A De Novo Deletion in the Regulators of Complement Activation Cluster Producing a Hybrid Complement Factor H/Complement Factor H–Related 3 Gene in Atypical Hemolytic Uremic Syndrome

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Abstract

<jats:p>The regulators of complement activation cluster at chromosome 1q32 contains the complement factor H (<jats:italic toggle="yes">CFH</jats:italic>) and five complement factor H–related (<jats:italic toggle="yes">CFHR</jats:italic>) genes. This area of the genome arose from several large genomic duplications, and these low-copy repeats can cause genome instability in this region. Genomic disorders affecting these genes have been described in atypical hemolytic uremic syndrome, arising commonly through nonallelic homologous recombination. We describe a novel <jats:italic toggle="yes">CFH/CFHR3</jats:italic> hybrid gene secondary to a <jats:italic toggle="yes">de novo</jats:italic> 6.3-kb deletion that arose through microhomology–mediated end joining rather than nonallelic homologous recombination. We confirmed a transcript from this hybrid gene and showed a secreted protein product that lacks the recognition domain of factor H and exhibits impaired cell surface complement regulation. The fact that the formation of this hybrid gene arose as a <jats:italic toggle="yes">de novo</jats:italic> event suggests that this cluster is a dynamic area of the genome in which additional genomic disorders may arise.</jats:p>

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