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Human Mutation

Rosangela Ferese, Monica Bonetti, Federica Consoli, Valentina Guida, Anna Sarkozy, Francesca R Lepri, Paolo Versacci, Stefano Gambardella, Giulio Calcagni, Katia Margiotti, Francesca Piceci Sparascio, Hossein Hozhabri, Tommaso Mazza, Maria Cristina Digilio, Bruno Dallapiccola, Marco Tartaglia, Bruno Marino, Jeroen den Hertog, Alessandro De Luca
Atrioventricular septal defect (AVSD) may occur as part of a complex disorder (e.g., Down syndrome, heterotaxy), or as isolate cardiac defect. Multiple lines of evidence support a role of calcineurin/NFAT signaling in AVSD, and mutations in CRELD1, a protein functioning as a regulator of calcineurin/NFAT signaling have been reported in a small fraction of affected subjects. In this study, 22 patients with isolated AVSD and 38 with AVSD and heterotaxy were screened for NFATC1 gene mutations. Sequence analysis identified three missense variants in three individuals, including a subject with isolated AVSD [p...
July 14, 2018: Human Mutation
Debora Baroni, Cristiana Picco, Oscar Moran
Voltage-dependent sodium channels are responsible of the rising phase of the action potential in excitable cells. These integral membrane proteins are composed of a pore-forming α-subunit, and one or more auxiliary β subunits. Mutation p.Asp25Asn (D25N; c.73G > A) of the β1 subunit, coded by the gene SCN1B, has been reported in a patient with generalized epilepsy with febrile seizure plus type 1 (GEFS+). In HEK cells, the heterologous co-expression of D25N-β1 subunit with Nav1.2, Nav1.4 and Nav1.5 α subunits, representative of brain, skeletal muscle and heart voltage gated sodium channels, determines a reduced sodium channel functional expression and a negative shift of the activation and inactivation steady state curves...
July 10, 2018: Human Mutation
Erich Roessler, Ping Hu, Juliana Marino, Sungkook Hong, Rachel Hart, Seth Berger, Ariel Martinez, Yu Abe, Paul Kruszka, James W Thomas, James C Mullikin, Yupeng Wang, Wendy S W Wong, John E Niederhuber, Benjamin D Solomon, Antônio Richieri-Costa, L A Ribeiro-Bicudo, Maximilian Muenke
Next generation sequencing (NGS) promises to accelerate gene discovery in human disease. Here we applied targeted capture to examine 153 genes representative of all the major vertebrate developmental pathways among 333 probands to rank their relative significance as causes for holoprosencephaly (HPE). HPE involves a small number of genes damaged by gross chromosomal re-arrangements, micro-deletions, or clustered novel or de novo mutations. Yet the typical incomplete penetrance and variable expressivity remain unexplained...
July 10, 2018: Human Mutation
Klaasjan G Ouwens, Rick Jansen, Bas Tolhuis, P Eline Slagboom, Brenda W J H Penninx, Dorret I Boomsma
Post-zygotic mutations are DNA changes acquired from the zygote stage onwards throughout the lifespan. These changes lead to differences in DNA sequence among cells of an individual, potentially contributing to the etiology of complex disorders. Here we compared whole genome DNA sequence data of two monozygotic twin pairs, 40 and 100 years old, to detect somatic mosaicism. DNA samples were sequenced twice on two Illumina platforms (13X and 40X read depth) for increased specificity. Using differences in allelic ratios resulted in sets of 1720 and 1739 putative post-zygotic mutations in the 40-year-old twin pair and 100-year-old twin pair, respectively, for subsequent enrichment analysis...
July 6, 2018: Human Mutation
Sandra M Sánchez-Sánchez, Juliana Magdalon, Karina Griesi-Oliveira, Guilherme Yamamoto, Carolina Santacruz-Perez, Mariana Fogo, Maria Rita Passos-Bueno, Andrea L Sertié
The Reelin-DAB1 signaling pathway plays a crucial role in regulating neuronal migration and synapse function. While many rare heterozygous variants in the Reelin gene (RELN) have been identified in patients with autism spectrum disorder (ASD), most variants are still of unknown clinical significance. Also, genetic data suggest that heterozygous variants in RELN alone appear to be insufficient to cause ASD. Here, we describe the identification and functional characterization of rare compound heterozygous missense variants in RELN in a patient with ASD in whom we have previously reported hyperfunctional mTORC1 signaling of yet unknown etiology...
July 3, 2018: Human Mutation
Nguyen Dang Ton, Hidewaki Nakagawa, Nguyen Hai Ha, Nguyen Thuy Duong, Vu Phuong Nhung, Le Thi Thu Hien, Huynh Thi Thu Hue, Nguyen Huy Hoang, Jing Hao Wong, Kaoru Nakano, Kazuhiro Maejima, Aya Sasaki-Oku, Tatsuhiko Tsunoda, Akihiro Fujimoto, Nong Van Hai
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) or dioxin, is commonly considered the most toxic man-made substance. Dioxin exposure impacts human health and diseases, birth defects and teratogenesis were frequently observed in children of persons who have been exposed to dioxin. However, the impact of dioxin on human mutation rate in trios has not yet been elucidated in the whole genome level. To identify and characterize the genetic alterations in the individuals exposed to dioxin, we perfomed whole genome sequencing (WGS) of nine Vietnamese trios whose fathers were exposed to dioxin...
July 3, 2018: Human Mutation
Gemma Montalban, Eugenia Fraile-Bethencourt, Irene López-Perolio, Pedro Pérez-Segura, Mar Infante, Mercedes Durán, María Concepción Alonso-Cerezo, Adrià López-Fernández, Orland Diez, Miguel de la Hoya, Eladio A Velasco, Sara Gutiérrez-Enríquez
Many BRCA1 and BRCA2 (BRCA1/2) genetic variants have been studied at mRNA level and linked to hereditary breast and ovarian cancer due to splicing alteration. In silico tools are reliable when assessing variants located in consensus splice sites, but we may identify variants in complex genomic contexts for which bioinformatics is not precise enough. In this study, we characterize BRCA2 c.7976+5G > T variant located in intron 17 which has an atypical donor site (GC). This variant was identified in three unrelated Spanish families and we have detected exon 17 skipping as the predominant transcript occurring in carriers...
July 3, 2018: Human Mutation
Concetta Altamura, Sabrina Lucchiari, Dalila Sahbani, Gianna Ulzi, Giacomo P Comi, Paola D'Ambrosio, Roberta Petillo, Luisa Politano, Liliana Vercelli, Tiziana Mongini, Maria Teresa Dotti, Rosanna Cardani, Giovanni Meola, Mauro Lo Monaco, Emma Matthews, Michael G Hanna, Maria Rosaria Carratù, Diana Conte, Paola Imbrici, Jean-François Desaphy
Myotonia congenita (MC) is a skeletal muscle hyper-excitability disorder caused by loss-of-function mutations in the ClC-1 chloride channel. Mutations are scattered over the entire sequence of the channel protein, with more than 30 mutations located in the poorly characterized cytosolic C-terminal domain. In this study, we characterized, through patch clamp, seven ClC-1 mutations identified in patients affected by MC of various severity and located in the C-terminal region. The p.Val829Met, p.Thr832Ile, p...
June 23, 2018: Human Mutation
Ida Höijer, Yu-Chih Tsai, Tyson A Clark, Paul Kotturi, Niklas Dahl, Eva-Lena Stattin, Marie-Louise Bondeson, Lars Feuk, Ulf Gyllensten, Adam Ameur
Amplification of DNA is required as a mandatory step during library preparation in most targeted sequencing protocols. This can be a critical limitation when targeting regions that are highly repetitive or with extreme guanine-cytosine (GC) content, including repeat expansions associated with human disease. Here we used an amplification-free protocol for targeted enrichment utilizing the CRISPR/Cas9 system (No-Amp Targeted sequencing) in combination with Single Molecule, Real-Time (SMRT) sequencing for studying repeat elements in the huntingtin (HTT) gene, where an expanded CAG repeat is causative for Huntington disease...
June 22, 2018: Human Mutation
Josephina A N Meester, Maja Sukalo, Kim C Schröder, Denny Schanze, Gareth Baynam, Guntram Borck, Nuria C Bramswig, Duygu Duman, Brigitte Gilbert-Dussardier, Muriel Holder-Espinasse, Peter Itin, Diana S Johnson, Shelagh Joss, Hannele Koillinen, Fiona McKenzie, Jenny Morton, Heike Nelle, Willie Reardon, Claudia Roll, Mustafa A Salih, Ravi Savarirayan, Ingrid Scurr, Miranda Splitt, Elizabeth Thompson, Hannah Titheradge, Colm P Travers, Lionel Van Maldergem, Margo Whiteford, Dagmar Wieczorek, Geert Vandeweyer, Richard Trembath, Lut Van Laer, Bart L Loeys, Martin Zenker, Laura Southgate, Wim Wuyts
Adams-Oliver syndrome (AOS) is a rare developmental disorder, characterized by scalp aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance. Data on the frequency and distribution of mutations in large cohorts is currently limited. The purpose of this study was therefore to comprehensively examine the genetic architecture of AOS in an extensive cohort...
June 20, 2018: Human Mutation
Yanhan Deng, Zongzhe Li, Juan Liu, Zheng Wang, Yanyan Cao, Yong Mou, Bohua Fu, Biwen Mo, Jianghong Wei, Zhenshun Cheng, Liman Luo, Jingping Li, Ying Shu, Xiaomei Wang, Guangwei Luo, Shuo Yang, Yingnan Wang, Jing Zhu, Jingping Yang, Ming Wu, Xuyan Xu, Renying Ge, Xueqin Chen, Qingzhen Peng, Guang Wei, Yaqing Li, Hua Yang, Shirong Fang, Xiaoju Zhang, Weining Xiong
Idiopathic pulmonary fibrosis (IPF) is a genetic heterogeneous disease with high mortality and poor prognosis. However, a large fraction of genetic cause remains unexplained, especially in sporadic IPF (∼80% IPF). By systemically reviewing related literature and potential pathogenic pathways, 92 potentially IPF-related genes were selected and sequenced in genomic DNAs from 253 sporadic IPF patients and 125 matched health controls using targeted massively parallel next-generation sequencing. The identified risk variants were confirmed by Sanger sequencing...
June 19, 2018: Human Mutation
Eline Overwater, Luisa Marsili, Marieke J H Baars, Annette F Baas, Irma van de Beek, Eelco Dulfer, Johanna M van Hagen, Yvonne Hilhorst-Hofstee, Marlies Kempers, Ingrid P Krapels, Leonie A Menke, Judith M A Verhagen, Kak K Yeung, Petra J G Zwijnenburg, Maarten Groenink, Peter van Rijn, Marjan M Weiss, Els Voorhoeve, J Peter van Tintelen, Arjan C Houweling, Alessandra Maugeri
Simultaneous analysis of multiple genes using next generation sequencing (NGS) technology has become widely available. Copy number variations (CNVs) in disease-associated genes have emerged as a cause for several hereditary disorders. CNVs are, however, not routinely detected using NGS analysis. The aim of this study was to assess the diagnostic yield and the prevalence of CNVs using our panel of Hereditary Thoracic Aortic Disease (H-TAD) associated genes. 810 patients suspected of H-TAD were analysed by targeted NGS analysis of 21 H-TAD associated genes...
June 16, 2018: Human Mutation
Richard T Wang, Florian Barthelemy, Ann S Martin, Emilie D Douine, Ascia Eskin, Ann Lucas, Jenifer Lavigne, Holly Peay, Negar Khanlou, Lee Sweeney, Rita M Cantor, M Carrie Miceli, Stanley F Nelson
Antisense oligonucleotide (AON) mediated exon skipping is an emerging therapeutic for individuals with Duchenne muscular dystrophy (DMD). Skipping of exons adjacent to common exon deletions in DMD using AONs can produce in-frame transcripts and functional protein. Targeted skipping of DMD exons 8, 44, 45, 50, 51, 52, 53, and 55 are predicted to benefit 47% of affected individuals. We observed a correlation between mutation subgroups and age at loss of ambulation in DuchenneConnect, a large database of phenotypic and genetic data for DMD (N = 765)...
June 16, 2018: Human Mutation
Pilar Mur, Ann-Sofie Jemth, Luka Bevc, Nuno Amaral, Matilde Navarro, Rafael Valdés-Mas, Tirso Pons, Gemma Aiza, Miguel Urioste, Alfonso Valencia, Conxi Lázaro, Victor Moreno, Xose S Puente, Pål Stenmark, Ulrika Warpman-Berglund, Gabriel Capellá, Thomas Helleday, Laura Valle
The causal association of NUDT1 ( = MTH1) and OGG1 with hereditary colorectal cancer (CRC) remains unclear. Here we sought to provide additional evidence for or against the causal contribution of NUDT1 and OGG1 mutations to hereditary CRC and/or polyposis. Mutational screening was performed using pooled DNA amplification and targeted next generation sequencing in 529 families (441 uncharacterized MMR-proficient familial non-polyposis colorectal cancer and 88 polyposis cases). Co-segregation, in silico analyses, in vitro functional assays and case-control associations, were carried out to characterize the identified variants...
June 13, 2018: Human Mutation
Manuela Priolo, Denny Schanze, Katrin Tatton-Brown, Paul A Mulder, Jair Tenorio, Kreepa Kooblall, Inés Hernández Acero, Fowzan S Alkuraya, Pedro Arias, Laura Bernardini, Emilia K Bijlsma, Trevor Cole, Christine Coubes, Irene Dapia, Sally Davies, Nataliya Di Donato, Nursel H Elcioglu, Jill A Fahrner, Alison Foster, Noelia García González, Ilka Huber, Maria Iascone, Ann-Sophie Kaiser, Arveen Kamath, Jan Liebelt, Sally Ann Lynch, Saskia M Maas, Corrado Mammì, Inge B Mathijssen, Shane McKee, Leonie A Menke, Ghayda M Mirzaa, Tara Montgomery, Dorothee Neubauer, Thomas E Neumann, Letizia Pintomalli, Maria Antonietta Pisanti, Astrid S Plomp, Sue Price, Claire Salter, Fernando Santos-Simarro, Pierre Sarda, Mabel Segovia, Charles Shaw-Smith, Sarah Smithson, Mohnish Suri, Rita Maria Valdez, Arie Van Haeringen, Johanna M Van Hagen, Marcela Zollino, Pablo Lapunzina, Rajesh V Thakker, Martin Zenker, Raoul C Hennekam
Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip and prominent chin...
June 13, 2018: Human Mutation
Edoardo Giacopuzzi, Mattia Laffranchi, Romina Berardelli, Viola Ravasio, Ilaria Ferrarotti, Bibek Gooptu, Giuseppe Borsani, Annamaria Fra
The growth of publicly available data informing upon genetic variations, mechanisms of disease and disease sub-phenotypes offers great potential for personalised medicine. Computational approaches are likely required to assess large numbers of novel genetic variants. However, the integration of genetic, structural and pathophysiological data still represents a challenge for computational predictions and their clinical use. We addressed these issues for alpha-1-antitrypsin deficiency, a disease mediated by mutations in the SERPINA1 gene encoding alpha-1-antitrypsin...
June 7, 2018: Human Mutation
Mert Karakaya, Markus Storbeck, Eike A Strathmann, Andrea Delle Vedove, Irmgard Hölker, Janine Altmueller, Leyla Naghiyeva, Lea Schmitz-Steinkrüger, Katharina Vezyroglou, Susanne Motameny, Salem Alawbathani, Holger Thiele, Ayse Ipek Polat, Derya Okur, Reza Boostani, Ehsan Ghayoor Karimiani, Gilbert Wunderlich, Didem Ardicli, Haluk Topaloglu, Janbernd Kirschner, Bertold Schrank, Reza Maroofian, Olafur Magnusson, Uluc Yis, Peter Nürnberg, Raoul Heller, Brunhilde Wirth
Spinal muscular atrophies (SMA) is a heterogeneous group of disorders characterized by muscular atrophy, weakness, and hypotonia due to suspected lower motor neuron degeneration (LMND). In a large cohort of 3,465 individuals suspected with SMA submitted for SMN1 testing to our routine diagnostic laboratory, 48% carried a homozygous SMN1 deletion, 2.8% a subtle mutation and an SMN1 deletion while 49.2% remained undiagnosed. Recently, several other genes implicated in SMA/LMND have been reported. Despite several efforts to establish a diagnostic algorithm for non-5q-SMA (SMA without deletion or point mutations in SMN1 [5q13...
June 2, 2018: Human Mutation
Artem Kiselev, Raquel Vaz, Anastasia Knyazeva, Aleksandr Khudiakov, Svetlana Tarnovskaya, Jiao Liu, Alexey Sergushichev, Sergey Kazakov, Dmitrij Frishman, Natalia Smolina, Tatiana Pervunina, John Jorholt, Gunnar Sjoberg, Tatiana Vershinina, Dmitriy Rudenko, Anders Arner, Thomas Sejersen, Anna Lindstrand, Anna Kostareva
Mutations in FLNC for a long time are known in connection to neuromuscular disorders and only recently were described in association with various cardiomyopathies. Here, we report a new clinical phenotype of filaminopathy in four unrelated patients with early-onset restrictive cardiomyopathy (RCM) in combination with congenital myopathy due to FLNC mutations (NM_001458.4:c.3557C>T, p.A1186V, rs1114167361 in three probands and c.[3547G>C; 3548C>T], p.A1183L, rs1131692185 in one proband). In all cases, concurrent myopathy was confirmed by neurological examination, electromyography, and morphological studies...
June 1, 2018: Human Mutation
Raman Kumar, Alison Gardner, Claire C Homan, Evelyn Douglas, Heather Mefford, Dagmar Wieczorek, Hermann-Josef Lüdecke, Zornitza Stark, Simon Sadedin, Catherine Bearce Nowak, Jessica Douglas, Gretchen Parsons, Paul Mark, Lourdes Loidi, Gail E Herman, Theresa Mihalic Mosher, Meredith K Gillespie, Lauren Brady, Mark Tarnopolsky, Irene Madrigal, Jesús Eiris, Laura Domènech Salgado, Raquel Rabionet, Tim M Strom, Naoko Ishihara, Hidehito Inagaki, Hiroki Kurahashi, Tracy Dudding-Byth, Elizabeth E Palmer, Michael Field, Jozef Gecz
Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID). We now report an additional six affected individuals from five unrelated families with two de novo and three maternally inherited pathogenic or likely pathogenic variants in THOC2 extending the genotypic and phenotypic spectrum...
May 31, 2018: Human Mutation
Yohan Bignon, Alexi Alekov, Nadia Frachon, Olivier Lahuna, Carine Jean-Baptiste Doh-Egueli, Georges Deschênes, Rosa Vargas-Poussou, Stéphane Lourdel
Dent disease is an X-linked recessive renal tubular disorder characterized by low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure. Inactivating mutations of CLCN5, the gene encoding the 2Cl- /H+ exchanger ClC-5, have been reported in patients with Dent disease 1. In vivo studies in mice harboring an artificial mutation in the "gating glutamate" of ClC-5 (c.632A > C, p.Glu211Ala) and mathematical modeling suggest that endosomal chloride concentration could be an important parameter in endocytosis, rather than acidification as earlier hypothesized...
May 23, 2018: Human Mutation
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