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      Rare Genetic Diseases: Nature's Experiments on Human Development

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          Abstract

          Rare genetic diseases are the result of a continuous forward genetic screen that nature is conducting on humans. Here, we present epistemological and systems biology arguments highlighting the importance of studying these rare genetic diseases. We contend that the expanding catalog of mutations in ∼4,000 genes, which cause ∼6,500 diseases and their annotated phenotypes, offer a wide landscape for discovering fundamental mechanisms required for human development and involved in common diseases. Rare afflictions disproportionately affect the nervous system in children, but paradoxically, the majority of these disease-causing genes are evolutionarily ancient and ubiquitously expressed in human tissues. We propose that the biased prevalence of childhood rare diseases affecting nervous tissue results from the topological complexity of the protein interaction networks formed by ubiquitous and ancient proteins encoded by childhood disease genes. Finally, we illustrate these principles discussing Menkes disease, an example of the discovery power afforded by rare diseases.

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          Clinical Genetics; Human Genetics

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          Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database

          Rare diseases, an emerging global public health priority, require an evidence-based estimate of the global point prevalence to inform public policy. We used the publicly available epidemiological data in the Orphanet database to calculate such a prevalence estimate. Overall, Orphanet contains information on 6172 unique rare diseases; 71.9% of which are genetic and 69.9% which are exclusively pediatric onset. Global point prevalence was calculated using rare disease prevalence data for predefined geographic regions from the ‘Orphanet Epidemiological file’ (http://www.orphadata.org/cgi-bin/epidemio.html). Of the 5304 diseases defined by point prevalence, 84.5% of those analysed have a point prevalence of <1/1 000 000. However 77.3–80.7% of the population burden of rare diseases is attributable to the 4.2% (n = 149) diseases in the most common prevalence range (1–5 per 10 000). Consequently national definitions of ‘Rare Diseases’ (ranging from prevalence of 5 to 80 per 100 000) represent a variable number of rare disease patients despite sharing the majority of rare disease in their scope. Our analysis yields a conservative, evidence-based estimate for the population prevalence of rare diseases of 3.5–5.9%, which equates to 263–446 million persons affected globally at any point in time. This figure is derived from data from 67.6% of the prevalent rare diseases; using the European definition of 5 per 10 000; and excluding rare cancers, infectious diseases, and poisonings. Future registry research and the implementation of rare disease codification in healthcare systems will further refine the estimates.
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            A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva.

            Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of skeletal malformations and progressive extraskeletal ossification. We mapped FOP to chromosome 2q23-24 by linkage analysis and identified an identical heterozygous mutation (617G --> A; R206H) in the glycine-serine (GS) activation domain of ACVR1, a BMP type I receptor, in all affected individuals examined. Protein modeling predicts destabilization of the GS domain, consistent with constitutive activation of ACVR1 as the underlying cause of the ectopic chondrogenesis, osteogenesis and joint fusions seen in FOP.
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              Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young.

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                Author and article information

                Contributors
                Journal
                iScience
                iScience
                iScience
                Elsevier
                2589-0042
                01 May 2020
                22 May 2020
                01 May 2020
                : 23
                : 5
                : 101123
                Affiliations
                [1 ]Department of Cell Biology, Emory University, Atlanta, GA 30322, USA
                Author notes
                []Corresponding author vfaunde@ 123456emory.edu
                Article
                S2589-0042(20)30308-4 101123
                10.1016/j.isci.2020.101123
                7229282
                32422592
                450ace6a-c48a-4834-b523-92396cee2baf
                © 2020 The Author(s)

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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                clinical genetics,human genetics
                clinical genetics, human genetics

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