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Unraveling Structural Rearrangements of the CFH Gene Cluster in Atypical Hemolytic Uremic Syndrome Patients Using

Nikolai Tschernoster1, Florian Erger2, Patrick R Walsh3

  • 1Cologne Center for Genomics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Institute of Human Genetics, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

The Journal of Molecular Diagnostics : JMD
|April 10, 2022
PubMed

Insights

Molecular combing technology effectively detects structural variants in the Complement Factor H (CFH) gene cluster, improving genetic diagnosis for complement-related diseases. This method aids in understanding complex genetic variations linked to kidney and immune disorders.

Area of Science:

  • Genetics
  • Molecular Biology
  • Immunology

Background:

  • The Complement Factor H (CFH) gene cluster, including CFH and CFHR1-5, is crucial for regulating the complement system's alternative pathway.
  • Mutations and structural variants (SVs) in the CFH gene cluster are associated with renal pathologies and immune diseases like age-related macular degeneration and systemic lupus erythematosus.
  • Analyzing SVs in the CFH gene cluster is difficult due to high sequence homology.

Purpose of the Study:

  • To apply Molecular Combing Technology for detecting and visualizing SVs within the CFH gene cluster.
  • To completely resolve structural haplotypes of the CFH gene cluster.
  • To improve molecular genetic yield in diagnosing CFH/CFHR-associated diseases.

Main Methods:

  • Next-generation sequencing (NGS) gene panel sequencing as a first-line approach.
  • Genomic Vision's Molecular Combing Technology for SV detection and visualization.
  • Targeted enrichment for long DNA fragments (Samplix Xdrop) and Oxford Nanopore sequencing for breakpoint determination.

Main Results:

  • Molecular combing successfully detected and visualized SVs within the CFH gene cluster.
  • Three novel SVs were identified: a CFH/CFHR1 hybrid gene in two patients and a rare heterozygous CFHR4/CFHR1 deletion in a third patient.
  • The combination of molecular combing and NGS improved the molecular genetic yield in this pilot study.

Conclusions:

  • Molecular Combing Technology is a valuable tool for resolving complex structural variations in the CFH gene cluster.
  • This approach enhances the molecular genetic diagnosis of patients with atypical hemolytic uremic syndrome and complement factor 3 glomerulopathy.
  • Further validation in larger cohorts is warranted to establish this cost-effective method for CFH/CFHR-associated diseases.

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