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      Statistical Validation of Rare Complement Variants Provides Insights into the Molecular Basis of Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy

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          Abstract

          <p class="first" id="P1">Atypical haemolytic uraemic syndrome (aHUS) and C3 glomerulopathy (C3G) are associated with dysregulation and over-activation of the complement alternative pathway. Typically, gene analysis for aHUS and C3G is undertaken in small patient numbers, yet it is unclear which genes most frequently predispose to aHUS or C3G. Accordingly, we performed a six-centre analysis of 610 rare genetic variants in 13 mostly complement genes ( <i>CFH, CFI, CD46, C3, CFB, CFHR1, CFHR3, CFHR4, CFHR5, CFP, PLG, DGKE,</i> and <i>THBD</i>) from &gt;3500 patients with aHUS and C3G. We report 371 novel rare variants for aHUS and 82 for C3G. Our new interactive Database of Complement Gene Variants was used to extract allele frequency data for these 13 genes using the Exome Aggregation Consortium (ExAC) server as the reference genome. For aHUS, significantly more protein-altering rare variation was found in five genes <i>CFH, CFI, CD46, C3</i> and <i>DGKE</i> than in ExAC (allele frequency &lt;0.01%), thus correlating these with aHUS. For C3G, an association was only found for rare variants in <i>C3</i> and the N-terminal C3b-binding or C-terminal non-surface-associated regions of <i>CFH</i>. In conclusion, the RV analyses showed non-random distributions over the affected proteins, and different distributions were observed between aHUS and C3G that clarify their phenotypes. </p>

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          Rare and common variants: twenty arguments.

          Genome-wide association studies have greatly improved our understanding of the genetic basis of disease risk. The fact that they tend not to identify more than a fraction of the specific causal loci has led to divergence of opinion over whether most of the variance is hidden as numerous rare variants of large effect or as common variants of very small effect. Here I review 20 arguments for and against each of these models of the genetic basis of complex traits and conclude that both classes of effect can be readily reconciled.
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            An algorithm for progressive multiple alignment of sequences with insertions.

            Dynamic programming algorithms guarantee to find the optimal alignment between two sequences. For more than a few sequences, exact algorithms become computationally impractical, and progressive algorithms iterating pairwise alignments are widely used. These heuristic methods have a serious drawback because pairwise algorithms do not differentiate insertions from deletions and end up penalizing single insertion events multiple times. Such an unrealistically high penalty for insertions typically results in overmatching of sequences and an underestimation of the number of insertion events. We describe a modification of the traditional alignment algorithm that can distinguish insertion from deletion and avoid repeated penalization of insertions and illustrate this method with a pair hidden Markov model that uses an evolutionary scoring function. In comparison with a traditional progressive alignment method, our algorithm infers a greater number of insertion events and creates gaps that are phylogenetically consistent but spatially less concentrated. Our results suggest that some insertion/deletion "hot spots" may actually be artifacts of traditional alignment algorithms.
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              Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference.

              In both atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) complement plays a primary role in disease pathogenesis. Herein we report the outcome of a 2015 Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference where key issues in the management of these 2 diseases were considered by a global panel of experts. Areas addressed included renal pathology, clinical phenotype and assessment, genetic drivers of disease, acquired drivers of disease, and treatment strategies. In order to help guide clinicians who are caring for such patients, recommendations for best treatment strategies were discussed at length, providing the evidence base underpinning current treatment options. Knowledge gaps were identified and a prioritized research agenda was proposed to resolve outstanding controversial issues.
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                Author and article information

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                Journal
                The Journal of Immunology
                J.I.
                The American Association of Immunologists
                0022-1767
                1550-6606
                March 19 2018
                April 01 2018
                April 01 2018
                March 02 2018
                : 200
                : 7
                : 2464-2478
                Article
                10.4049/jimmunol.1701695
                6324840
                29500241
                a4640c9d-3425-4bb6-bde5-9015a8af5d4d
                © 2018
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