proteins, mostly comprised of albumin. Phytic acid (PA) concentration and PA/Zn molar ratio were decreased under Zn application. Six genotypes increased shoot ureides concentration in response to Zn fertilization, indicating potential improvements to biological nitrogen fixation. This study provides valuable information on the potential for Zn application to increase cowpea grain nutritional quality by increasing Zn and soluble storage protein and decreasing PA concentration. These results might be useful for future breeding programs aiming to increase cowpea grain Zn concentrations through biofortification.
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http://dx.doi.org/10.1016/j.plaphy.2021.02.020DOI Listing
May 2021

Microbial composition of a hydropower cooling water system reveals thermophilic bacteria with a possible role in primary biofilm formation.

Biofouling 2021 Feb 18;37(2):246-256. Epub 2021 Mar 18.

Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.

Microfouling, ie biofilm formation on surfaces, can have an economic impact and requires costly maintenance in water-powered energy generation systems. In this study, the microbiota of a cooling system (filter and heat exchanger) in the Irapé hydroelectric power plant in Brazil was examined. The goal was to identify bacteria that could be targeted to more efficiently reduce biofilm formation. Two sampling campaigns were made corresponding to two well-defined seasons of the Brazilian Cerrado biome: the dry (campaign 1) and the wet (campaign 2). Microfouling communities varied considerably over time in samples obtained at different times after the last clearance of the heat exchanger. The thermophilic bacteria , and were exclusive and abundant in the microfouling of the heat exchanger in campaign 2, while methanotrophs and iron-reducing bacteria were abundant only in filter sediments. These findings could help to guide strategies for ecofriendly measures to reduce biofilm fouling in hydroelectric power plants, minimizing environmental and economic losses.
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http://dx.doi.org/10.1080/08927014.2021.1897790DOI Listing
February 2021

Clinical and molecular delineation of spondylocostal dysostosis type 3.

Clin Genet 2021 Mar 16. Epub 2021 Mar 16.

Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.

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http://dx.doi.org/10.1111/cge.13952DOI Listing
March 2021

Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior.

Genet Med 2021 Mar 3. Epub 2021 Mar 3.

Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.

Purpose: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis.

Methods: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes.

Results: These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes.

Conclusion: These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.
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http://dx.doi.org/10.1038/s41436-021-01114-zDOI Listing
March 2021

Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye.

Authors:
Zheng Li Zhenxun Wang Mei Chin Lee Matthias Zenkel Esther Peh Mineo Ozaki Fotis Topouzis Satoko Nakano Anita Chan Shuwen Chen Susan E I Williams Andrew Orr Masakazu Nakano Nino Kobakhidze Tomasz Zarnowski Alina Popa-Cherecheanu Takanori Mizoguchi Shin-Ichi Manabe Ken Hayashi Shigeyasu Kazama Kenji Inoue Yosai Mori Kazunori Miyata Kazuhisa Sugiyama Tomomi Higashide Etsuo Chihara Ryuichi Ideta Satoshi Ishiko Akitoshi Yoshida Kana Tokumo Yoshiaki Kiuchi Tsutomu Ohashi Toshiya Sakurai Takako Sugimoto Hideki Chuman Makoto Aihara Masaru Inatani Kazuhiko Mori Yoko Ikeda Morio Ueno Daniel Gaston Paul Rafuse Lesya Shuba Joseph Saunders Marcelo Nicolela George Chichua Sergo Tabagari Panayiota Founti Kar Seng Sim Wee Yang Meah Hui Meng Soo Xiao Yin Chen Anthi Chatzikyriakidou Christina Keskini Theofanis Pappas Eleftherios Anastasopoulos Alexandros Lambropoulos Evangelia S Panagiotou Dimitrios G Mikropoulos Ewa Kosior-Jarecka Augustine Cheong Yuanhan Li Urszula Lukasik Monisha E Nongpiur Rahat Husain Shamira A Perera Lydia Álvarez Montserrat García Héctor González-Iglesias Andrés Fernández-Vega Cueto Luis Fernández-Vega Cueto Federico Martinón-Torres Antonio Salas Çilingir Oguz Nevbahar Tamcelik Eray Atalay Bilge Batu Murat Irkec Dilek Aktas Burcu Kasim Yury S Astakhov Sergei Y Astakhov Eugeny L Akopov Andreas Giessl Christian Mardin Claus Hellerbrand Jessica N Cooke Bailey Robert P Igo Jonathan L Haines Deepak P Edward Steffen Heegaard Sonia Davila Patrick Tan Jae H Kang Louis R Pasquale Friedrich E Kruse André Reis Trevor R Carmichael Michael Hauser Michele Ramsay Georg Mossböck Nilgun Yildirim Kei Tashiro Anastasios G P Konstas Miguel Coca-Prados Jia Nee Foo Shigeru Kinoshita Chie Sotozono Toshiaki Kubota Michael Dubina Robert Ritch Janey L Wiggs Francesca Pasutto Ursula Schlötzer-Schrehardt Ying Swan Ho Tin Aung Wai Leong Tam Chiea Chuen Khor

JAMA 2021 02;325(8):753-764

Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.

Importance: Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness.

Objective: To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function.

Design, Setting, And Participants: A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome.

Exposures: Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function.

Main Outcomes And Measures: The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P < 2.5 × 10-6. The secondary outcomes included biochemical enzymatic assays and gene expression analyses.

Results: The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P = 6.1 × 10-7). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n = 1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n = 2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n = 1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n = 1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P < .001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P < .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome.

Conclusions And Relevance: In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.
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http://dx.doi.org/10.1001/jama.2021.0507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903258PMC
February 2021

Micronutrient fertilization enhances ROS scavenging system for alleviation of abiotic stresses in plants.

Plant Physiol Biochem 2021 Mar 30;160:386-396. Epub 2021 Jan 30.

São Paulo State University "Júlio de Mesquita Filho" (UNESP), Rua Domingos da Costa Lopes 780, 17602-496, Tupã, SP, Brazil. Electronic address:

Reactive oxygen species (ROS) such as hydrogen peroxide at low concentrations act as signaling of several abiotic stresses. Overproduction of hydrogen peroxide causes the oxidation of plant cell lipid phosphate layer promoting senescence and cell death. To mitigate the effect of ROS, plants develop antioxidant defense mechanisms (superoxide dismutase, catalase, guaiacol peroxidase), ascorbate-glutathione cycle enzymes (ASA-GSH) (ascorbate peroxidase, monodehydroascorbate reductase, dehydroascorbate reductase and glutathione reductase), which have the function of removing and transforming ROS into non-toxic substances to maintain cellular homeostasis. Foliar or soil application of fertilizers containing B, Cu, Fe, Mn, Mo, Ni, Se and Zn at low concentrations has the ability to elicit and activate antioxidative enzymes, non-oxidizing metabolism, as well as sugar metabolism to mitigate damage by oxidative stress. Plants treated with micronutrients show higher tolerance to abiotic stress and better nutritional status. In this review, we summarized results indicating micronutrient actions in order to reduce ROS resulting the increase of photosynthetic capacity of plants for greater crop yield. This meta-analysis provides information on the mechanism of action of micronutrients in combating ROS, which can make plants more tolerant to several types of abiotic stress such as extreme temperatures, salinity, heavy metals and excess light.
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http://dx.doi.org/10.1016/j.plaphy.2021.01.040DOI Listing
March 2021

Nano-selenium, silicon and HO boost growth and productivity of cucumber under combined salinity and heat stress.

Ecotoxicol Environ Saf 2021 Apr 4;212:111962. Epub 2021 Feb 4.

Department of Biosystems Engineering, School of Sciences and Engineering, São Paulo State University (UNESP), Tupã-SP 17602-496, Brazil. Electronic address:

The production of cucumber under combined salinity and heat stress is a crucial challenge facing many countries particularly in arid environments. This challenge could be controlled through exogenous foliar application of some bio-stimulants or anti-stressors. This study was carried out to investigate the management and improving cucumber production under combined salinity and heat stress. Nano-selenium (nano-Se, 25 mg L), silicon (Si, 200 mg L) and hydrogen peroxide (HO, 20 mmol L) were foliar applied on cucumber plants as anti-stress compounds. The results revealed that studied anti-stressors improved growth and productivity of cucumber grown in saline soil regardless the kind of anti-stressor under heat stress. The foliar application of nano-Se (25 mg L) clearly improved cucumber growth parameters (plant height and leaf area) compared to other anti-stressor and control. Foliar Si application showed the greatest impact on enzymatic antioxidant capacities among the other anti-stressor treatments. This applied rate of Si also showed the greatest increase in marketable fruit yield and yield quality (fruit firmness and total soluble solids) compared to untreated plants. These increases could be due to increasing nutrient uptake particularly N, P, K, and Mg, as well as Se (by 40.2% and 43%) in leaves and Si (by 11.2% and 22.1% in fruits) in both seasons, respectively. The potential role of Si in mitigating soil salinity under heat stress could be referred to high Si content found in leaf which regulates water losses via transpiration as well as high nutrient uptake of other nutrients (N, P, K, Mg and Se). The distinguished high K content found in cucumber leaves might help stressed plants to tolerate studied stresses by regulating the osmotic balance and controlling stomatal opening, which support cultivated plants to adapt to soil salinity under heat stress. Further studies are needed to be carried out concerning the different response of cultivated plants to combined stresses.
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http://dx.doi.org/10.1016/j.ecoenv.2021.111962DOI Listing
April 2021

Chimeric synthetic reference standards enable cross-validation of positive and negative controls in SARS-CoV-2 molecular tests.

Sci Rep 2021 01 29;11(1):2636. Epub 2021 Jan 29.

Genomics and Epigenetics Theme, Garvan Institute of Medical Research, Sydney, NSW, Australia.

DNA synthesis in vitro has enabled the rapid production of reference standards. These are used as controls, and allow measurement and improvement of the accuracy and quality of diagnostic tests. Current reference standards typically represent target genetic material, and act only as positive controls to assess test sensitivity. However, negative controls are also required to evaluate test specificity. Using a pair of chimeric A/B RNA standards, this allowed incorporation of positive and negative controls into diagnostic testing for the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). The chimeric standards constituted target regions for RT-PCR primer/probe sets that are joined in tandem across two separate synthetic molecules. Accordingly, a target region that is present in standard A provides a positive control, whilst being absent in standard B, thereby providing a negative control. This design enables cross-validation of positive and negative controls between the paired standards in the same reaction, with identical conditions. This enables control and test failures to be distinguished, increasing confidence in the accuracy of results. The chimeric A/B standards were assessed using the US Centres for Disease Control real-time RT-PCR protocol, and showed results congruent with other commercial controls in detecting SARS-CoV-2 in patient samples. This chimeric reference standard design approach offers extensive flexibility, allowing representation of diverse genetic features and distantly related sequences, even from different organisms.
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http://dx.doi.org/10.1038/s41598-021-81760-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846570PMC
January 2021

Ultrasound as a Valuable Imaging Modality in Sclerosing Lymphocytic Lobulitis: Imaging Features Based on a Retrospective Cohort Analysis of 51 Cases.

Can Assoc Radiol J 2021 Jan 18:846537120983122. Epub 2021 Jan 18.

Hospital São Paulo, Universidade Federal de São Paulo, São Paulo, Brazil.

Purpose: Sclerosing lymphocytic lobulitis (SLL) is a rare benign breast condition usually associated with diabetes mellitus and whose imaging features have been assessed in few studies, limiting the adoption of diagnostic guidelines. We aimed to identify the main morphological features associated with SLL on imaging examinations (mainly ultrasound and mammography) and to retrospectively evaluate the role that each method played in the diagnostic workup (detection and indication for biopsy).

Methods: A retrospective study was conducted in a high-volume single center, encompassing 51 consecutive patients (100% female; 26-78 y; 43.7 ± 15.5 y) with histopathologically proven SLL (59 lesions; 0.5-6.1 cm).

Results: Most lesions (31/59; 53%) were found in asymptomatic individuals. Ultrasound detected 91.1% (51 out of 56 lesions assessed by this modality), of which 94.1% were non-circumscribed masses (BI-RADS® 4). Mammography detected 41.6% (15 out of 36 lesions assessed by this modality), with a predominance (80%) of non-calcified ones (masses, asymmetries and distortion). Two-year follow-up was achieved in 29 lesions (49%), showing complete remission (45%) or stability (41%) in most cases.

Conclusions: Most lesions in this retrospective sample have been detected by means of ultrasound and had their need for biopsy indicated by this modality. Female diabetic patients younger than 40 years presenting with a palpable lesion and a non-circumscribed mass on ultrasound could be submitted to core biopsy; histopathologic findings suggestive of SLL should be considered concordant in this scenario, with subsequent conservative treatment.
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http://dx.doi.org/10.1177/0846537120983122DOI Listing
January 2021

Early-onset parkinsonism in PPP2R5D-related neurodevelopmental disorder.

Eur J Med Genet 2021 Jan 15;64(1):104123. Epub 2020 Dec 15.

Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg FAU, Erlangen, Germany. Electronic address:

PPP2R5D-related neurodevelopmental disorder (NDD) is a rare autosomal-dominant disease with developmental delay and mild to severe intellectual disability. So far, fewer than 30 affected individuals with mostly recurrent, de novo missense variants in PPP2R5D were reported. Recently, parkinsonism with an onset between 20 and 40 years was reported in four adult individuals with the same p.(Glu200Lys) variant in PPP2R5D. By trio exome sequencing we now identified the variant p.(Glu198Lys) in a 29 year old woman presenting with typical clinical manifestations of PPP2R5D-related neurodevelopmental disorder and additionally with motor decline and levodopa responsive, early-onset parkinsonism from her mid-twenties on. Accordingly, a clear reduction of dopamine transporter in the striatum on both sides was revealed by brain scintigraphy. Our findings further expand the molecular and clinical spectrum of PPP2R5D-related NDD and confirm the association with parkinsonism in early adulthood. This has marked implications for prognosis of PPP2R5D-related NDDs and for the therapeutic management of motor decline and parkinson-like symptoms in affected individuals.
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http://dx.doi.org/10.1016/j.ejmg.2020.104123DOI Listing
January 2021

Selenium biofortification enhances ROS scavenge system increasing yield of coffee plants.

Ecotoxicol Environ Saf 2021 Feb 11;209:111772. Epub 2020 Dec 11.

São Paulo State University (UNESP), School of Sciences and Engineering, Tupã 17602-496, SP, Brazil. Electronic address:

There are conclusive evidences of selenium (Se) deficiency in Brazilian soils and foods. Brazil is the largest producer and consumer of coffee worldwide, which favors agronomic biofortification of its coffee. This study aimed to evaluate effects of foliar application of three formulations and six rates of Se on antioxidant metabolism, agronomic biofortification and yield of coffee beans. Seven Se concentrations (0, 10, 20, 40, 80, 100 and 160 mg L) were applied from three formulations of Se (sodium selenate, nano-Se 1500, and nano-Se 5000). Selenium application up to 40 mg L increased the concentration of photosynthetic pigments such as chlorophylls, pheophytins and carotenoids in coffee leaves. Foliar application of Se ranging from 20 to 80 mg L decreased lipid peroxidation and concentration of hydrogen peroxide, but increased superoxide dismutase, ascorbate peroxidase, catalase and glutathione reductase activities in coffee leaves. These results indicated that foliar Se application stimulates antioxidative metabolism to mitigate reactive oxygen species. Foliar application of 20 mg Se L of sodium selenate increased coffee yield by 38%, and 160 mg Se L of nano-Se 5000 increased dramatically coffee yield by 42%. Selenium concentration in grains ranged from 0.116 to 4.47 mg kg (sodium selenate), 4.84 mg kg (nano-Se 1500) and 5.82 mg kg (nano-Se 5000). The results suggest the beneficial effect of Se on the increment of photosynthetic pigments, antioxidative metabolism, increased coffee yield and nutritional quality of grains. The recommended foliar Se application in this study can mitigate abiotic stressors such as high temperatures resulting in higher yield of coffee plants.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111772DOI Listing
February 2021

Hormesis in plants: Physiological and biochemical responses.

Ecotoxicol Environ Saf 2021 Jan 8;207:111225. Epub 2020 Sep 8.

São Paulo State University "Júlio de Mesquita Filho" (UNESP), Rua Domingos da Costa Lopes 780, Postal Code 17602-496, Tupã, SP, Brazil. Electronic address:

Hormesis is a favorable response to low level exposures to substance or to adverse conditions. This phenomenon has become a target to achieve greater crop productivity. This review aimed to address the physiological mechanisms for the induction of hormesis in plants. Some herbicides present a hormetic dose response. Among them, those with active ingredients glyphosate, 2,4-D and paraquat. The application of glyphosate as a hormesis promoter is therefore showing promess . Glyphosate has prominent role in shikimic acid pathway, decreasing lignin synthesis resulting in improved growth and productivity of several crops. Further studies are still needed to estimate optimal doses for other herbicides of crops or agricultural interest. Biostimulants are also important, since they promote effects on secondary metabolic pathways and production of reactive oxygen species (ROS). When ROS are produced, hydrogen peroxide act as a signaling molecule that promote cell walls malleability allowing inward water transport causing cell expansion. . Plants'ability to overcome several abiotic stress conditions is desirable to avoid losses in crop productivity and economic losses. This review compiles information on how hormesis in plants can be used to achieve new production levels.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111225DOI Listing
January 2021

Assessment of selenium spatial distribution using μ-XFR in cowpea (Vigna unguiculata (L.) Walp.) plants: Integration of physiological and biochemical responses.

Ecotoxicol Environ Saf 2021 Jan 8;207:111216. Epub 2020 Sep 8.

São Paulo State University (UNESP), Via de Acesso Prof. Paulo Donato Castellane S/n, Jaboticabal, SP, Postal Code 14884-900, Brazil; São Paulo State University (UNESP), Rua Domingos da Costa Lopes 780, Tupã-SP, Postal Code 17602-496, Brazil. Electronic address:

Low concentrations of selenium (Se) are beneficial for plant growth. Foliar Se application at high concentrations is toxic to plants due to the formation of reactive oxygen species (ROS). This study characterized Se toxicity symptoms using X-ray fluorescence (XRF) technique in response to foliar Se application in cowpea plants. Five Se concentrations (0, 10, 25, 50, 100 e 150 g ha) were sprayed on leaves as sodium selenate. The visual symptoms of Se toxicity in cowpea leaves were separated into two stages: I) necrotic points with an irregular distribution and internerval chlorosis at the leaf limb border (50-100 g ha); II) total chlorosis with the formation of dark brown necrotic lesions (150 g ha). Foliar Se application at 50 g ha increased photosynthetic pigments and yield. Ultrastructural analyses showed that Se foliar application above 50 g ha disarranged the upper epidermis of cowpea leaves. Furthermore, Se application above 100 g ha significantly increased the hydrogen peroxide concentration and lipid peroxidation inducing necrotic leaf lesions. Mapping of the elements in leaves using the XRF revealed high Se intensity, specifically in leaf necrotic lesions accompanied by calcium (Ca) as a possible attenuating mechanism of plant stress. The distribution of Se intensities in the seeds was homogeneous, without specific accumulation sites. Phosphorus (P) and sulfur (S) were found primarily located in the embryonic region. Understanding the factors involved in Se accumulation and its interaction with Ca support new preventive measurement technologies to prevent Se toxicity in plants.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111216DOI Listing
January 2021

A novel splice variant expands the LAMC3-associated cortical phenotype to frontal only polymicrogyria and adult-onset epilepsy.

Am J Med Genet A 2020 11 9;182(11):2761-2764. Epub 2020 Sep 9.

Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.

Bi-allelic loss-of-function variants in LAMC3, encoding extracellular matrix protein laminin gamma 3, represent a rare cause of occipital polymicrogyria with epilepsy, developmental delay and cognitive impairment. So far, only five families have been reported. We now identified a novel, homozygous splice variant in LAMC3 in an individual with an unusual manifestation of cortical malformation. She presented with polymicrogyria in the frontal but not the occipital lobes, with adult-onset seizures and normal psychomotor development and cognition. Additionally, ictal asystole, requiring implantation of a pacemaker, and nonepileptic seizures occurred. This case expands the spectrum of LAMC3-associated cortical malformation phenotypes to frontal only polymicrogyria and adult-onset of epilepsy.
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http://dx.doi.org/10.1002/ajmg.a.61846DOI Listing
November 2020

Coffea arabica seedlings genotypes are tolerant to high induced selenium stress: Evidence from physiological plant responses and antioxidative performance.

Ecotoxicol Environ Saf 2020 Oct 19;203:111016. Epub 2020 Jul 19.

São Paulo State University (UNESP), Passeio Monção 830, Postal Code 15.385-000, Ilha Solteira, SP, Brazil; São Paulo State University (UNESP), Rua Domingos da Costa Lopes 780, Postal Code 17.602-496, Tupã, SP, Brazil. Electronic address:

Selenium (Se) is considered a beneficial element to higher plants based on its regulation of antioxidative system under abiotic or biotic stresses. However, the limit of beneficial and toxic physiological effects of Se is very narrow. In the present study, the antioxidant performance, nutritional composition, long-distance transport of Se, photosynthetic pigments, and growth of Coffea arabica genotypes in response to Se concentration in solution were evaluated. Five Coffea arabica genotypes (Obatã, IPR99, IAC125, IPR100 and Catucaí) were used, which were grown in the absence and presence of Se (0 and 1.0 mmol L) in nutrient solution. The application of 1 mmol L Se promoted root browning in all genotypes. There were no visual symptoms of leaf toxicity, but there was a reduction in the concentration of phosphorus and sulfur in the shoots of plants exposed to high Se concentration. Except for genotype Obatã, the coffee seedlings presented strategies for regulating Se uptake by reducing long-distance transport of Se from roots to shoots. The concentrations of total chlorophyll, total pheophytin, and carotenoids were negatively affected in genotypes Obatã, IPR99, and IAC125 upon exposure to Se at 1 mmol L. HO production was reduced in genotypes IPR99, IPR100, and IAC125 upon exposure to Se, resulting in lower activity of superoxide dismutase (SOD), and catalase (CAT). These results suggest that antioxidant metabolism was effective in regulating oxidative stress in plants treated with Se. The increase in sucrose, and decrease in SOD, CAT and ascorbate peroxidase (APX) activities, as well as Se compartmentalization in the roots, were the main biochemical and physiological modulatory effects of coffee seedlings under stress conditions due to excess of Se.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111016DOI Listing
October 2020

7q31.2q31.31 deletion downstream of FOXP2 segregating in a family with speech and language disorder.

Am J Med Genet A 2020 11 4;182(11):2737-2741. Epub 2020 Sep 4.

Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.

Chromosomal 7q31 deletions have been described in individuals with variable neurodevelopmental phenotypes including speech and language impairment. These copy number variants usually encompass FOXP2, haploinsufficiency of which represents a widely acknowledged cause for specific speech and language disorders. By chromosomal microarray analysis we identified a 4.7 Mb microdeletion at 7q31.2q31.31 downstream of FOXP2 in three family members presenting with variable speech, language and neurodevelopmental phenotypes. The index individual showed delayed speech development with impaired speech production, reduced language comprehension, and additionally learning difficulties, microcephaly, and attention deficit. His younger sister had delayed speech development with impaired speech production and partially reduced language comprehension. Their mother had attended a school for children with speech and language deficiencies and presented with impaired articulation. The deletion had occurred de novo in the mother, includes 15 protein-coding genes and is located in close proximity to the 3' end of FOXP2. Though a novel locus at 7q31.2q31.31 associated with mild neurodevelopmental and more prominent speech and language impairment is possible, the close phenotypic overlap with FOXP2-associated speech and language disorder rather suggests a positional effect on FOXP2 expression and function.
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http://dx.doi.org/10.1002/ajmg.a.61838DOI Listing
November 2020

Soybean seed vigor discrimination by using infrared spectroscopy and machine learning algorithms.

Anal Methods 2020 09;12(35):4303-4309

UFMS - Universidade Federal de Mato Grosso do Sul, Campo Grande, MS, Brazil.

A novel approach to distinguish soybean seed vigor based on Fourier transform infrared spectroscopy (FTIR) associated with chemometric methods is presented. Batches with high and low vigor soybean seeds were analyzed. Support vector machine (SVM), K-nearest neighbors (KNN), and discriminant analysis were applied to the raw spectral and reduced-dimensionality data from PCA (principal component analysis). Proteins, fatty acids, and amides were identified as the main molecules responsible for the discrimination of the batches. The cross-validation tests pointed out that high vigor soybean seeds were successfully discriminated from low vigor ones with an accuracy of 100%. These findings indicate FTIR spectroscopy associated with multivariate analysis as a new alternative approach to discriminate seed vigor.
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http://dx.doi.org/10.1039/d0ay01238fDOI Listing
September 2020

Selenium toxicity stress-induced phenotypical, biochemical and physiological responses in rice plants: Characterization of symptoms and plant metabolic adjustment.

Ecotoxicol Environ Saf 2020 Oct 27;202:110916. Epub 2020 Jun 27.

São Paulo State University (UNESP), 15385-000, Ilha Solteira, SP, Brazil; São Paulo State University (UNESP), 17602-496, Tupã, SP, Brazil. Electronic address:

Selenium (Se) at low concentration is considered benefit element to plants. The range between optimal and toxic concentration of Se is narrow and varies among plant species. This study aimed to evaluate the phenotypic, physiological and biochemical responses of four rice genotypes (BRS Esmeralda, BRSMG Relâmpago, BRS Bonança and Bico Ganga) grown hydroponically treated with sodium selenate (1.5 mM L). Selenium treated plants showed a dramatically decrease of soluble proteins, chlorophylls, and carotenoids concentration, resulting in the visual symptoms of toxicity characterized as leaf chlorosis and necrosis. Selenium toxicity caused a decrease on shoot and root dry weight of rice plants. Excess Se increased the oxidative stress monitored by the levels of hydrogen peroxide and lipid peroxidation. The enzymatic antioxidant system (catalase, superoxide dismutase, and ascorbate peroxidase) increased in response to Se supply. Interestingly, primary metabolism compounds such as sucrose, total sugars, nitrate, ammonia and amino acids increased in Se-treated plants. The increase in these metabolites may indicate a defense mechanism for the osmotic readjustment of rice plants to mitigate the toxicity caused by Se. However, these metabolites were not effective to minimize the damages on phenotypic traits such as leaf chlorosis and reduced shoot and root dry weight in response to excess Se. Increased sugars profile combined with antioxidant enzymes activities can be an effective biomarkers to indicate stress induced by Se in rice plants. This study shows the physiological attributes that must be taken into account for success in the sustainable cultivation of rice in environments containing excess Se.
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http://dx.doi.org/10.1016/j.ecoenv.2020.110916DOI Listing
October 2020

Clinical and radiographic evaluation of high viscosity bulk-fill resin composite restorations.

Am J Dent 2020 Aug;33(4):213-217

Faculdade São Leopoldo Mandic, Instituto de Pesquisa São Leopoldo Mandic, Campinas, São Paulo, Brazil,

Purpose: To perform a clinical and radiographic evaluation comparing Filtek Bulk Fill high viscosity bulk-fill resins with Filtek Z350 XT nanoparticulate for 1 year.

Methods: 58 restorations were performed for each material (bulk-fill and nanoparticulate), for a total of 116 restorations. Among these, 42 Class I and 16 Class II restorations were performed for each group, in molars and premolars. Clinical evaluation was performed 7 days (baseline), 6 months and 1 year after restorations, using the World Dental Federation (FDI) criteria. Radiographs were obtained at 7 days and 1 year after the restoration was placed and the radiopacity was measured using Image J software at the same time interval.

Results: Of the 70 restorations available for evaluation at 1 year, the Mann-Whitney and Friedman tests showed no statistically significant difference for the FDI criteria analyzed. Greater radiopacity was observed for bulk-fill resin compared to nanoparticulate (two-way ANOVA, P= 0.022). This same test showed no difference in radiopacity between the groups in the two evaluation periods (P= 0.062). The high viscosity bulk-fill resin composite presented similar clinical performance to nanoparticulate resin in this evaluation period and higher radiopacity was observed for this material when compared to nanoparticulate resin, in both time periods.

Clinical Significance: The high viscosity bulk-fill resin composite showed similar performance to the nanoparticulate resin during the evaluation period of 1 year. Radiopacity showed high values for the bulk-fill resin when compared to nanoparticulate resin. The bulk-fill resin has potential to be used in posterior teeth.
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August 2020

Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases.

Am J Hum Genet 2020 09 5;107(3):527-538. Epub 2020 Aug 5.

Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen 91054, Germany. Electronic address:

Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%-41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E-08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E-09); this effect was stronger when including IL36RN mutations (1.48E-13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.
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http://dx.doi.org/10.1016/j.ajhg.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477008PMC
September 2020

Urban critical infrastructure disruption after a radiological dispersive device event.

J Environ Radioact 2020 Oct 1;222:106358. Epub 2020 Aug 1.

Nuclear Engineering Graduate Program, Federal University of Rio de Janeiro (COPPE/UFRJ), Rio de Janeiro, Brazil. Electronic address:

This study aims to evaluate the impacts of the activation of a hypothetical radiological dispersal device (RDD) on the urban critical infrastructure (health facilities and public transport). A densely populated urban region was chosen as a scenery. Additionally, the influence of local environmental factors in the post-detonation process was verified. The source term was Cs-137 due to its mobility in the environment and relative ease of access. The approach used for the evaluation of the consequences was a computer simulation by Gaussian modeling. The HotSpot Health Physics Codes software was applied in conjunction with the RESRAD-RDD software. The results suggest that there is a strong influence of the local atmospheric stability classes (Pasquill-Gifford classes) on both the total equivalent effective dose (TEDE) and soil contamination. Consequently, the impacts on critical urban infrastructure follow the same trend. The method used for comparing the simulated and reference limits was the proportional ratio. All calculated values for radioactive contamination were divided by the reference value adopted by the RESRAD-RDD model for urban critical infrastructure. The results indicate that the information compiled is useful to support the decision-making process, although it is not sufficient to provide care and support for longer periods than those considered in the initial response phase.
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http://dx.doi.org/10.1016/j.jenvrad.2020.106358DOI Listing
October 2020

Breast MRI texture analysis for prediction of BRCA-associated genetic risk.

BMC Med Imaging 2020 07 29;20(1):86. Epub 2020 Jul 29.

Department of Radiology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.

Background: BRCA1/2 deleterious variants account for most of the hereditary breast and ovarian cancer cases. Prediction models and guidelines for the assessment of genetic risk rely heavily on criteria with high variability such as family cancer history. Here we investigated the efficacy of MRI (magnetic resonance imaging) texture features as a predictor for BRCA mutation status.

Methods: A total of 41 female breast cancer individuals at high genetic risk, sixteen with a BRCA1/2 pathogenic variant and twenty five controls were included. From each MRI 4225 computer-extracted voxels were analyzed. Non-imaging features including clinical, family cancer history variables and triple negative receptor status (TNBC) were complementarily used. Lasso-principal component regression (L-PCR) analysis was implemented to compare the predictive performance, assessed as area under the curve (AUC), when imaging features were used, and lasso logistic regression or conventional logistic regression for the remaining analyses.

Results: Lasso-selected imaging principal components showed the highest predictive value (AUC 0.86), surpassing family cancer history. Clinical variables comprising age at disease onset and bilateral breast cancer yielded a relatively poor AUC (~ 0.56). Combination of imaging with the non-imaging variables led to an improvement of predictive performance in all analyses, with TNBC along with the imaging components yielding the highest AUC (0.94). Replacing family history variables with imaging components yielded an improvement of classification performance of ~ 4%, suggesting that imaging compensates the predictive information arising from family cancer structure.

Conclusions: The L-PCR model uncovered evidence for the utility of MRI texture features in distinguishing between BRCA1/2 positive and negative high-risk breast cancer individuals, which may suggest value to diagnostic routine. Integration of computer-extracted texture analysis from MRI modalities in prediction models and inclusion criteria might play a role in reducing false positives or missed cases especially when established risk variables such as family history are missing.
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http://dx.doi.org/10.1186/s12880-020-00483-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388478PMC
July 2020

CRISPR/Cas9 mediated generation of human ARID1B heterozygous knockout hESC lines to model Coffin-Siris syndrome.

Stem Cell Res 2020 Jun 29;47:101889. Epub 2020 Jun 29.

Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Department of Stem Cell Biology, 91054 Erlangen, Germany; Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Institute of Biochemistry, 91054 Erlangen, Germany.

ARID1B haploinsufficiency induced by missense or nonsense mutations of ARID1B is a cause of Coffin-Siris syndrome (CSS), a neurodevelopmental disorder associated with intellectual disability. At present, no appropriate human stem cell model for ARID1B-associated CSS has been reported. Here, we describe the generation and validation of ARID1B hESCs by introducing out of frame deletions into exon 5 or 6 of ARID1B with CRISPR/Cas9 genome editing. These ARID1B hESC lines allow to study the pathophysiology of ARID1B-associated CSS in 2D and 3D models of human neurodevelopment.
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http://dx.doi.org/10.1016/j.scr.2020.101889DOI Listing
June 2020

A universal and independent synthetic DNA ladder for the quantitative measurement of genomic features.

Nat Commun 2020 07 17;11(1):3609. Epub 2020 Jul 17.

Garvan Institute of Medical Research, Sydney, New South Wales, Australia.

Standard units of measurement are required for the quantitative description of nature; however, few standard units have been established for genomics to date. Here, we have developed a synthetic DNA ladder that defines a quantitative standard unit that can measure DNA sequence abundance within a next-generation sequencing library. The ladder can be spiked into a DNA sample, and act as an internal scale that measures quantitative genetics features. Unlike previous spike-ins, the ladder is encoded within a single molecule, and can be equivalently and independently synthesized by different laboratories. We show how the ladder can measure diverse quantitative features, including human genetic variation and microbial abundance, and also estimate uncertainty due to technical variation and improve normalization between libraries. This ladder provides an independent quantitative unit that can be used with any organism, application or technology, thereby providing a common metric by which genomes can be measured.
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http://dx.doi.org/10.1038/s41467-020-17445-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367866PMC
July 2020

A case of severe autosomal recessive spinocerebellar ataxia type 18 with a novel nonsense variant in GRID2.

Eur J Med Genet 2020 Sep 2;63(9):103998. Epub 2020 Jul 2.

Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg FAU, Erlangen, Germany. Electronic address:

Autosomal-recessive spinocerebellar ataxia type 18 (SCAR18) is a rare neurologic disorder. It is caused by bi-allelic aberrations in the GRID2 gene, encoding an ionotropic glutamate receptor. In total, 20 affected individuals with mainly homozygous/compound heterozygous intragenic deletions/duplications, two different missense variants and one nonsense variant in GRID2 have been reported, so far. SCAR18 is characterized by delayed psychomotor development, intellectual disability, severely impaired gait due to cerebellar ataxia, ocular movement abnormalities, and cerebellar atrophy in brain imaging. By trio exome sequencing, we now identified a novel homozygous nonsense variant (c.568C > T; p.Gln190*) in GRID2 in a four year old female from a consanguineous family who presented with a particularly severe manifestation of SCAR18. The girl was born after an uneventful pregnancy and showed early-onset, profoundly delayed psychomotor development with no achieved psychomotor milestones at age 4 years. Additionally, she presented with severe muscular hypotonia, progressive truncal and appendicular ataxia, binocular vertical nystagmus, central hearing loss and incomplete loss of sight. She was dystrophic, interacted only very little and had behavioral anomalies such as eating hair and bruxism. Brain imaging showed cerebellar hypoplasia, extended cerebrospinal fluid spaces and beginning reduction of cerebral volume. Our findings further delineate the mutational and clinical spectrum of GRID2-associated spinocerebellar ataxia type 18 and indicate that homozygous nonsense variants are possibly associated with the severe end of the SCAR18 phenotypic spectrum.
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http://dx.doi.org/10.1016/j.ejmg.2020.103998DOI Listing
September 2020

Targeted sequencing of FH-deficient uterine leiomyomas reveals biallelic inactivating somatic fumarase variants and allows characterization of missense variants.

Mod Pathol 2020 11 1;33(11):2341-2353. Epub 2020 Jul 1.

Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.

Uterine leiomyomas (ULs) constitute a considerable health burden in the general female population. The fumarate hydratase (FH) deficient subtype is found in up to 1.6% and can occur in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. We sequenced 13 FH deficient ULs from a previous immunohistochemical screen using a targeted panel and identified biallelic FH variants in all. In eight, we found an FH point mutation (two truncating, six missense) with evidence for loss of the second allele. Variant allele-frequencies in all cases with a point mutation pointed to somatic variants. Spatial clustering of the identified missense variants in the lyase domain indicated altered fumarase oligomerization with subsequent degradation as explanation for the observed FH deficiency. Biallelic FH deletions in five tumors confirm the importance of copy number loss as mutational mechanism. By curating all pathogenic FH variants and calculating their population frequency, we estimate a carrier frequency of up to 1/2,563. Comparing with the prevalence of FH deficient ULs, we conclude that most are sporadic and estimate 2.7-13.9% of females with an FH deficient UL to carry a germline FH variant. Further prospective tumor/normal sequencing studies are needed to develop a reliable screening strategy for HLRCC in women with ULs.
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http://dx.doi.org/10.1038/s41379-020-0596-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581509PMC
November 2020

Update on clinical screening of maturity-onset diabetes of the young (MODY).

Diabetol Metab Syndr 2020 8;12:50. Epub 2020 Jun 8.

Disciplina de Endocrinologia, Centro de Diabetes, Universidade Federal de São Paulo (UNIFESP), Rua Estado de Israel, 639-Vila Clementino, São Paulo, SP CEP: 04022-001 Brazil.

Background: Maturity-onset diabetes of the young (MODY) is the most common type of monogenic diabetes, being characterized by beta-cell disfunction, early onset, and autosomal dominant inheritance. Despite the rapid evolution of molecular diagnosis methods, many MODY cases are misdiagnosed as type 1 or type 2 diabetes. High costs of genetic testing and limited knowledge of MODY as a relevant clinical entity are some of the obstacles that hinder correct MODY diagnosis and treatment. We present a broad review of clinical syndromes related to most common MODY subtypes, emphasizing the role of biomarkers that can help improving the accuracy of clinical selection of candidates for molecular diagnosis.

Main Body: To date, MODY-related mutations have been reported in at least 14 different genes. Mutations in glucokinase (), hepatocyte nuclear factor-1 homeobox A (), and hepatocyte nuclear factor-4 homeobox A () are the most common causes of MODY. Accurate etiological diagnosis can be challenging. Many biomarkers such as apolipoprotein-M (ApoM), aminoaciduria, complement components, and glycosuria have been tested, but have not translated into helpful diagnostic tools. High-sensitivity C-reactive protein (hs-CRP) levels are lower in -MODY and have been tested in some studies to discriminate -MODY from other types of diabetes, although more data are needed. Overall, presence of pancreatic residual function and absence of islet autoimmunity seem the most promising clinical instruments to select patients for further investigation.

Conclusions: The selection of diabetic patients for genetic testing is an ongoing challenge. Metabolic profiling, diabetes onset age, pancreatic antibodies, and C-peptide seem to be useful tools to better select patients for genetic testing. Further studies are needed to define cut-off values in different populations.
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http://dx.doi.org/10.1186/s13098-020-00557-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282127PMC
June 2020