Genotype/phenotype correlations in complement factor H deficiency arising from uniparental isodisomy.

Area of Science:

• Genetics
• Nephrology
• Immunology

Background:

• Atypical hemolytic uremic syndrome (aHUS) is a rare, severe thrombotic microangiopathy.
• Complement factor H (CFH) deficiency is a known genetic cause of aHUS.
• Understanding genetic modifiers is crucial for predicting disease phenotype.

Observation:

• An 8-month-old male infant presented with aHUS responsive to plasma therapy.
• He was diagnosed with homozygous CFH deficiency due to a specific CFH mutation (c.2880delT [p.Phe960fs]).
• Genetic analysis revealed paternal uniparental isodisomy of chromosome 1.

Findings:

• The patient carried a homozygous aHUS risk haplotype (CD46GGAAC) on chromosome 1.
• Factor H-like protein 1 (FHL-1) was present in the aHUS patient.
• Comparison with another CFH-deficient patient showed different CD46 haplotypes and FHL-1 presence, correlating with distinct kidney phenotypes (aHUS vs. endocapillary glomerulonephritis).

Implications:

• Homozygous CFH deficiency can manifest with varying kidney diseases.
• Genetic modifiers, including CD46 and FHL-1, play a significant role in determining the clinical phenotype.
• This highlights the complex interplay between genetic mutations and modifier genes in complement-mediated kidney diseases.