Background and Objectives Atypical hemolytic uremic syndrome (aHUS) is mostly attributed
to dysregulation of the alternative complement pathway (ACP) secondary to disease-causing
variants in complement components or regulatory proteins. Hereditary aHUS due to C3
disruption is rare, usually caused by heterozygous activating mutations in the C3
gene, and transmitted as autosomal dominant traits. We studied the molecular basis
of early-onset aHUS, associated with an unusual finding of a novel homozygous activating
deletion in C3. Design, Setting, Participants, & Measurements A male neonate with
eculizumab-responsive fulminant aHUS and C3 hypocomplementemia, and six of his healthy
close relatives were investigated. Genetic analysis on genomic DNA was performed by
exome sequencing of the patient, followed by targeted Sanger sequencing for variant
detection in his close relatives. Complement components analysis using specific immunoassays
was performed on frozen plasma samples from the patient and mother. Results Exome
sequencing revealed a novel homozygous variant in exon 26 of C3 (c.3322_3333del, p.Ile1108_Lys1111del),
within the highly conserved thioester-containing domain (TED), fully segregating with
the familial disease phenotype, as compatible with autosomal recessive inheritance.
Complement profiling of the patient showed decreased C3 and FB levels, with elevated
levels of the terminal membrane attack complex, while his healthy heterozygous mother
showed intermediate levels of C3 consumption. Conclusions Our findings represent the
first description of aHUS secondary to a novel homozygous deletion in C3 with ensuing
unbalanced C3 over-activation, highlighting a critical role for the disrupted C3-TED
domain in the disease mechanism.
