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Human Mutation

Leila Youssefian, Hassan Vahidnezhad, Amir Hossein Saeidian, Hamidreza Mahmoudi, Razieh Karamzadeh, Ariana Kariminejad, Jianhe Huang, Leping Li, Thomas F Jannace, Paolo Fortina, Sirous Zeinali, Thomas W White, Jouni Uitto
Ichthyosis follicularis, a distinct cutaneous entity reported in combination with atrichia, and photophobia has been associated with mutations in MBTPS2. We sought the genetic cause of a novel syndrome of ichthyosis follicularis, bilateral severe sensorineural hearing loss and punctate palmoplantar keratoderma in two families. We performed whole exome sequencing on three patients from two families. The pathogenicity and consequences of mutations were studied in Xenopus oocyte expression system and by molecular dynamics simulation analysis...
November 15, 2018: Human Mutation
Elisa Gelli, Anna Maria Pinto, Serena Somma, Valentina Imperatore, Marta G Cannone, Theodora Hadjistilianou, Sonia De Francesco, Daniela Galimberti, Aurora Currò, Mirella Bruttini, Francesca Mari, Alessandra Renieri, Francesca Ariani
Retinoblastoma (RB), which represents the most common childhood eye cancer, is caused by biallelic inactivation of RB1 gene. Promoter hypermethylation is quite frequent in RB tissues but conclusive evidence of soma-wide predisposing epimutations is currently scant. Here, 50 patients who tested negative for RB1 germline sequence alterations were screened for aberrant promoter methylation using methylation-specific MLPA. The assay, performed on blood, identified a sporadic patient with methylation of CpG106, absent in parents' DNA...
November 14, 2018: Human Mutation
Nehir Edibe Kurtas, Luciano Xumerle, Lorena Leonardelli, Massimo Delledonne, Alfredo Brusco, Krystyna Chrzanowska, Albert Schinzel, Daniela Larizza, Silvana Guerneri, Federica Natacci, Maria Clara Bonaglia, Paolo Reho, Emmanouil Manolakos, Teresa Mattina, Fiorenza Soli, Aldesia Provenzano, Ahmed H Al-Rikabi, Edoardo Errichiello, Lusine Nazaryan-Petersen, Sabrina Giglio, Niels Tommerup, Thomas Liehr, Orsetta Zuffardi
We studied by a whole genomic approach and trios genotyping, 12 de novo, non-recurrent small supernumerary marker chromosomes (sSMC), detected as mosaics during pre- or postnatal diagnosis and associated with increased maternal age. Four sSMCs contained pericentromeric portions only, whereas eight had additional non-contiguous portions of the same chromosome, assembled together in a disordered fashion by repair-based mechanisms in a chromothriptic event. Maternal hetero/isodisomy was detected with a paternal origin of the sSMC in some cases, whereas in others two maternal alleles in the sSMC region and biparental haplotypes of the homologs were detected...
November 9, 2018: Human Mutation
Yan Cui, Helen Morrison
The Neurofibromatosis type 1 (NF1) tumor suppressor gene is one of the most frequently mutated genes in human tumors. Research on the NF1 proteins has been partially hindered by the difficulties in cloning and propagating the full-length coding cDNAs. We have now established a condition for propagating the natural ORFs and have assembled the ORFs for human NF1 type 1 and 2 isoforms. Furthermore, we were able to eliminate the cDNA cloning toxicity by introducing a mini-intron. These NF1 mini-genes were expressed similarly to the intron-less version and could be used to purify full-length NF1 proteins...
November 8, 2018: Human Mutation
Daniela Scalet, Iva Maestri, Alessio Branchini, Francesco Bernardi, Mirko Pinotti, Dario Balestra
The ability of variants of the spliceosomal U1snRNA to rescue splicing has been proven in several human disease models, but not for nucleotide changes at the conserved GT nucleotide of 5' splice sites (5'ss), frequent and associated with severe phenotypes. Here, we focused on variants at the 5'ss of F9 intron 3, leading to factor IX (FIX) deficiency (Haemophilia B). Through minigene expression we demonstrated that all changes induce complete exon 3 skipping, which explains the associated Haemophilia B phenotype...
November 8, 2018: Human Mutation
Hesham M Ismail, Navaneethakrishnan Krishnamoorthy, Nader Al-Dewik, Hatem Zayed, Nura A Mohamed, Valeria Di Giacomo, Sapna Gupta, Johannes Häberle, Beat Thöny, Henk J Blom, Waren D Kruger, Tawfeg Ben-Omran, Gheyath K Nasrallah
Homocystinuria is a rare inborn error of methionine metabolism caused by cystathionine β-synthase (CBS) deficiency. The prevalence of homocystinuria in Qatar is 1:1,800 births, mainly due to a founder Qatari missense mutation, c.1006C>T; p.R336C (p.Arg336Cys). We characterized the structure-function relationship of the p.R336C mutant protein, and investigated the effect of different chemical chaperones to restore p.R336C-CBS activity using three models: In silico, ΔCBS yeast, and CRISPR/Cas9 p.R336C knock-in HEK293T and HepG2 cell lines...
November 8, 2018: Human Mutation
Maximilian Weustenfeld, Reiner Eidelpes, Matthias Schmuth, William B Rizzo, Johannes Zschocke, Markus A Keller
The Sjögren-Larsson Syndrome (SLS) is a rare autosomal recessive disorder caused by pathogenic variants in the ALDH3A2 gene, which codes for fatty aldehyde dehydrogenase (FALDH). FALDH prevents the accumulation of toxic fatty aldehydes by converting them into fatty acids. Pathogenic ALDH3A2 variants cause symptoms such as ichthyosis, spasticity, intellectual disability, and a wide range of less common clinical features. Interpreting patient-to-patient variability is often complicated by inconsistent reporting and negatively impacts on establishing robust criteria to measure the success of SLS treatments...
October 29, 2018: Human Mutation
Paola Fortugno, Francesco Angelucci, Gianluca Cestra, Letizia Camerota, Angelo Salvatore Ferraro, Sonia Cordisco, Luigi Uccioli, Daniele Castiglia, Barbara De Angelis, Ingo Kurth, Uwe Kornak, Francesco Brancati
Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. Several pathways have been implicated in the pathogenesis of neuronal degeneration in HSAN, while recent observations point to an emerging role of cytoskeleton organization and function. Here, we report novel biallelic mutations in the DST gene encoding dystonin, a large cytolinker protein of the plakin family, in an adult form of HSAN type VI...
October 29, 2018: Human Mutation
Fiona McLachlan, Anna Martinez Sires, Catherine M Abbott
The multi-subunit eEF1 complex plays a crucial role in de novo protein synthesis. The central functional component of the complex is eEF1A, which occurs as two independently encoded variants with reciprocal expression patterns: whilst eEF1A1 is widely expressed, eEF1A2 is found only in neurons and muscle. Heterozygous mutations in the gene encoding eEF1A2, EEF1A2, have recently been shown to cause epilepsy, autism and intellectual disability. The remaining subunits of the eEF1 complex, eEF1Bα, eEF1Bδ, eEF1Bγ and valyl-tRNA synthetase (VARS), together form the GTP exchange factor for eEF1A and are ubiquitously expressed, in keeping with their housekeeping role...
October 29, 2018: Human Mutation
Ester Castellsagué, Rui Li, Rosa Aligue, Sara González, Judit Sanz, Edgar Martin, Àngela Velasco, Gabriel Capellá, Colin Jr Stewart, August Vidal, Jacek Majewski, Barbara Rivera, Paz Polak, Xavier Matias-Guiu, Joan Brunet, William D Foulkes
We describe a family in which four siblings exhibited multiple or classic colonic polyposis with or without colorectal carcinoma (CRC). One female developed three primary tumors including CRC and carcinomas of the ovary and breast. Whole exome sequencing of germline DNA from affected and unaffected individuals revealed a novel missense mutation in the exonuclease domain of POLE (c. 833C>A; p.Thr278Lys) associated with a highly penetrant, autosomal dominant inheritance pattern. Functional studies in yeast and demonstration of a high mutational burden in the available tumors confirmed the pathogenicity of the novel variant...
October 26, 2018: Human Mutation
Mariska Davids, Thomas Markello, Lynne A Wolfe, Xenia Chepa-Lotrea, Cynthia J Tifft, William A Gahl, May Christine Malicdan
The genetic etiologies of many rare disorders, including early infantile epileptic encephalopathies, are largely undiagnosed. A 6-year old girl was admitted to the National Institutes of Health Undiagnosed Diseases Program with profound intellectual disability, infantile onset seizures, chronic respiratory failure, facial dysmorphisms, skeletal abnormalities and atrial septum defect. A large region of homozygosity was discovered on chromosome 16, spanning 16q22.1-16q24.3 caused by uniparental disomy (UPD) that included a maternally inherited homozygous microdeletion covering exon 6 of WWOX (NM_016373...
October 25, 2018: Human Mutation
Francesc Muyas, Mattia Bosio, Anna Puig, Hana Susak, Laura Domènech-Salgado, Georgia Escaramis, Luis Zapata, German Demidov, Xavier Estivill, Raquel Rabionet, Stephan Ossowski
In recent years, Next Generation Sequencing (NGS) has become a cornerstone of clinical genetics and diagnostics. Many clinical applications require high precision, especially if rare events such as somatic mutations in cancer or genetic variants causing rare diseases need to be identified. Although random sequencing errors can be modeled statistically and deep sequencing minimizes their impact, systematic errors remain a problem even at high depth of coverage. Understanding their source is crucial to increase precision of clinical NGS applications...
October 24, 2018: Human Mutation
Kelvin C de Andrade, Megan N Frone, Talia Wegman-Ostrosky, Payal P Khincha, Jung Kim, Amina Amadou, Karina M Santiago, Fernanda P Fortes, Nathanaël Lemonnier, Lisa Mirabello, Douglas R Stewart, Pierre Hainaut, Luiz P Kowalski, Sharon A Savage, Maria I Achatz
Reports of variable cancer penetrance in Li-Fraumeni syndrome (LFS) have raised questions regarding the prevalence of pathogenic germline TP53 variants. We previously reported higher-than-expected population prevalence estimates in sequencing databases composed of individuals unselected for cancer history. This study aimed to expand and further evaluate the prevalence of pathogenic and likely pathogenic germline TP53 variants in the gnomAD dataset (n = 138,632). Variants were selected and classified based on our previously published algorithm and compared with alternative estimates based on three different classification databases: ClinVar, HGMD, and the UMD_TP53 website...
October 23, 2018: Human Mutation
Ingrid M Knarston, Gorjana Robevska, Jocelyn A van den Bergen, Stefanie Eggers, Brittany Croft, Jason Yates, Remko Hersmus, Leendert H J Looijenga, Fergus J Cameron, Klaus Monhike, Katie L Ayers, Andrew H Sinclair
Several recent reports have described a missense variant in the gene NR5A1 (c.274C>T; p.Arg92Trp) in a significant number of 46,XX ovotesticular or testicular Disorders of Sex Development (DSD) cases. The affected residue falls within the DNA-binding domain of the NR5A1 protein, however the exact mechanism by which it causes testicular development in 46,XX individuals remains unclear. We have screened a cohort of 26 patients with 46,XX (ovo)testicular DSD and identified three unrelated individuals with this NR5A1 variant (p...
October 23, 2018: Human Mutation
Christel Vaché, Simona Torriano, Valérie Faugère, Nejla Erkilic, David Baux, Gema Garcia-Garcia, Christian P Hamel, Isabelle Meunier, Xavier Zanlonghi, Michel Koenig, Vasiliki Kalatzis, Anne-Françoise Roux
Choroideremia is a monogenic X-linked recessive chorioretinal disease linked to pathogenic variants in the CHM gene. These variants are commonly base-pair changes, frameshifts, or large deletions. However, a few rare or unusual events comprising large duplications, a retrotransposon insertion, a pseudo-exon activation, and two c-98 promoter substitutions have also been described. Following an exhaustive molecular diagnosis, we identified and characterized three novel atypical disease-causing variants in three unrelated male patients...
October 19, 2018: Human Mutation
Cheryl Shoubridge, Robert J Harvey, Tracy Dudding-Byth
The IQSEC2- related disorders represent a spectrum of X-chromosome phenotypes with intellectual disability (ID) as the cardinal feature. Here, we review the increasing number of reported families and isolated cases have been reported with a variety of different pathogenic variants. The spectrum of clinical features is expanding with early-onset seizures as a frequent comorbidity in both affected male and female patients. There is a growing number of female patients with de novo loss-of-function variants in IQSEC2 have a more severe phenotype than the heterozygous state would predict, particularly if IQSEC2 is thought to escape X-inactivation...
October 17, 2018: Human Mutation
Dorota Rowczenio, Candida C Quarta, Marianna Fontana, Carol J Whelan, Ana Martinez-Naharro, Hadija Trojer, Anna Baginska, Stuart M Ferguson, Janet Gilbertson, Tamer Rezk, Sajitha Sachchithanantham, Shameem Mahmood, Richa Manwani, Faye Sharpley, Ashutosh D Wechalekar, Philip N Hawkins, Julian D Gillmore, Helen J Lachmann
Transthyretin amyloidosis (ATTR) is caused by deposition of either wild-type (ATTRwt) or variant (ATTRm) transthyretin. ATTRwt presents with restrictive cardiomyopathy, while ATTRm displays a range of organ involvement. This retrospective analysis includes all patients referred to a single UK center in the last 25 years for clinical and laboratory assessment of known or suspected amyloidosis who underwent TTR gene sequencing. A total of 4459 patients were included in this study; 37% had final diagnosis of ATTR amyloidosis; 27% light chain amyloidosis; 0...
October 17, 2018: Human Mutation
Liliana C Patiño, Isabelle Beau, Adrien Morel, Brigitte Delemer, Jacques Young, Nadine Binart, Paul Laissue
Primary ovarian insufficiency (POI) is a frequently occurring disease affecting women under 40 years old. Recently, we have analysed unrelated POI women via whole-exome sequencing (WES) and identified NOTCH2 mutations underlying possible functional effects. The present study involved reanalysing of WES assays. We used in the KGN granulosa-like cell model, a synthetic gene reporter construct driving luciferase gene expression to assess the functional effects of five NOTCH2 mutations identified in POI patients...
October 10, 2018: Human Mutation
Elodie M Richard, Regie Lp Santos-Cortez, Rabia Faridi, Atteeq U Rehman, Kwanghyuk Lee, Mohsin Shahzad, Anushree Acharya, Asma A Khan, Ayesha Imtiaz, Imen Chakchouk, Christina Takla, Izoduwa Abbe, Maria Rafeeq, Khurram Liaqat, Taimur Chaudhry, Michael J Bamshad, Deborah A Nickerson, Isabelle Schrauwen, Shaheen N Khan, Robert J Morell, Saba Zafar, Muhammad Ansar, Zubair M Ahmed, Wasim Ahmad, Sheik Riazuddin, Thomas B Friedman, Suzanne M Leal, Saima Riazuddin
Consanguineous Pakistani pedigrees segregating deafness have contributed decisively to the discovery of 31 of the 68 genes associated with nonsyndromic autosomal recessive hearing loss (HL) worldwide. In this study, we utilized genome-wide genotyping, Sanger and exome sequencing to identify 163 DNA variants in 41 previously reported HL genes segregating in 321 Pakistani families. Of these, 71 (43.6%) variants identified in 29 genes are novel. As expected from genetic studies of disorders segregating in consanguineous families, the majority of affected individuals (94...
October 10, 2018: Human Mutation
Ninad Oak, Rajarshi Ghosh, Kuan-Lin Huang, David A Wheeler, Li Ding, Sharon E Plon
MicroRNA (miRNA) expression is frequently deregulated in human disease, in contrast, disease-associated miRNA mutations are understudied. We developed Annotative Database of miRNA Elements, ADmiRE, which combines multiple existing and new biological annotations to aid prioritization of causal miRNA variation. We annotated 10,206 mature (3,257 within seed region) miRNA variants from multiple large sequencing datasets including gnomAD (15,496 genomes; 123,136 exomes). The pattern of miRNA variation closely resembles protein-coding exonic regions, with no difference between intragenic and intergenic miRNAs (P = 0...
October 10, 2018: Human Mutation
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