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Missense variants & pathogenicity prediction

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https://www.readbyqxmd.com/read/28204848/nonsyndromic-oligodontia-does-the-tooth-agenesis-code-tac-enable-prediction-of-the-causative-mutation
#1
Niko C Bock, Sarah Lenz, Gisela Ruiz-Heiland, Sabine Ruf
OBJECTIVES: The literature suggests an association between phenotype and causative mutation in nonsyndromic oligodontia. Thus, the present study was designed to verify this hypothesis in a consecutive cohort of patients. METHODS: All patients with nonsyndromic oligodontia who had been treated at the study center (Department of Orthodontics, University of Giessen, Germany) over the period 1986-2013 were contacted. Candidates were included only if at least one more family member had hypo- or oligodontia (i...
February 15, 2017: Journal of Orofacial Orthopedics, Fortschritte der Kieferorthopädie
https://www.readbyqxmd.com/read/28193117/exome-sequencing-identifies-de-novo-dync1h1-mutations-associated-with-distal-spinal-muscular-atrophy-and-malformations-of-cortical-development
#2
Yulin Chen, Yufei Xu, Guoqiang Li, Niu Li, Tingting Yu, Ru-En Yao, Xiumin Wang, Yiping Shen, Jian Wang
Exome sequencing has become a formidable tool for identifying potential de novo variants in causative genes of human diseases, such as neurodegenerative disorders. This article describes a 16-month-old girl with spinal muscular atrophy with lower extremity predominance and a 13-month-old girl with malformations of cortical development. Exome sequencing identified a novel de novo heterozygous missense mutation c.3395G>A (p.Gly1132Glu) and a previously reported de novo heterozygous missense mutation c.10151G>A (p...
March 2017: Journal of Child Neurology
https://www.readbyqxmd.com/read/28148925/a-novel-mutation-in-the-proteolytic-domain-of-lonp1-causes-atypical-codas-syndrome
#3
Takehiko Inui, Mai Anzai, Yusuke Takezawa, Wakaba Endo, Yosuke Kakisaka, Atsuo Kikuchi, Akira Onuma, Shigeo Kure, Ichizo Nishino, Chihiro Ohba, Hirotomo Saitsu, Naomichi Matsumoto, Kazuhiro Haginoya
Cerebral, ocular, dental, auricular, skeletal (CODAS) syndrome is a rare autosomal recessive multisystem disorder caused by mutations in LONP1. It is characterized by intellectual disability, cataracts, delayed tooth eruption, malformed auricles and skeletal abnormalities. We performed whole-exome sequencing on a 12-year-old Japanese male with severe intellectual disability, congenital bilateral cataracts, spasticity, hypotonia with motor regression and progressive cerebellar atrophy with hyperintensity of the cerebellar cortex on T2-weighted images...
February 2, 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/28145426/two-novel-bmp-2-variants-identified-in-patients-with-thoracic-ossification-of-the-ligamentum-flavum
#4
Xiaochen Qu, Zhongqiang Chen, Dongwei Fan, Shen Xiang, Chuiguo Sun, Yan Zeng, Weishi Li, Zhaoqing Guo, Qiang Qi, Woquan Zhong, Yun Jiang
Thoracic ossification of the ligamentum flavum (TOLF)is a common cause of thoracic spinal canal stenosis and has been reported almost exclusively in East Asian countries. In this study, we established a relationship between bone morphogenic protein 2 (BMP-2) and TOLF. We divided patients into two groups according to severity of ossification and identified susceptible loci through exome sequencing. We identified 39 novel likely pathogenic variants in 29 genes in the transforming growth factor-beta (TGF-β) superfamily or TGF-β/BMPs signaling pathway, including two missense variants in BMP-2 (NM_001200...
February 1, 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28108859/the-arc-gene-confers-genetic-susceptibility-to-alzheimer-s-disease-in-han-chinese
#5
Rui Bi, Li-Li Kong, Min Xu, Guo-Dong Li, Deng-Feng Zhang, Tao Li, Yiru Fang, Chen Zhang, Buchang Zhang, Yong-Gang Yao
Alzheimer's disease (AD) is the most common form of dementia. The deposition of β-amyloid (Aβ) plaques in the brain was considered one of the main neuropathological hallmarks of AD. As the loss of synapses always occurs during AD progression, AD has been gradually regarded as a "synaptopathy." The activity-regulated cytoskeleton-associated protein (Arc) was recently identified as a key factor for AD due to its active roles in synaptic plasticity, learning, memory, and Aβ generation. However, there is little evidence to support the association of the Arc gene with AD...
January 20, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28073787/col6a5-variants-in-familial-neuropathic-chronic-itch
#6
Filippo Martinelli-Boneschi, Marina Colombi, Marco Castori, Grazia Devigili, Roberto Eleopra, Rayaz A Malik, Marco Ritelli, Nicoletta Zoppi, Chiara Dordoni, Melissa Sorosina, Paola Grammatico, Hassan Fadavi, Monique M Gerrits, Rowida Almomani, Catharina G Faber, Ingemar S J Merkies, Daniela Toniolo, Massimiliano Cocca, Claudio Doglioni, Stephen G Waxman, Sulayman D Dib-Hajj, Michela M Taiana, Jenny Sassone, Raffaella Lombardi, Daniele Cazzato, Andrea Zauli, Silvia Santoro, Margherita Marchi, Giuseppe Lauria
Itch is thought to represent the peculiar response to stimuli conveyed by somatosensory pathways shared with pain through the activation of specific neurons and receptors. It can occur in association with dermatological, systemic and neurological diseases, or be the side effect of certain drugs. However, some patients suffer from chronic idiopathic itch that is frequently ascribed to psychological distress and for which no biomarker is available to date. We investigated three multigenerational families, one of which diagnosed with joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT), characterized by idiopathic chronic itch with predominantly proximal distribution...
January 9, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28057753/a-novel-kleefstra-syndrome-associated-variant-that-affects-the-conserved-tplx-motif-within-the-ankyrin-repeat-of-ehmt1-leads-to-abnormal-protein-folding
#7
Patrick R Blackburn, Alexander Tischer, Michael T Zimmermann, Jennifer L Kemppainen, Sujatha Sastry, Amy E Knight Johnson, Margot A Cousin, Nicole J Boczek, Gavin Oliver, Vinod K Misra, Ralitza H Gavrilova, Gwen A Lomberk, Matthew Auton, Raul A Urrutia, Eric W Klee
Kleefstra syndrome (KS) (MIM# 610253), also known as 9q34 deletion syndrome, is an autosomal dominant disorder caused by haploinsufficiency of euchromatic histone methyltransferase-1 (EHMT1). The clinical phenotype of KS includes moderate to severe intellectual disability with absent speech, hypotonia, brachycephaly, congenital heart defects, and dysmorphic facial features with hypertelorism, synophrys, macroglossia, protruding tongue, and prognathism. Only a few cases of de novo missense mutations in EHMT1 giving rise to KS have been described...
January 5, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28054173/association-of-ahsg-with-alopecia-and-mental-retardation-apmr-syndrome
#8
M Reza Sailani, Fereshteh Jahanbani, Jafar Nasiri, Mahdiyeh Behnam, Mansoor Salehi, Maryam Sedghi, Majid Hoseinzadeh, Shinichi Takahashi, Amin Zia, Joshua Gruber, Janet Linnea Lynch, Daniel Lam, Juliane Winkelmann, Semira Amirkiai, Baoxu Pang, Shannon Rego, Safoura Mazroui, Jonathan A Bernstein, Michael P Snyder
Alopecia with mental retardation syndrome (APMR) is a very rare autosomal recessive condition that is associated with total or partial absence of hair from the scalp and other parts of the body as well as variable intellectual disability. Here we present whole-exome sequencing results of a large consanguineous family segregating APMR syndrome with seven affected family members. Our study revealed a novel predicted pathogenic, homozygous missense mutation in the AHSG (OMIM 138680) gene (AHSG: NM_001622:exon7:c...
January 4, 2017: Human Genetics
https://www.readbyqxmd.com/read/28032242/molecular-pathological-study-on-lrrc10-in-sudden-unexplained-nocturnal-death-syndrome-in-the-chinese-han-population
#9
Lei Huang, Shuangbo Tang, Yili Chen, Liyong Zhang, Kun Yin, Yeda Wu, Jinxiang Zheng, Qiuping Wu, Jonathan C Makielski, Jianding Cheng
Sudden unexplained nocturnal death syndrome (SUNDS) is a perplexing disorder to both forensic pathologists and clinic physicians. Clinical features of SUNDS survivors suggested that SUNDS is similar to Brugada syndrome (BrS). Leucine-rich repeat containing 10 (LRRC10) gene was a newly identified gene linked to dilated cardiomyopathy, a disease associated with sudden cardiac death. To investigate the prevalence and spectrum of genetic variants of LRRC10 gene in SUNDS and BrS, the coding regions of LRRC10 were genetically screened in 113 sporadic SUNDS victims (from January 2005 to December 2015, 30...
December 28, 2016: International Journal of Legal Medicine
https://www.readbyqxmd.com/read/28031081/restrictive-cardiomyopathy-resulting-from-a-troponin-i-type-3-mutation-in-a-chinese-family
#10
Yan-Ping Ruan, Chao-Xia Lu, Xiao-Yi Zhao, Rui-Juan Liang, Hui Lian, Michael Routledge, Wei Wu, Xue Zhang, Zhong-Jie Fan
Objective To identify the pathogenic variant responsible for restrictive cardiomyopathy (RCM) in a Chinese family.Methods Next generation sequencing was used for detecting the mutation and Results verified by sequencing. We used restriction enzyme digestion to test the mutation in the family members and 200 unrelated normal subjects without any cardiac inherited diseases when the mutation was identified.Results Five individuals died from cardiac diseases, two of whom suffered from sudden cardiac death. Two individuals have suffered from chronic cardiac disorders...
March 20, 2016: Chinese Medical Sciences Journal, Chung-kuo i Hsüeh K'o Hsüeh Tsa Chih
https://www.readbyqxmd.com/read/28028996/genetic-profiles-of-korean-patients-with-glucose-6-phosphate-dehydrogenase-deficiency
#11
Jaewoong Lee, Joonhong Park, Hayoung Choi, Jiyeon Kim, Ahlm Kwon, Woori Jang, Hyojin Chae, Myungshin Kim, Yonggoo Kim, Jae Wook Lee, Nack Gyun Chung, Bin Cho
BACKGROUND: We describe the genetic profiles of Korean patients with glucose-6-phosphate dehydrogenase (G6PD) deficiencies and the effects of G6PD mutations on protein stability and enzyme activity on the basis of in silico analysis. METHODS: In parallel with a genetic analysis, the pathogenicity of G6PD mutations detected in Korean patients was predicted in silico. The simulated effects of G6PD mutations were compared to the WHO classes based on G6PD enzyme activity...
March 2017: Annals of Laboratory Medicine
https://www.readbyqxmd.com/read/27984190/mutation-screening-of-pdgfb-gene-in-chinese-population-with-primary-familial-brain-calcification
#12
Xiang-Ping Yao, Chong- Wang, Hui-Zhen Su, Xin-Xin Guo, Ying-Qian Lu, Miao Zhao, Yao-Bin Liu, Jing-Hui Lai, Hai-Ting Chen, Ning Wang, Wan-Jin Chen
BACKGROUND: Until recently, primary familial brain calcification (PFBC) has been determined by four genes, SLC20A2, PDGFRB, PDGFB and XPR1. No studies have been carried out to analyze the gene mutation of PDGFB in Chinese population. OBJECTIVE: To screen mutations of PDGFB gene in a large cohort of Chinese PFBC patients with no SLC20A2 mutations. METHODS: We recruited 192 PFBC patients, including 21 index cases and 171 sporadic cases, in our study...
October 28, 2016: Gene
https://www.readbyqxmd.com/read/27931036/clinical-exome-sequencing-reveals-mkrn3-pathogenic-variants-in-familial-and-nonfamilial-idiopathic-central-precocious-puberty
#13
Nelmar Valentina Ortiz-Cabrera, Rosa Riveiro-Álvarez, Miguel Ángel López-Martínez, Pilar Pérez-Segura, Isabel Aragón-Gómez, María José Trujillo-Tiebas, Leandro Soriano-Guillén
BACKGROUND/AIMS: Idiopathic central precocious puberty (ICPP) is the premature activation of the hypothalamic-pituitary-gonadal axis in the absence of organic disease. Up to now, just gain-of-function mutations of KISS1/KISS1R and loss-of-function mutations of the maternally imprinted gene MKRN3 are the known genetic causes of ICPP. Our intention is to evaluate variants present in genes related to the pubertal onset pathway that could act as disease-causing or predisposing variants. METHODS: We studied the clinical exome of 20 patients diagnosed with ICPP using the Illumina platform...
December 9, 2016: Hormone Research in Pædiatrics
https://www.readbyqxmd.com/read/27928163/tbcd-may-be-a-causal-gene-in-progressive-neurodegenerative-encephalopathy-with-atypical-infantile-spinal-muscular-atrophy
#14
Toshio Ikeda, Akihiko Nakahara, Rie Nagano, Maiko Utoyama, Megumi Obara, Hiroshi Moritake, Tamayo Uechi, Jun Mitsui, Hiroyuki Ishiura, Jun Yoshimura, Koichiro Doi, Naoya Kenmochi, Shinichi Morishita, Ichizo Nishino, Shoji Tsuji, Hiroyuki Nunoi
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder caused by survival motor neuron gene mutations. Variant forms of SMA accompanied by additional clinical presentations have been classified as atypical SMA and are thought to be caused by variants in as yet unidentified causative genes. Here, we presented the clinical findings of two siblings with an SMA variant followed by progressive cerebral atrophy, and the results of whole-exome sequencing analyses of the family quartet that was performed to identify potential causative variants...
December 8, 2016: Journal of Human Genetics
https://www.readbyqxmd.com/read/27919260/a-frameshift-mutation-in-mocos-is-associated-with-familial-renal-syndrome-xanthinuria-in-tyrolean-grey-cattle
#15
Leonardo Murgiano, Vidhya Jagannathan, Christian Piffer, Inmaculada Diez-Prieto, Marilena Bolcato, Arcangelo Gentile, Cord Drögemüller
BACKGROUND: Renal syndromes are occasionally reported in domestic animals. Two identical twin Tyrolean Grey calves exhibited weight loss, skeletal abnormalities and delayed development associated with kidney abnormalities and formation of uroliths. These signs resembled inherited renal tubular dysplasia found in Japanese Black cattle which is associated with mutations in the claudin 16 gene. Despite demonstrating striking phenotypic similarities, no obvious presence of pathogenic variants of this candidate gene were found...
December 5, 2016: BMC Veterinary Research
https://www.readbyqxmd.com/read/27903293/personalized-medicine-approach-confirms-a-milder-case-of-abat-deficiency
#16
A Besse, A K Petersen, J V Hunter, V Appadurai, S R Lalani, P E Bonnen
ABAT deficiency (OMIM 613163) is a rare inborn error of metabolism caused by recessive variants in the gene 4-aminobutyric acid transaminase (ABAT), which is responsible for both the catalysis of GABA and maintenance of nucleoside pools in the mitochondria. To date, only a few patients have been reported worldwide. Their clinical presentation has been remarkably consistent with primary features of severe psychomotor retardation, encephalopathy, hypotonia, and infantile-onset refractory epilepsy. We report a new case of ABAT deficiency that marks an important departure from previous clinical findings...
December 1, 2016: Molecular Brain
https://www.readbyqxmd.com/read/27878139/compound-heterozygous-ldlr-variant-in-severely-affected-familial-hypercholesterolemia-patient
#17
Faisal A Al-Allaf, Abdullah Alashwal, Zainularifeen Abduljaleel, Mohiuddin M Taher, Abdellatif Bouazzaoui, Hala Abalkhail, Ahmad F Al-Allaf, Mohammad Athar
Familial hypercholesterolemia (FH) is most commonly caused by mutations in the LDL receptor (LDLR), which is responsible for hepatic clearance of LDL from the blood circulation. We described a severely affected FH proband and their first-degree blood relatives; the proband was resistant to statin therapy and was managed on an LDL apheresis program. In order to find the causative genetic variant in this family, direct exon sequencing of the LDLR, APOB and PCSK9 genes was performed. We identified a compound heterozygous mutation in the proband with missense p...
November 23, 2016: Acta Biochimica Polonica
https://www.readbyqxmd.com/read/27821657/the-ucl-low-density-lipoprotein-receptor-gene-variant-database-pathogenicity-update
#18
Sarah Leigh, Marta Futema, Ros Whittall, Alison Taylor-Beadling, Maggie Williams, Johan T den Dunnen, Steve E Humphries
BACKGROUND: Familial hypercholesterolaemia (OMIM 143890) is most frequently caused by variations in the low-density lipoprotein receptor (LDLR) gene. Predicting whether novel variants are pathogenic may not be straightforward, especially for missense and synonymous variants. In 2013, the Association of Clinical Genetic Scientists published guidelines for the classification of variants, with categories 1 and 2 representing clearly not or unlikely pathogenic, respectively, 3 representing variants of unknown significance (VUS), and 4 and 5 representing likely to be or clearly pathogenic, respectively...
November 7, 2016: Journal of Medical Genetics
https://www.readbyqxmd.com/read/27817865/mecr-mutations-cause-childhood-onset-dystonia-and-optic-atrophy-a-mitochondrial-fatty-acid-synthesis-disorder
#19
Gali Heimer, Juha M Kerätär, Lisa G Riley, Shanti Balasubramaniam, Eran Eyal, Laura P Pietikäinen, J Kalervo Hiltunen, Dina Marek-Yagel, Jeffrey Hamada, Allison Gregory, Caleb Rogers, Penelope Hogarth, Martha A Nance, Nechama Shalva, Alvit Veber, Michal Tzadok, Andreea Nissenkorn, Davide Tonduti, Florence Renaldo, Ichraf Kraoua, Celeste Panteghini, Lorella Valletta, Barbara Garavaglia, Mark J Cowley, Velimir Gayevskiy, Tony Roscioli, Jonathon M Silberstein, Chen Hoffmann, Annick Raas-Rothschild, Valeria Tiranti, Yair Anikster, John Christodoulou, Alexander J Kastaniotis, Bruria Ben-Zeev, Susan J Hayflick
Mitochondrial fatty acid synthesis (mtFAS) is an evolutionarily conserved pathway essential for the function of the respiratory chain and several mitochondrial enzyme complexes. We report here a unique neurometabolic human disorder caused by defective mtFAS. Seven individuals from five unrelated families presented with childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities on MRI. All affected individuals were found to harbor recessive mutations in MECR encoding the mitochondrial trans-2-enoyl-coenzyme A-reductase involved in human mtFAS...
December 1, 2016: American Journal of Human Genetics
https://www.readbyqxmd.com/read/27804176/comparison-of-bioinformatics-prediction-molecular-modeling-and-functional-analyses-of-foxc1-mutations-in-patients-with-axenfeld-rieger-syndrome
#20
Morteza Seifi, Tim Footz, Sherry A M Taylor, Michael A Walter
Mutations in the forkhead box C1 gene (FOXC1) cause Axenfeld-Rieger syndrome (ARS). Here, we investigated the effect of four ARS missense variants on FOXC1 structure and function, and examined the predictive value of four in silico programs for all 31 FOXC1 missense variants identified to date. Molecular modeling of the FOXC1 forkhead domain predicts that c.402G> A (p.C135Y) alters FOXC1's structure. In contrast, c.378A> G (p.H128R) and c.481A> G (p.M161V) are not predicted to change FOXC1's structure...
February 2017: Human Mutation
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