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      The genotypic and phenotypic spectrum of PIGA deficiency.

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          Abstract

          Phosphatidylinositol glycan biosynthesis class A protein (PIGA) is one of the enzymes involved in the biosynthesis of glycosylphosphatidylinositol (GPI) anchor proteins, which function as enzymes, adhesion molecules, complement regulators and co-receptors in signal transduction pathways. Until recently, only somatic PIGA mutations had been reported in patients with paroxysmal nocturnal hemoglobinuria (PNH), while germline mutations had not been observed, and were suspected to result in lethality. However, in just two years, whole exome sequencing (WES) analyses have identified germline PIGA mutations in male patients with XLIDD (X-linked intellectual developmental disorder) with a wide spectrum of clinical presentations.

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          Aminoglycoside antibiotics mediate context-dependent suppression of termination codons in a mammalian translation system

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            Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome.

            Hyperphosphatasia mental retardation (HPMR) syndrome is an autosomal recessive form of mental retardation with distinct facial features and elevated serum alkaline phosphatase. We performed whole-exome sequencing in three siblings of a nonconsanguineous union with HPMR and performed computational inference of regions identical by descent in all siblings to establish PIGV, encoding a member of the GPI-anchor biosynthesis pathway, as the gene mutated in HPMR. We identified homozygous or compound heterozygous mutations in PIGV in three additional families.
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              FLAGS, frequently mutated genes in public exomes

              Background Dramatic improvements in DNA-sequencing technologies and computational analyses have led to wide use of whole exome sequencing (WES) to identify the genetic basis of Mendelian disorders. More than 180 novel rare-disease-causing genes with Mendelian inheritance patterns have been discovered through sequencing the exomes of just a few unrelated individuals or family members. As rare/novel genetic variants continue to be uncovered, there is a major challenge in distinguishing true pathogenic variants from rare benign mutations. Methods We used publicly available exome cohorts, together with the dbSNP database, to derive a list of genes (n = 100) that most frequently exhibit rare (<1%) non-synonymous/splice-site variants in general populations. We termed these genes FLAGS for FrequentLy mutAted GeneS and analyzed their properties. Results Analysis of FLAGS revealed that these genes have significantly longer protein coding sequences, a greater number of paralogs and display less evolutionarily selective pressure than expected. FLAGS are more frequently reported in PubMed clinical literature and more frequently associated with diseased phenotypes compared to the set of human protein-coding genes. We demonstrated an overlap between FLAGS and the rare-disease causing genes recently discovered through WES studies (n = 10) and the need for replication studies and rigorous statistical and biological analyses when associating FLAGS to rare disease. Finally, we showed how FLAGS are applied in disease-causing variant prioritization approach on exome data from a family affected by an unknown rare genetic disorder. Conclusions We showed that some genes are frequently affected by rare, likely functional variants in general population, and are frequently observed in WES studies analyzing diverse rare phenotypes. We found that the rate at which genes accumulate rare mutations is beneficial information for prioritizing candidates. We provided a ranking system based on the mutation accumulation rates for prioritizing exome-captured human genes, and propose that clinical reports associating any disease/phenotype to FLAGS be evaluated with extra caution. Electronic supplementary material The online version of this article (doi:10.1186/s12920-014-0064-y) contains supplementary material, which is available to authorized users.
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                Author and article information

                Journal
                Orphanet J Rare Dis
                Orphanet journal of rare diseases
                Springer Science and Business Media LLC
                1750-1172
                1750-1172
                Feb 27 2015
                : 10
                Affiliations
                [1 ] Centre for Molecular Medicine and Therapeutics, Vancouver, Canada. maja@cmmt.ubc.ca.
                [2 ] Department of Medical Genetics, University of British Columbia, Vancouver, Canada. maja@cmmt.ubc.ca.
                [3 ] Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. maja@cmmt.ubc.ca.
                [4 ] Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. gsinclair@cw.bc.ca.
                [5 ] Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada. gsinclair@cw.bc.ca.
                [6 ] Biochemical Genetics Laboratory, Department of Pathology, BC Children's Hospital, University of British Columbia, Vancouver, Canada. gsinclair@cw.bc.ca.
                [7 ] Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. sstockler@cw.bc.ca.
                [8 ] Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada. sstockler@cw.bc.ca.
                [9 ] Child & Family Research Institute, Vancouver, BC, Canada. sstockler@cw.bc.ca.
                [10 ] Department of Medical Genetics, University of British Columbia, Vancouver, Canada. mvallen@cw.bc.ca.
                [11 ] Child & Family Research Institute, Vancouver, BC, Canada. mvallen@cw.bc.ca.
                [12 ] Division of Hematology, Oncology & BMT, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada. jrozmus@cw.bc.ca.
                [13 ] Child & Family Research Institute, Vancouver, BC, Canada. jrozmus@cw.bc.ca.
                [14 ] Centre for Molecular Medicine and Therapeutics, Vancouver, Canada. casper@cmmt.ubc.ca.
                [15 ] Department of Medical Genetics, University of British Columbia, Vancouver, Canada. casper@cmmt.ubc.ca.
                [16 ] Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. casper@cmmt.ubc.ca.
                [17 ] Department of Paediatric Neurology, Children's Hospital Oxford, John Radcliffe Hospital, Oxford, UK. roberta@biancheri.com.
                [18 ] Department of Medical Genetics, University of British Columbia, Vancouver, Canada. toh@cw.bc.ca.
                [19 ] Child & Family Research Institute, Vancouver, BC, Canada. toh@cw.bc.ca.
                [20 ] Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. Bryan.Sayson@cw.bc.ca.
                [21 ] Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada. Bryan.Sayson@cw.bc.ca.
                [22 ] Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. MLafek@cw.bc.ca.
                [23 ] Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada. MLafek@cw.bc.ca.
                [24 ] Centre for Molecular Medicine and Therapeutics, Vancouver, Canada. colinross1@gmail.com.
                [25 ] Department of Medical Genetics, University of British Columbia, Vancouver, Canada. colinross1@gmail.com.
                [26 ] Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. colinross1@gmail.com.
                [27 ] Child & Family Research Institute, Vancouver, BC, Canada. colinross1@gmail.com.
                [28 ] Department of Medical Genetics, University of British Columbia, Vancouver, Canada. wrobinson@cfri.ca.
                [29 ] Child & Family Research Institute, Vancouver, BC, Canada. wrobinson@cfri.ca.
                [30 ] Centre for Molecular Medicine and Therapeutics, Vancouver, Canada. wyeth@cmmt.ubc.ca.
                [31 ] Department of Medical Genetics, University of British Columbia, Vancouver, Canada. wyeth@cmmt.ubc.ca.
                [32 ] Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. wyeth@cmmt.ubc.ca.
                [33 ] Child & Family Research Institute, Vancouver, BC, Canada. wyeth@cmmt.ubc.ca.
                [34 ] Department of Neuroradiology, Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, I-16147, Genoa, Italy. andrearossi@ospedale-gaslini.ge.it.
                [35 ] Centre for Molecular Medicine and Therapeutics, Vancouver, Canada. cvankarnebeek@cw.bc.ca.
                [36 ] Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. cvankarnebeek@cw.bc.ca.
                [37 ] Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada. cvankarnebeek@cw.bc.ca.
                [38 ] Child & Family Research Institute, Vancouver, BC, Canada. cvankarnebeek@cw.bc.ca.
                Article
                10.1186/s13023-015-0243-8
                10.1186/s13023-015-0243-8
                4348372
                25885527
                ae9add4f-6814-4a13-a759-621db8841c6c
                History

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