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Elisabeth Salzer, Deniz Cagdas, Miroslav Hons, Emily M Mace, Wojciech Garncarz, Özlem Yüce Petronczki, René Platzer, Laurène Pfajfer, Ivan Bilic, Sol A Ban, Katharina L Willmann, Malini Mukherjee, Verena Supper, Hsiang Ting Hsu, Pinaki P Banerjee, Papiya Sinha, Fabienne McClanahan, Gerhard J Zlabinger, Winfried F Pickl, John G Gribben, Hannes Stockinger, Keiryn L Bennett, Johannes B Huppa, Loïc Dupré, Özden Sanal, Ulrich Jäger, Michael Sixt, Ilhan Tezcan, Jordan S Orange, Kaan Boztug
RASGRP1 is an important guanine nucleotide exchange factor and activator of the RAS-MAPK pathway following T cell antigen receptor (TCR) signaling. The consequences of RASGRP1 mutations in humans are unknown. In a patient with recurrent bacterial and viral infections, born to healthy consanguineous parents, we used homozygosity mapping and exome sequencing to identify a biallelic stop-gain variant in RASGRP1. This variant segregated perfectly with the disease and has not been reported in genetic databases. RASGRP1 deficiency was associated in T cells and B cells with decreased phosphorylation of the extracellular-signal-regulated serine kinase ERK, which was restored following expression of wild-type RASGRP1...
October 24, 2016: Nature Immunology
Sarah L Nickerson, Renate Marquis-Nicholson, Karen Claxton, Fern Ashton, Ivone U S Leong, Debra O Prosser, Jennifer M Love, Alice M George, Graham Taylor, Callum Wilson, R J McKinlay Gardner, Donald R Love
No abstract text is available yet for this article.
February 2016: Pathology
Nadia A Akawi, Salma Ben-Salem, Jozef Hertecant, Anne John, Thachillath Pramathan, Praseetha Kizhakkedath, Bassam R Ali, Lihadh Al-Gazali
BACKGROUND: The group of ELAC2-related encephalomyopathies is a recent addition to the rapidly growing heterogeneous mitochondrial disorders. RESULTS: We describe a highly inbred consanguineous Pakistani family with multiple affected children in 2 branches exhibiting moderately severe global developmental delay. Using homozygosity mapping, we mapped the phenotype in this family to a single locus on chromosome 17. In addition, whole-exome sequencing identified a homozygous splicing mutation (c...
October 21, 2016: Orphanet Journal of Rare Diseases
Rola F Turki, Mourad Assidi, Huda A Banni, Hanan A Zahed, Sajjad Karim, Hans-Juergen Schulten, Muhammad Abu-Elmagd, Abdulrahim A Rouzi, Osama Bajouh, Hassan S Jamal, Mohammed H Al-Qahtani, Adel M Abuzenadah
BACKGROUND: Recurrent pregnancy loss (RPL) or recurrent spontaneous abortion is an obstetric complication that affects couples at reproductive age. Previous reports documented a clear relationship between parents with chromosomal abnormalities and both recurrent miscarriages and infertility. However, limited data is available from the Arabian Peninsula which is known by higher rates of consanguineous marriages. The main goal of this study was to determine the prevalence of chromosomal abnormalities and thrombophilic polymorphisms, and to correlate them with RPL and consanguinity in Saudi Arabia...
October 10, 2016: BMC Medical Genetics
Michel J Massaad, Jia Zhou, Daisuke Tsuchimoto, Janet Chou, Haifa Jabara, Erin Janssen, Salomé Glauzy, Brennan G Olson, Henner Morbach, Toshiro K Ohsumi, Klaus Schmitz, Markianos Kyriacos, Jennifer Kane, Kumiko Torisu, Yusaku Nakabeppu, Luigi D Notarangelo, Eliane Chouery, Andre Megarbane, Peter B Kang, Eman Al-Idrissi, Hasan Aldhekri, Eric Meffre, Masayuki Mizui, George C Tsokos, John P Manis, Waleed Al-Herz, Susan S Wallace, Raif S Geha
Alterations in the apoptosis of immune cells have been associated with autoimmunity. Here, we have identified a homozygous missense mutation in the gene encoding the base excision repair enzyme Nei endonuclease VIII-like 3 (NEIL3) that abolished enzymatic activity in 3 siblings from a consanguineous family. The NEIL3 mutation was associated with fatal recurrent infections, severe autoimmunity, hypogammaglobulinemia, and impaired B cell function in these individuals. The same homozygous NEIL3 mutation was also identified in an asymptomatic individual who exhibited elevated levels of serum autoantibodies and defective peripheral B cell tolerance, but normal B cell function...
October 17, 2016: Journal of Clinical Investigation
Ahmad Alodaib, Nara Sobreira, Wendy A Gold, Lisa G Riley, Nicole J Van Bergen, Meredith J Wilson, Bruce Bennetts, David R Thorburn, Corinne Boehm, John Christodoulou
Recent advances in next-generation sequencing strategies have led to the discovery of many novel disease genes. We describe here a non-consanguineous family with two affected boys presenting with early onset of severe axonal neuropathy, optic atrophy, intellectual disability, auditory neuropathy and chronic respiratory and gut disturbances. Whole-exome sequencing (WES) was performed on all family members and we identified compound heterozygous variants (c.[760C>A];[1528G>C];p.[(Gln254Lys);(Ala510Pro)] in the polyribonucleotide nucleotidyltransferase 1 (PNPT1) gene in both affected individuals...
October 19, 2016: European Journal of Human Genetics: EJHG
Valérie Bernard, Sakina Kherra, Bruno Francou, Jérôme Fagart, Say Viengchareun, Jérôme Guéchot, Asmahane Ladjouze, Anne Guiochon-Mantel, Kenneth S Korach, Nadine Binart, Marc Lombès, Sophie Christin-Maitre
CONTEXT: Estrogens influence many physiological processes in mammals, including reproduction. Estrogen peripheral actions are mainly mediated through estrogen receptors (ER) α and β, encoded by ESR1 and ESR2 genes, respectively. OBJECTIVE: To describe a family in which three members presented with estrogen insensitivity. DESIGN AND SETTING: Clinical evaluation, genetic and mutational analysis were performed in an academic medical center...
October 18, 2016: Journal of Clinical Endocrinology and Metabolism
Priyanka Srivastava, Himani Pandey, Divya Agarwal, Kausik Mandal, Shubha R Phadke
We describe three consanguineous Indian families with a distinct form of spondyloepiphyseal dysplasia (SED Omani type). It is an autosomal recessive disorder due to mutation in CHST3 gene. CHST3 gene encodes the enzyme chondroitin 6-O-sulfotransferase-1 (C6ST-1) which mediates the sulfation of proteoglycans, (chondroitin sulfate), in the extracellular matrix of cartilage. CHST3 gene was sequenced in probands from three different families with SED. In two families missense mutations (c.904G>C predicting the substitution D302H) and c...
October 18, 2016: American Journal of Medical Genetics. Part A
Shahida Moosa, Helena Böhrer-Rabel, Janine Altmüller, Filippo Beleggia, Peter Nürnberg, Yun Li, Gökhan Yigit, Bernd Wollnik
Heterozygous germline mutations in MTOR have been shown to underlie Smith-Kingsmore syndrome, a rare autosomal dominant syndrome characterized by macrocephaly, developmental delay, and dysmorphic facial features. Recently, two unrelated families with the MTOR mutation, c.5395G>A p.(Glu1799Lys), were reported. Here, we describe siblings from a non-consanguineous German family in whom we identified the same heterozygous missense mutation in MTOR. Remarkably, in all reported families with Smith-Kingsmore syndrome and the MTOR c...
October 18, 2016: American Journal of Medical Genetics. Part A
Hamidreza Khodadadi, Luis J Azcona, Vajiheh Aghamollaii, Mir Davood Omrani, Masoud Garshasbi, Shaghayegh Taghavi, Abbas Tafakhori, Gholam Ali Shahidi, Javad Jamshidi, Hossein Darvish, Coro Paisán-Ruiz
INTRODUCTION: Atypical parkinsonism is a neurodegenerative disease that includes diverse neurological and psychiatric manifestations. OBJECTIVES: We aimed to identify the disease-cauisng mutations in a consanguineous family featuring intellectual disability and parkinsonism. METHODS: Full phenotypic characterization, followed by genome-wide single-nucleotide polymorphism genotyping and whole-genome sequencing, was carried out in all available family members...
October 18, 2016: Movement Disorders: Official Journal of the Movement Disorder Society
Ihssane El Bouchikhi, Laila Bouguenouch, Fatima Zohra Moufid, Mohammed Iraqui Houssaini, Khadija Belhassan, Imane Samri, Ayoub Tahri Joutei, Karim Ouldim, Samir Atmani
OBJECTIVE: Secundum atrial septal defect (ASDII) has multifactorial etiology that is combination of environmental (e.g., mother's exposure to toxicity, ethnicity) and genetic causes. Aim of the present study was to screen a Moroccan population with ASDII for NKX2-5 variants and to assess risk factors that may contribute to emergence of the disorder. METHODS: Thirty-two non-syndromic ASDII patients were screened for NKX2-5 variants using direct sequencing of polymerase chain reactionamplified coding regions...
October 12, 2016: Anatolian Journal of Cardiology
Mohammad F Aljabri, Naglaa M Kamal, Moinuddin Arif, Asrar M AlQaedi, Enas Y M Santali
BACKGROUND: Biotin-thiamine-responsive basal ganglia disease (BTRBGD) is a neurometabolic autosomal recessive (AR) disorder characterized by subacute encephalopathy with confusion, convulsions, dysarthria, and dystonia. The disease is completely reversible if treated early with biotin and thiamine, and can be fatal if left untreated.We herein present our experience with in an extended family study of an index case of BTRBGD aiming to support its AR mode of inheritance, diagnose asymptomatic and missed symptomatic cases, and provide family screening with proper genetic counseling...
October 2016: Medicine (Baltimore)
Yu Kobayashi, Jun Tohyama, Tomoyuki Akiyama, Shinichi Magara, Hideshi Kawashima, Noriyuki Akasaka, Mitsuko Nakashima, Hirotomo Saitsu, Naomichi Matsumoto
Cerebral folate deficiency due to folate receptor 1 gene (FOLR1) mutations is an autosomal recessive disorder resulting from a brain-specific folate transport defect. It is characterized by late infantile onset, severe psychomotor regression, epilepsy, and leukodystrophy. We describe a consanguineous girl exhibiting severe developmental regression, intractable epilepsy, polyneuropathy, and profound hypomyelination with cortical involvement. Magnetic resonance imaging showed cortical disturbances in addition to profound hypomyelination and cerebellar atrophy...
October 12, 2016: Brain & Development
Maryam Beheshtian, Mojgan Babanejad, Hela Azaiez, Niloofar Bazazzadegan, Diana Kolbe, Christina Sloan-Heggen, Sanaz Arzhangi, Kevin Booth, Marzieh Mohseni, Kathy Frees, Mohammad Hossein Azizi, Ahmad Daneshi, Mohammad Farhadi, Kimia Kahrizi, Richard Jh Smith, Hossein Najmabadi
A significant contribution to the causes of hereditary hearing impairment comes from genetic factors. More than 120 genes and 160 loci have been identified to be involved in hearing impairment. Given that consanguine populations are more vulnerable to most inherited diseases, such as hereditary hearing loss (HHL), the genetic picture of HHL among the Iranian population, which consists of at least eight ethnic subgroups with a high rate of intermarriage, is expected to be highly heterogeneous. Using an electronic literature review through various databases such as PubMed, MEDLINE, and Scopus, we review the current picture of HHL in Iran...
October 1, 2016: Archives of Iranian Medicine
Motasem Melhem, Mohamed Abu-Farha, Dinu Antony, Ashraf Al Madhoun, Chiara Bacchelli, Fadi Alkayal, Irina AlKhairi, Sumi John, Mohamad Alomari, Phillip L Beales, Osama Alsmadi
OBJECTIVE: To characterize the underlying genetic and molecular defects in a consanguineous family with life-long blood disorder manifested with thrombocytopenia (low platelets count) and anemia. METHODS: Genetic linkage analysis, exome sequencing and functional genomics were carried out to identify and characterize the defective gene. RESULTS: We identification of a novel truncation mutation (p.C108*) in Chromosome 6 Open Reading Frame 25 (C6orf25) gene in this family...
October 15, 2016: European Journal of Haematology
Marivi Nabong Moen, Roar Fjær, El Hassan Hamdani, Jon K Laerdahl, Robin Johansen Menchini, Magnus Dehli Vigeland, Ying Sheng, Dag Erik Undlien, Bjørnar Hassel, Mustafa A Salih, Heba Y El Khashab, Kaja Kristine Selmer, Farrukh Abbas Chaudhry
Progressive myoclonus epilepsy is a heterogeneous group of disorders characterized by myoclonic and tonic-clonic seizures, ataxia and cognitive decline. We here present two affected brothers. At 9 months of age the elder brother developed ataxia and myoclonic jerks. In his second year he lost the ability to walk and talk, and he developed drug-resistant progressive myoclonus epilepsy. The cerebrospinal fluid level of glutamate was decreased while glutamine was increased. His younger brother manifested similar symptoms from 6 months of age...
October 14, 2016: Brain: a Journal of Neurology
Maryam Zamanian, Mohammad Reza Baneshi, AliAkbar Haghdoost, Farzaneh Zolala
OBJECTIVES: Abortion is a sensitive issue; many cultures disapprove of it, which leads to under-reporting. This study sought to estimate the rate of abortion visibility in the city of Kerman, Iran-that is, the percentage of acquaintances who knew about a particular abortion. For estimating the visibility rate, it is crucial to use the network scale-up method, which is a new, indirect method of estimating sensitive behaviours more accurately. MATERIALS AND METHODS: This cross-sectional study was conducted in Kerman, Iran using various methods to ensure the cooperation of clinicians and women...
October 13, 2016: BMJ Open
M Corton, A Avila-Fernández, L Campello, M Sánchez, B Benavides, M I López-Molina, L Fernández-Sánchez, R Sánchez-Alcudia, L R J da Silva, N Reyes, E Martín-Garrido, O Zurita, P Fernández-San José, R Pérez-Carro, F García-García, J Dopazo, B García-Sandoval, N Cuenca, C Ayuso
Retinitis pigmentosa (RP), the most frequent form of inherited retinal dystrophy is characterized by progressive photoreceptor degeneration. Many genes have been implicated in RP development, but several others remain to be identified. Using a combination of homozygosity mapping, whole-exome and targeted next-generation sequencing, we found a novel homozygous nonsense mutation in SAMD11 in five individuals diagnosed with adult-onset RP from two unrelated consanguineous Spanish families. SAMD11 is ortholog to the mouse major retinal SAM domain (mr-s) protein that is implicated in CRX-mediated transcriptional regulation in the retina...
October 13, 2016: Scientific Reports
Flavia Palombo, Nadia Al-Wardy, Guido Alberto Gnecchi Ruscone, Manuela Oppo, Mohammed Nasser Al Kindi, Andrea Angius, Khalsa Al Lamki, Giorgia Girotto, Tania Giangregorio, Matteo Benelli, Alberto Magi, Marco Seri, Paolo Gasparini, Francesco Cucca, Marco Sazzini, Mazin Al Khabori, Tommaso Pippucci, Giovanni Romeo
The increased risk for autosomal recessive disorders is one of the most well-known medical implications of consanguinity. In the Sultanate of Oman, a country characterized by one of the highest rates of consanguineous marriages worldwide, prevalence of genetic hearing loss (GHL) is estimated to be 6/10 000. Families of GHL patients have higher consanguinity rates than the general Omani population, indicating a major role for recessive forms. Mutations in GJB2, the most commonly mutated GHL gene, have been sporadically described...
October 13, 2016: Journal of Human Genetics
Sarenur Gokben, Huseyin Onay, Sanem Yilmaz, Tahir Atik, Gul Serdaroglu, Hande Tekin, Ferda Ozkinay
We investigated the genetic background of early-onset epileptic encephalopathy (EE) using targeted next generation sequencing analysis. Thirty sporadic or familial cases associated with early-onset EE were included. An early-onset EE gene panel including sixteen genes (ARX, CDKL5, CNTNAP2, FOLR1, FOXG1, LAMC3, MBD5, MECP2, NTNG1, PCDH19, PNKP, SCN1A, SCN1B, SCN2A, STXBP1, KCNQ2) was constituted. Nine definite and three potential causal mutations in 30 cases (40 %) were identified. All mutations presented heterozygously except one...
October 12, 2016: Acta Neurologica Belgica
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