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      The many faces of peroxisomal disorders: Lessons from a large Arab cohort

      1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 1 , 2 , 3 , 4 , 3 , 5 , 6 , 7 , 5 , 8 , 3 , 5 , 5 , 8 , 9 , 5 , 10 , 11 , 12 , 8 , 13 , 14 , 15 , 16 , 17 , 1 , 18 , 1 , 18 , 1 , 18 , 19 , 20 , 3 , 21 , 3 , 5 , 1 , 2 , 9 , 22 , 23 , 24 , 1 , 1 , 3 , 18
      Clinical Genetics

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          Defects in the peroxisomes biogenesis and/or function result in peroxisomal disorders. In this study, we describe the largest Arab cohort to date (72 families) of clinically, biochemically and molecularly characterized patients with peroxisomal disorders. At the molecular level, we identified 43 disease-causing variants, half of which are novel. The founder nature of many of the variants allowed us to calculate the minimum disease burden for these disorders in our population ~1:30 000, which is much higher than previous estimates in other populations. Clinically, we found an interesting trend toward genotype/phenotype correlation in terms of long-term survival. Nearly half (40/75) of our peroxisomal disorders patients had documented survival beyond 1 year of age. Most unusual among the long-term survivors was a multiplex family in which the affected members presented as adults with non-specific intellectual disability and epilepsy. Other unusual presentations included the very recently described peroxisomal fatty acyl-CoA reductase 1 disorder as well as CRD, spastic paraparesis, white matter (CRSPW) syndrome. We conclude that peroxisomal disorders are highly heterogeneous in their clinical presentation. Our data also confirm the demonstration that milder forms of Zellweger spectrum disorders cannot be ruled out by the "gold standard" very long chain fatty acids assay, which highlights the value of a genomics-first approach in these cases.

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          Most cited references37

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          Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

          The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants. 1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence (e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.
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            Is Open Access

            Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes

            Retinal dystrophy (RD) is a heterogeneous group of hereditary diseases caused by loss of photoreceptor function and contributes significantly to the etiology of blindness globally but especially in the industrialized world. The extreme locus and allelic heterogeneity of these disorders poses a major diagnostic challenge and often impedes the ability to provide a molecular diagnosis that can inform counseling and gene-specific treatment strategies. In a large cohort of nearly 150 RD families, we used genomic approaches in the form of autozygome-guided mutation analysis and exome sequencing to identify the likely causative genetic lesion in the majority of cases. Additionally, our study revealed six novel candidate disease genes ( C21orf2 , EMC1 , KIAA1549 , GPR125 , ACBD5 , and DTHD1 ), two of which ( ACBD5 and DTHD1 ) were observed in the context of syndromic forms of RD that are described for the first time.
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              Biochemistry of mammalian peroxisomes revisited.

              In this review, we describe the current state of knowledge about the biochemistry of mammalian peroxisomes, especially human peroxisomes. The identification and characterization of yeast mutants defective either in the biogenesis of peroxisomes or in one of its metabolic functions, notably fatty acid beta-oxidation, combined with the recognition of a group of genetic diseases in man, wherein these processes are also defective, have provided new insights in all aspects of peroxisomes. As a result of these and other studies, the indispensable role of peroxisomes in multiple metabolic pathways has been clarified, and many of the enzymes involved in these pathways have been characterized, purified, and cloned. One aspect of peroxisomes, which has remained ill defined, is the transport of metabolites across the peroxisomal membrane. Although it is clear that mammalian peroxisomes under in vivo conditions are closed structures, which require the active presence of metabolite transporter proteins, much remains to be learned about the permeability properties of mammalian peroxisomes and the role of the four half ATP-binding cassette (ABC) transporters therein.

                Author and article information

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                Clinical Genetics
                Clin Genet
                February 2019
                February 2019
                December 18 2018
                : 95
                : 2
                : 310-319
                [1 ]Department of Genetics; King Faisal Specialist Hospital and Research Center; Riyadh Saudi Arabia
                [2 ]The Newborn Screening and Biochemical Genetics Laboratory; King Faisal Specialist Hospital and Research Center; Riyadh Saudi Arabia
                [3 ]Department of Anatomy and Cell Biology; College of Medicine, Alfaisal University; Riyadh Saudi Arabia
                [4 ]Department of Pediatrics; Prince Sultan Military Medical City; Riyadh Saudi Arabia
                [5 ]Department of Medical Genetics; King Faisal Specialist Hospital and Research Center; Riyadh Saudi Arabia
                [6 ]Department of Pediatrics; Security Forces Hospital; Riyadh Saudi Arabia
                [7 ]Department of Pediatrics; Royal Hospital; Muscat Oman
                [8 ]Medical Genetic Division, Department of Pediatrics, King Abdullah International Medical Research Centre; King Saud Bin Abdulaziz University for Health Sciences; Riyadh Saudi Arabia
                [9 ]Department of Pediatrics College of Medicine and King Saud University Medical City; King Saud University; Riyadh Saudi Arabia
                [10 ]Department of Pediatrics; Makkah Maternity and Children's Hospital; Makkah Saudi Arabia
                [11 ]Department of Pediatrics Dr. Sulimann AL Habib Medical Group; Riyadh Saudi Arabia
                [12 ]Department of Pediatrics, Division of Pediatric Neurology Children Hospital; Ain Shams University; Cairo Egypt
                [13 ]Pediatrics Department; King Faisal Specialist Hospital and Research Center; Riyadh Saudi Arabia
                [14 ]Pediatrics Medical Genetic Unit (PMGU), Pediatrics Department; Qatif Central Hospital; Qatif Saudi Arabia
                [15 ]Armed Forces Hospital Southern Region; Pediatric Directorate and Genetic Unit Khamis Mushayt; Khamis Mushait Saudi Arabia
                [16 ]Maternity and Children's Hospital; Dammam Saudi Arabia
                [17 ]Department of Pediatrics; Sanad Hospital; Riyadh Saudi Arabia
                [18 ]Saudi Human Genome Program; King Abdulaziz City for Science and Technology; Riyadh Saudi Arabia
                [19 ]Department of Medicine; King Saud Bin Abdulaziz University for Health Sciences; Riyadh Saudi Arabia
                [20 ]Division of Genetics; Brigham and Women's Hospital; Boston Massachusetts
                [21 ]Department of Obstetrics and Gynecology; King Faisal Specialist Hospital and Research Center; Riyadh Saudi Arabia
                [22 ]Department of Pediatrics; Mubarak Al-Kabeer Hospital; Kuwait Kuwait
                [23 ]Pediatric Department; Al-Jahra Hospital, Ministry of Health; Kuwait Kuwait
                [24 ]Department of Pediatric Subspecialties; Children's Hospital; Riyadh Saudi Arabia
                © 2018





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