Incomplete penetrance of CD46 mutation causing familial atypical hemolytic uremic syndrome

Background: Hemolytic uremic syndrome (HUS) secondary to homozygous mutations in CD46 is uncommon. While heterozygous individuals may remain asymptomatic, homozygous mutations with severely depleted CD46 surface expression without disease manifestation is rare.

Methods: We report on two siblings with features suggestive of hemolytic uremic syndrome. Estimation of CD46 expression by flow cytometry and gene sequencing were performed in members of this family.

Results: Three siblings, two of whom were symptomatic, had markedly decreased (<10%) cell surface expression of CD46 and homozygous splice site mutation (IVS2 + 2 T > G) in the CD46 gene; the other 10-year-old sibling was asymptomatic. The illness was preceded by dengue shock syndrome in the index case. Both parents and two other siblings were heterozygous for this CD46 mutation.

Conclusions: Homozygous IVS2 + 2 T > G mutation in CD46 gene, similar to heterozygous mutation, may be clinically silent at least during childhood. The role of antecedent infections in triggering the disease requires further examination.