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https://www.readbyqxmd.com/read/28427807/targeted-next-generation-sequencing-in-patients-with-myotonia-congenita
#1
Valentina Ferradini, Marco Cassone, Sara Nuovo, Ilaria Bagni, Rosaria D'Apice, Annalisa Botta, Giuseppe Novelli, Federica Sangiuolo
INTRODUCTION: Myotonia Congenita (MC) is a nondystrophic skeletal muscle disease characterized by muscle stiffness, weakness, delayed skeletal relaxation and hypertrophic muscle. The disease can be inherited as dominant or recessive. More than 130 mutations in CLCN1 gene have been identified. MATERIALS AND METHODS: We analyzed the entire coding region and exon-intron boundaries of the CLCN1 gene in 40 MC patients. Samples already Sanger-sequenced were successively evaluated by Next Generation Sequencing (NGS), on Ion Torrent PGM...
April 17, 2017: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/28424332/improving-genetic-diagnosis-in-mendelian-disease-with-transcriptome-sequencing
#2
Beryl B Cummings, Jamie L Marshall, Taru Tukiainen, Monkol Lek, Sandra Donkervoort, A Reghan Foley, Veronique Bolduc, Leigh B Waddell, Sarah A Sandaradura, Gina L O'Grady, Elicia Estrella, Hemakumar M Reddy, Fengmei Zhao, Ben Weisburd, Konrad J Karczewski, Anne H O'Donnell-Luria, Daniel Birnbaum, Anna Sarkozy, Ying Hu, Hernan Gonorazky, Kristl Claeys, Himanshu Joshi, Adam Bournazos, Emily C Oates, Roula Ghaoui, Mark R Davis, Nigel G Laing, Ana Topf, Peter B Kang, Alan H Beggs, Kathryn N North, Volker Straub, James J Dowling, Francesco Muntoni, Nigel F Clarke, Sandra T Cooper, Carsten G Bönnemann, Daniel G MacArthur
Exome and whole-genome sequencing are becoming increasingly routine approaches in Mendelian disease diagnosis. Despite their success, the current diagnostic rate for genomic analyses across a variety of rare diseases is approximately 25 to 50%. We explore the utility of transcriptome sequencing [RNA sequencing (RNA-seq)] as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare muscle disorders. We describe an integrated approach to analyze patient muscle RNA-seq, leveraging an analysis framework focused on the detection of transcript-level changes that are unique to the patient compared to more than 180 control skeletal muscle samples...
April 19, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28423518/a-novel-pathogenic-splice-acceptor-site-germline-mutation-in-intron-14-of-the-apc-gene-in-a-chinese-family-with-familial-adenomatous-polyposis
#3
Dan Wang, Shengyun Liang, Zhao Zhang, Guoru Zhao, Yuan Hu, Shengran Liang, Xipeng Zhang, Santasree Banerjee
Familial adenomatous polyposis (FAP) is an autosomal dominant precancerous condition, clinically characterized by the presence of multiple colorectal adenomas or polyps. Patients with FAP has a high risk of developing colorectal cancer (CRC) from these colorectal adenomatous polyps by the mean age of diagnosis at 40 years. Germline mutations of the APC gene cause familial adenomatous polyposis (FAP). Colectomy has recommended for the FAP patients with significant polyposis. Here, we present a clinical molecular study of a four generation Chinese family with FAP...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28420620/identification-of-lrp5-mutations-in-families-with-familial-exudative-vitreoretinopathy
#4
Liu Yuqing, Zhu Xiong, Li Shujin, Yang Yeming, Yang Mu, Zhao Peiquan, Zhu Xianjun
Familial exudative vitreoretinopathy (FEVR) is a hereditary eye disease characterized by defects in the development of periphery retinal vessels. However, the clinical phenotypes of FEVR vary widely from asymptomatic to complete blindness. We analyzed patients from three Chinese families and one sporadic patient with FEVR to investigate the clinical features and disease-causing mutations. Ocular phenotypes included increased ramification of the peripheral retinal vessels, a peripheral avascular zone, inferotemporal dragging of the optic disc and macula, and retinal folds...
March 20, 2017: Yi Chuan, Hereditas
https://www.readbyqxmd.com/read/28420613/genetic-analysis-and-identification-of-candidate-genes-for-two-spotted-leaf-mutants-spl101-and-spl102-in-rice
#5
Han Xiaobin, Xu Ran, Duan Penggen, Yu Haiyue, Luo Yuehua, Li Yunhai
Spotted-leaf mutants form spots in leaves or leaf sheaths under normal condition. The spotted-leaf phenotypes are similar to hypersensitive reaction of plants attacked by pathogen. Identification and characterization of the spotted-leaf mutants are helpful for understanding the mechanisms of resistance to plant diseases. Here, we identify two spotted-leaf mutants spl101 and spl102 from an EMS-treated elite japonica cultivar KYJ (Kuanyejing). spl101 and spl102 form serious spots at the late heading stage. Genetic analyses show that the spotted-leaf phenotypes of both spl101 and spl102 are caused by a single recessive mutation, respectively...
April 20, 2017: Yi Chuan, Hereditas
https://www.readbyqxmd.com/read/28418914/met-exon-14-mutations-as-targets-in-routine-molecular-analysis-of-primary-sarcomatoid-carcinoma-of-the-lung
#6
Raphaël Saffroy, Vincent Fallet, Nicolas Girard, Julien Mazieres, Denis Moro Sibilot, Sylvie Lantuejoul, Isabelle Rouquette, Françoise Thivolet-Bejui, Thibaut Vieira, Martine Antoine, Jacques Cadranel, Antoinette Lemoine, Marie Wislez
MET exon 14 splicing mutations are new targetable oncogenic drivers reported in 3% of non-small cell lung cancer (NSCLC) cases and have been shown to be more common in pulmonary sarcomatoid carcinomas (PSCs). This study sought to screen mutations affecting MET exon 14 splice sites in a large SC cohort of Caucasian patients, with a large adenocarcinoma cohort as internal control.We tested 81 patients with SC and 150 with adenocarcinoma for splice site DNA mutations leading to RNA splicing-based skipping of MET exon 14...
March 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28408400/epigenetic-identity-in-aml-depends-on-disruption-of-non-promoter-regulatory-elements-and-is-affected-by-antagonistic-effects-of-mutations-in-epigenetic-modifiers
#7
Jacob Glass, Duane C Hassane, Bas Wouters, Hiroyoshi Kunimoto, Roberto Avellino, Francine E Garrett-Bakelman, Olga A Guryanova, Robert Bowman, Shira Redlich, Andrew Intlekofer, Cem Meydan, Tingting Qin, Mame P Fall, Alicia Alonso, Monica L Guzman, Peter Jm Valk, Craig B Thompson, Ross L Levine, Olivier Elemento, Ruud Delwel, Ari Melnick, Maria E Figueroa
Aberrant DNA methylation of gene promoters is a hallmark of AML. To define more precisely how cytosine methylation is redistributed in AML, we performed base-pair resolution methylome sequencing in 119 patients. We find that leukemic DNA methylation patterning is tightly linked to somatic mutations and primarily driven by regulatory elements outside of promoters and by CpG shores as opposed to CpG islands. Active enhancers displayed much stronger focal differential methylation than promoters and were generally aberrantly hypomethylated except in IDH2 mutant and CEBPA silenced AMLs...
April 13, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28403827/a-novel-mutation-in-homeobox-dna-binding-domain-of-hoxc13-gene-underlies-pure-hair-and-nail-ectodermal-dysplasia-ectd9-in-a-pakistani-family
#8
Anwar Kamal Khan, Noor Muhammad, Abdul Aziz, Sher Alam Khan, Khadim Shah, Abdul Nasir, Muzammil Ahmad Khan, Saadullah Khan
BACKGROUND: Pure hair and nail ectodermal dysplasia (PHNED) is a congenital disorder of hair abnormalities and nail dysplasia. Both autosomal recessive and dominant inheritance fashion of PHNED occurs. In literature, to date, five different forms of PHNED have been reported at molecular level, having three genes known and two loci with no gene yet. METHODS: In this study, a four generations consanguineous family of Pakistani origin with autosomal recessive PHNED was investigated...
April 12, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/28400976/iss-n1-makes-the-first-fda-approved-drug-for-spinal-muscular-atrophy
#9
Eric W Ottesen
Spinal muscular atrophy (SMA) is one of the leading genetic diseases of children and infants. SMA is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7. While various regulatory elements that modulate SMN2 exon 7 splicing have been proposed, intronic splicing silencer N1 (ISS-N1) has emerged as the most promising target thus far for antisense oligonucleotide-mediated splicing correction in SMA...
January 2017: Translational Neuroscience
https://www.readbyqxmd.com/read/28393214/a-novel-mutation-c-121%C3%A2-13t-a-in-the-polypyrimidine-tract-of-the-splice-acceptor-site-of-intron-2-causes-exon-3-skipping-in-mitochondrial-acetoacetyl-coa-thiolase-gene
#10
Yuka Aoyama, Hideo Sasai, Elsayed Abdelkreem, Hiroki Otsuka, Mina Nakama, Sandeep Kumar, Shrikiran Aroor, Anju Shukla, Toshiyuki Fukao
Mitochondrial acetoacetyl-CoA thiolase (T2) (gene symbol: ACAT1) deficiency is an autosomal recessive disorder affecting isoleucine catabolism and ketone body utilization. In this study, mutational analysis of an Indian T2-deficient patient revealed a homozygous mutation (c.121‑13T>A) located at the polypyrimidine tract of the splice acceptor site of intron 2, and exon 3 skipping was identified by cDNA analysis using cycloheximide. We made three mutant constructs (c.121‑13T>A, T>C, and T>G substitutions) followed by making a wild-type minigene construct that included an ACAT1 segment from exon 2 to 4 for a splicing experiment...
April 4, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28392951/three-novel-mutations-in-the-nphs1-gene-in-vietnamese-patients-with-congenital-nephrotic-syndrome
#11
Thi Kim Lien Nguyen, Van Dem Pham, Thu Huong Nguyen, Trung Kien Pham, Thi Quynh Huong Nguyen, Huy Hoang Nguyen
Congenital nephrotic syndrome, a rare and severe disease, is inherited as an autosomal recessive trait. The disease manifests shortly after birth and occurs predominantly in families of Finnish origin but has now been observed in all countries and races. Mutations in the NPHS1 gene, which encodes nephrin, are the main causes of congenital nephrotic syndrome in patients. In this study, we report the first mutational analysis of the NPHS1 gene in three unrelated children from three different Vietnamese families...
2017: Case Reports in Genetics
https://www.readbyqxmd.com/read/28392901/mutation-analysis-of-connexin-50-gene-among-iranian-families-with-autosomal-dominant-cataracts
#12
Masoumeh Mohebi, Saeed Chenari, Abolfazl Akbari, Fariba Ghassemi, Mehran Zarei-Ghanavati, Ghasem Fakhraie, Nahid Babaie, Mansour Heidari
OBJECTIVES: Childhood cataract is a genetically heterogeneous eye disorder that results in visual impairment. The aim of this study was to identify the genetic mutations of connexin 50 gene among Iranian families suffered from autosomal dominant congenital cataracts (ADCC). MATERIALS AND METHODS: Families, having at least two members with bilateral familial congenital cataract, were selected for the study. Probands were evaluated by detailed ophthalmologist's examination, and the pedigree analysis was performed...
March 2017: Iranian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/28391895/identification-of-a-novel-lmf1-nonsense-mutation-responsible-for-severe-hypertriglyceridemia-by-targeted-next-generation-sequencing
#13
Angelo B Cefalù, Rossella Spina, Davide Noto, Valeria Ingrassia, Vincenza Valenti, Antonina Giammanco, Francesca Fayer, Gabriella Misiano, Gianfranco Cocorullo, Chiara Scrimali, Ornella Palesano, Grazia I Altieri, Antonina Ganci, Carlo M Barbagallo, Maurizio R Averna
BACKGROUND: Severe hypertriglyceridemia (HTG) may result from mutations in genes affecting the intravascular lipolysis of triglyceride (TG)-rich lipoproteins. OBJECTIVE: The aim of this study was to develop a targeted next-generation sequencing panel for the molecular diagnosis of disorders characterized by severe HTG. METHODS: We developed a targeted customized panel for next-generation sequencing Ion Torrent Personal Genome Machine to capture the coding exons and intron/exon boundaries of 18 genes affecting the main pathways of TG synthesis and metabolism...
January 2017: Journal of Clinical Lipidology
https://www.readbyqxmd.com/read/28390600/sox10-mutation-causes-waardenburg-syndrome-associated-with-distinctive-phenotypic-features-in-an-iranian-family-a-clue-for-phenotype-directed-genetic-analysis
#14
Nazanin Jalilian, Mohammad Amin Tabatabaiefar, Hossein Alimadadi, Mohammad Reza Noori-Daloii
BACKGROUND: Waardenburg syndrome (WS) is a neurocristopathy characterized by hearing impairment and pigmentary disturbances in hair, eyes, and skin. WS is clinically heterogeneous and can be subdivided into four major types (WS1-WS4) where WS4 or Shah-Waardenburg is diagnosed when WS2 is accompanied by Hirschsprung disease (HD). Mutations of SOX10, EDN3/EDNRB have been identified in association with WS4. This study was aimed to determine the pathogenic variant in an Iranian pedigree affected with WS4...
May 2017: International Journal of Pediatric Otorhinolaryngology
https://www.readbyqxmd.com/read/28386709/in-silico-analysis-of-five-missense-mutations-in-cyp1b1-gene-in-pakistani-families-affected-with-primary-congenital-glaucoma
#15
Sabika Firasat, Haiba Kaul, Usman Ali Ashfaq, Sobia Idrees
PURPOSE: The purpose of this study was to characterize the five missense mutations in CYP1B1 gene identified in Pakistani families affected with primary congenital glaucoma (PCG) using various bioinformatics and protein modeling tools. METHODS: We previously reported four novel missense mutations in CYP1B1 gene segregating in consanguineous Pakistani families. These mutations were identified by direct sequencing of all coding exons, the exon-intron boundaries and the 5' untranslated region of CYP1B1 using genomic DNA from affected and unaffected family members...
April 6, 2017: International Ophthalmology
https://www.readbyqxmd.com/read/28384043/association-of-%C3%AE-secretase-functional-polymorphism-with-risk-of-schizophrenia
#16
Simin Rahimi-Aliabadi, Neda Shahmohammadibeni, Javad Jamshidi, Ehsan Esmaili Shandiz, Reza Mirfakhraie, Mina Ohadi, Farhad Ramezani Nejad, Nader Mansoori, Mohammad Taheri, Fatemeh Gholipour, Susan Moudi, Gouya Tayebi, Shahram Divsalar, Hossein Darvish, Abolfazl Movafagh
AIM: The NRG1-ERBB4 neurotransmitter signaling pathway plays a key role in the pathogenesis of schizophrenia (SZ). The intronic single-nucleotide polymorphism rs707284 in ERBB4 links to PI3K-AKT suppression in SZ. Another protein indirectly affecting NRG1-ERBB4 signaling is β-secretase, which is encoded by the BACE1 gene, and activates NRG1 by proteolytic cleavage. In this study, we aimed to investigate the association of ERBB4 rs707284 and BACE1 rs490460 with the risk of SZ in an Iranian population...
April 2017: Genetic Testing and Molecular Biomarkers
https://www.readbyqxmd.com/read/28379442/an-rrm-znf-rna-recognition-module-targets-rbm10-to-exonic-sequences-to-promote-exon-exclusion
#17
Katherine M Collins, Yaroslav A Kainov, Evangelos Christodolou, Debashish Ray, Quaid Morris, Timothy Hughes, Ian A Taylor, Eugene V Makeyev, Andres Ramos
RBM10 is an RNA-binding protein that plays an essential role in development and is frequently mutated in the context of human disease. RBM10 recognizes a diverse set of RNA motifs in introns and exons and regulates alternative splicing. However, the molecular mechanisms underlying this seemingly relaxed sequence specificity are not understood and functional studies have focused on 3΄ intronic sites only. Here, we dissect the RNA code recognized by RBM10 and relate it to the splicing regulatory function of this protein...
April 4, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28374749/pkr-activation-and-eif2%C3%AE-phosphorylation-mediate-human-globin-mrna-splicing-at-spliceosome-assembly
#18
Lena Ilan, Farhat Osman, Lise Sarah Namer, Einav Eliahu, Smadar Cohen-Chalamish, Yitzhak Ben-Asouli, Yona Banai, Raymond Kaempfer
Short elements in mammalian mRNA can control gene expression by activating the RNA-dependent protein kinase PKR that attenuates translation by phosphorylating cytoplasmic eukaryotic initiation factor 2α (eIF2α). We demonstrate a novel, positive role for PKR activation and eIF2α phosphorylation in human globin mRNA splicing. PKR localizes in splicing complexes and associates with splicing factor SC35. Splicing and early-stage spliceosome assembly on β-globin pre-mRNA depend strictly on activation of PKR by a codon-containing RNA fragment within exon 1 and on phosphorylation of nuclear eIF2α on Serine 51...
April 4, 2017: Cell Research
https://www.readbyqxmd.com/read/28371479/alu-mediated-deletion-of-pigl-in-a-patient-with-chime-syndrome
#19
Amy Knight Johnson, Gerald Bradley Schaefer, Jennifer Lee, Ying Hu, Daniela Del Gaudio
CHIME syndrome is a rare autosomal recessive neuroectodermal disorder associated with biallelic mutations in PIGL. To date, six molecularly confirmed cases of CHIME syndrome have been reported. Here, we report the seventh patient with biallelic PIGL mutations associated with CHIME syndrome and describe the first characterization of an intragenic deletion in PIGL. Our characterization of the deletion breakpoint junction demonstrated that the breakpoints occurred within Alu repeats and the deletion was most likely mediated by a microhomology event...
March 28, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28369983/microinsertions-in-prkaca-cause-activation-of-the-protein-kinase-a-pathway-in-cardiac-myxoma
#20
I-Ching Tseng, Wei-Ju Huang, Yu-Ling Jhuang, Ya-Yun Chang, Hung-Pin Hsu, Yung-Ming Jeng
Cardiac myxoma is the most common cardiac tumour. Most lesions occur sporadically, but occasional lesions develop in patients with Carney complex, a syndrome characterised by cardiac myxoma, spotty pigmentation, and endocrine overactivity. Two-thirds of patients with Carney complex harbour germline mutations in PRKAR1A, which encodes the type I regulatory subunit of protein kinase A (PKA). Most studies have not found a mutation in PRKAR1A in sporadic cardiac myxoma cases. Recent studies identified frequent mutation in PRKACA, the catalytic subunit of PKA, in cortisol-secreting adrenocortical adenoma cases...
March 28, 2017: Journal of Pathology
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