Oprescu, Stephanie N.; Chepa‐Lotrea, Xenia; Takase, Ryuichi; Golas, Gretchen; Markello, Thomas C.; Adams, David R.; Toro, Camilo; Gropman, Andrea L.; Hou, Ya‐Ming; Malicdan, May Christine V.; Gahl, William A.; Tifft, Cynthia J.; Antonellis, Anthony
doi: 10.1002/humu.23317pmid: N/A
Dyke, Stephanie O. M.; Knoppers, Bartha M.; Hamosh, Ada; Firth, Helen V.; Hurles, Matthew; Brudno, Michael; Boycott, Kym M.; Philippakis, Anthony A.; Rehm, Heidi L.
doi: 10.1002/humu.23278pmid: 28699299
The Matchmaker Exchange (MME) connects rare disease clinicians and researchers to facilitate the sharing of data from undiagnosed patients for the purpose of novel gene discovery. Such sharing raises the odds that two or more similar patients with candidate genes in common may be found, thereby allowing their condition to be more readily studied and understood. Consent considerations for data sharing in MME included both the ethical and legal differences between clinical and research settings and the level of privacy risk involved in sharing varying amounts of rare disease patient data to enable patient matches. In this commentary, we discuss these consent considerations and the resulting MME Consent Policy as they may be relevant to other international data sharing initiatives.
de Vosse, Esther; Dissel, Jaap T.
doi: 10.1002/humu.23302pmid: 28744922
IFN‐γ signaling is essential for the innate immune defense against mycobacterial infections. IFN‐γ signals through the IFN‐γ receptor, which consists of a tetramer of two IFN‐γR1 chains in complex with two IFN‐γR2 chains, where IFN‐γR1 is the ligand‐binding chain of the interferon‐γ receptor and IFN‐γR2 is the signal‐transducing chain of the IFN‐γ receptor. Germline mutations in the gene IFNGR1 encoding the IFN‐γR1 cause a primary immunodeficiency that mainly leads to mycobacterial infections. Here, we review the molecular basis of this immunodeficiency in the 130 individuals described to date, and report mutations in five new individuals, bringing the total number to 135 individuals from 98 kindreds. Forty unique IFNGR1 mutations have been reported and they exert either an autosomal dominant or an autosomal recessive effect. Mutations resulting in premature stopcodons represent the majority of IFNGR1 mutations (60%; 24 out of 40), followed by amino acid substitutions (28%, 11 out of 40). All known mutations, as well as 287 other variations, have been deposited in the online IFNGR1 variation database (www.LOVD.nl/IFNGR1). In this article, we review the function of IFN‐γR1 and molecular genetics of human IFNGR1.
Claustres, Mireille; Thèze, Corinne; des Georges, Marie; Baux, David; Girodon, Emmanuelle; Bienvenu, Thierry; Audrezet, Marie‐Pierre; Dugueperoux, Ingrid; Férec, Claude; Lalau, Guy; Pagin, Adrien; Kitzis, Alain; Thoreau, Vincent; Gaston, Véronique; Bieth, Eric;
Moulinier, Luc; Ripp, Raymond; Castillo, Gaston; Poch, Olivier; Sissler, Marie
doi: 10.1002/humu.23277pmid: 28608363
Numerous mutations in each of the mitochondrial aminoacyl‐tRNA synthetases (aaRSs) have been implicated in human diseases. The mutations are autosomal and recessive and lead mainly to neurological disorders, although with pleiotropic effects. The processes and interactions that drive the etiology of the disorders associated with mitochondrial aaRSs (mt‐aaRSs) are far from understood. The complexity of the clinical, genetic, and structural data requires concerted, interdisciplinary efforts to understand the molecular biology of these disorders. Toward this goal, we designed MiSynPat, a comprehensive knowledge base together with an ergonomic Web server designed to organize and access all pertinent information (sequences, multiple sequence alignments, structures, disease descriptions, mutation characteristics, original literature) on the disease‐linked human mt‐aaRSs. With MiSynPat, a user can also evaluate the impact of a possible mutation on sequence‐conservation‐structure in order to foster the links between basic and clinical researchers and to facilitate future diagnosis. The proposed integrated view, coupled with research on disease‐related mt‐aaRSs, will help to reveal new functions for these enzymes and to open new vistas in the molecular biology of the cell. The purpose of MiSynPat, freely available at http://misynpat.org, is to constitute a reference and a converging resource for scientists and clinicians.
Crispatzu, Giuliano; Kulkarni, Pranav; Toliat, Mohammad R.; Nürnberg, Peter; Herling, Marco; Herling, Carmen D.; Frommolt, Peter
doi: 10.1002/humu.23275pmid: 28598576
Next‐generation sequencing (NGS) has turned from a new and experimental technology into a standard procedure for cancer genome studies and clinical investigation. While a multitude of software packages for cancer genome data analysis have been made available, these need to be combined into efficient analytical workflows that cover multiple aspects relevant to a clinical environment and that deliver handy results within a reasonable time frame. Here, we introduce QuickNGS Cancer as a new suite of bioinformatics pipelines that is focused on cancer genomics and significantly reduces the analytical hurdles that still limit a broader applicability of NGS technology, particularly to clinically driven research. QuickNGS Cancer allows a highly efficient analysis of a broad variety of NGS data types, specifically considering cancer‐specific issues, such as biases introduced by tumor impurity and aneuploidy or the assessment of genomic variations regarding their biomedical relevance. It delivers highly reproducible analysis results ready for interpretation within only a few days after sequencing, as shown by a reanalysis of 140 tumor/normal pairs from The Cancer Genome Atlas (TCGA) in which QuickNGS Cancer detected a significant number of mutations in key cancer genes missed by a well‐established mutation calling pipeline. Finally, QuickNGS Cancer obtained several unexpected mutations in leukemias that could be confirmed by Sanger sequencing.
Livingstone, Mark; Folkman, Lukas; Yang, Yuedong; Zhang, Ping; Mort, Matthew; Cooper, David N.; Liu, Yunlong; Stantic, Bela; Zhou, Yaoqi
doi: 10.1002/humu.23283pmid: 28649752
Synonymous single‐nucleotide variants (SNVs), although they do not alter the encoded protein sequences, have been implicated in many genetic diseases. Experimental studies indicate that synonymous SNVs can lead to changes in the secondary and tertiary structures of DNA and RNA, thereby affecting translational efficiency, cotranslational protein folding as well as the binding of DNA‐/RNA‐binding proteins. However, the importance of these various features in disease phenotypes is not clearly understood. Here, we have built a support vector machine (SVM) model (termed DDIG‐SN) as a means to discriminate disease‐causing synonymous variants. The model was trained and evaluated on nearly 900 disease‐causing variants. The method achieves robust performance with the area under the receiver operating characteristic curve of 0.84 and 0.85 for protein‐stratified 10‐fold cross‐validation and independent testing, respectively. We were able to show that the disease‐causing effects in the immediate proximity to exon–intron junctions (1–3 bp) are driven by the loss of splicing motif strength, whereas the gain of splicing motif strength is the primary cause in regions further away from the splice site (4–69 bp). The method is available as a part of the DDIG server at http://sparks-lab.org/ddig.
Nakayama, Tojo; Wu, Jiang; Galvin‐Parton, Patricia; Weiss, Jody; Andriola, Mary R.; Hill, R. Sean; Vaughan, Dylan J.; El‐Quessny, Malak; Barry, Brenda J.; Partlow, Jennifer N.; Barkovich, A. James; Ling, Jiqiang; Mochida, Ganeshwaran H.
Grandin, Virginie; Sepulveda, Fernando E; Lambert, Nathalie; Al Zahrani, Mofareh; Al Idrissi, Eman; Al‐Mousa, Hamoud; Almanjomi, Fahd; Al‐Ghonaium, Abdulaziz; K. Habazi, Murad; A. Alghamdi, Hamza; Picard, Capucine; Bole‐Feysot, Christine; Nitschke, Patrick; Ménasché, Gaël;
Showing 1 to 10 of 20 Articles
doi: 10.1002/humu.23276pmid: 28603918
Most of the 2,000 variants identified in the CFTR (cystic fibrosis transmembrane regulator) gene are rare or private. Their interpretation is hampered by the lack of available data and resources, making patient care and genetic counseling challenging. We developed a patient‐based database dedicated to the annotations of rare CFTR variants in the context of their cis‐ and trans‐allelic combinations. Based on almost 30 years of experience of CFTR testing, CFTR‐France (https://cftr.iurc.montp.inserm.fr/cftr) currently compiles 16,819 variant records from 4,615 individuals with cystic fibrosis (CF) or CFTR‐RD (related disorders), fetuses with ultrasound bowel anomalies, newborns awaiting clinical diagnosis, and asymptomatic compound heterozygotes. For each of the 736 different variants reported in the database, patient characteristics and genetic information (other variations in cis or in trans) have been thoroughly checked by a dedicated curator. Combining updated clinical, epidemiological, in silico, or in vitro functional data helps to the interpretation of unclassified and the reassessment of misclassified variants. This comprehensive CFTR database is now an invaluable tool for diagnostic laboratories gathering information on rare variants, especially in the context of genetic counseling, prenatal and preimplantation genetic diagnosis. CFTR‐France is thus highly complementary to the international database CFTR2 focused so far on the most common CF‐causing alleles.
doi: 10.1002/humu.23250pmid: 28493438
Aminoacyl‐transfer RNA (tRNA) synthetases ligate amino acids to specific tRNAs and are essential for protein synthesis. Although alanyl‐tRNA synthetase (AARS) is a synthetase implicated in a wide range of neurological disorders from Charcot‐Marie‐Tooth disease to infantile epileptic encephalopathy, there have been limited data on their pathogenesis. Here, we report loss‐of‐function mutations in AARS in two siblings with progressive microcephaly with hypomyelination, intractable epilepsy, and spasticity. Whole‐exome sequencing identified that the affected individuals were compound heterozygous for mutations in AARS gene, c.2067dupC (p.Tyr690Leufs*3) and c.2738G>A (p.Gly913Asp). A lymphoblastoid cell line developed from one of the affected individuals showed a strong reduction in AARS abundance. The mutations decrease aminoacylation efficiency by 70%–90%. The p.Tyr690Leufs*3 mutation also abolished editing activity required for hydrolyzing misacylated tRNAs, thereby increasing errors during aminoacylation. Our study has extended potential mechanisms underlying AARS‐related disorders to include destabilization of the protein, aminoacylation dysfunction, and defective editing activity.
doi: 10.1002/humu.23274pmid: 28585352
Griscelli syndrome type 2 (GS2) is a rare and often fatal autosomal recessive, hyperinflammatory disorder. It is associated with hypopigmentation of the skin and the hair, resulting in the characteristic pigment accumulation and clumping in the hair shaft. Loss‐of‐function mutations in RAB27A, resulting from point mutations, short indel, or large deletions, account for all the cases reported to date. However, several GS2 cases originating from Saudi Arabia lack a genetic diagnosis. Here, we report on a new RAB27A genetic anomaly observed in seven Saudi Arabia families that had remained negative after extensive molecular genomic DNA testing. Linkage analysis and targeted sequencing of the RAB27A genomic region in several of these patients led to the identification of a common homozygous tandem duplication of 38 kb affecting exon 2–5 and resulting in a premature stop codon. The pathogenic effect of this duplication was confirmed by a cDNA analysis and functional assays. The identification of microhomology flanking the breakpoint site suggests a possible underlying mechanism.