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Functional characterization of 105 factor H variants associated with aHUS: lessons for variant classification.

ABSTRACT: Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy that can progress, when untreated, to end-stage renal disease. Most frequently, aHUS is caused by complement dysregulation due to pathogenic variants in genes that encode complement components and regulators. Among these genes, the factor H (FH) gene, CFH, presents with the highest frequency (15% to 20%) of variants and is associated with the poorest prognosis. Correct classification of CFH variants as pathogenic or benign is essential to clinical care but remains challenging owing to the dearth of functional studies. As a result, significant numbers of variants are reported as variants of uncertain significance. To address this knowledge gap, we expressed and functionally characterized 105 aHUS-associated FH variants. All FH variants were categorized as pathogenic or benign and, for each, we fully documented the nature of the pathogenicity. Twenty-six previously characterized FH variants were used as controls to validate and confirm the robustness of the functional assays used. Of the remaining 79 uncharacterized variants, only 29 (36.7%) alter FH expression or function in vitro and, therefore, are proposed to be pathogenic. We show that rarity in control databases is not informative for variant classification, and we identify important limitations in applying prediction algorithms to FH variants. Based on structural and functional data, we suggest ways to circumvent these difficulties and, thereby, improve variant classification. Our work highlights the need for functional assays to interpret FH variants accurately if clinical care of patients with aHUS is to be individualized and optimized.

SUBMITTER: Martin Merinero H

PROVIDER: S-EPMC8641096 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Atypical hemolytic uremic syndrome (aHUS) is a rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and renal failure. It is caused by genetic or acquired defects of the complement alternative pathway. Factor H autoantibodies (anti-FHs) have been reported in 10% of aHUS patients and are associated with the deficiency of factor H-related 1 (FHR1). However, FHR1 deficiency is not enough to cause aHUS, since it is also present in about 5% of Caucasian healthy subjects. In this study we evaluated the prevalence of genetic variants in CFH, CD46, CFI, CFB, C3, and THBD in aHUS patients with anti-FHs, using healthy subjects with FHR1 deficiency, here defined "supercontrols," as a reference group. "Supercontrols" are more informative than general population because they share at least one risk factor (FHR1 deficiency) with aHUS patients. We analyzed anti-FHs in 305 patients and 30 were positive. The large majority were children (median age: 7.7 [IQR, 6.6-9.9] years) and 83% lacked FHR1 (n = 25, cases) due to the homozygous CFHR3-CFHR1 deletion (n = 20), or the compound heterozygous CFHR3-CFHR1 and CFHR1-CFHR4 deletions (n = 4), or the heterozygous CFHR3-CFHR1 deletion combined with a frameshift mutation in CFHR1 that generates a premature stop codon (n = 1). Of the 960 healthy adult subjects 48 had the FHR1 deficiency ("supercontrols"). Rare likely pathogenetic variants in CFH, THBD, and C3 were found in 24% of cases (n = 6) compared to 2.1% of the "supercontrols" (P-value = 0.005). We also found that the CFH H3 and the CD46 GGAAC haplotypes are not associated with anti-FHs aHUS, whereas these haplotypes are enriched in aHUS patients without anti-FHs, which highlights the differences in the genetic basis of the two forms of the disease. Finally, we confirm that common infections are environmental factors that contribute to the development of anti-FHs aHUS in genetically predisposed individuals, which fits with the sharp peak of incidence during scholar-age. Further studies are needed to fully elucidate the complex genetic and environmental factors underlying anti-FHs aHUS and to establish whether the combination of anti-FHs with likely pathogenetic variants or other risk factors influences disease outcome and response to therapies.

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Functional characterization of 105 factor H variants associated with aHUS: lessons for variant classification.

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