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Unraveling structural rearrangements of the CFH gene cluster in atypical hemolytic uremic syndrome patients using molecular combing and long-fragment targeted sequencing

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Item Type:Article
Title:Unraveling structural rearrangements of the CFH gene cluster in atypical hemolytic uremic syndrome patients using molecular combing and long-fragment targeted sequencing
Creators Name:Tschernoster, N., Erger, F., Walsh, P.R., McNicholas, B., Fistrek, M., Habbig, S., Schumacher, L., Folz-Donahue, K., Kukat, C., Toliat, M.R., Becker, C., Thiele, H., Kavanagh, D., Nürnberg, P., Beck, B. and Altmüller, J.
Abstract:Complement factor H (CFH) and its related proteins have an essential role in regulating the alternative pathway of the complement system. Mutations and structural variants (SVs) of the CFH gene cluster, consisting of CFH and its five related genes (CFHR1-5), have been reported in renal pathologies as well as in complex immune diseases like age-related macular degeneration and systemic lupus erythematosus. SV analysis of this cluster is challenging due to its high degree of sequence homology. Following first-line NGS gene panel sequencing, we applied Genomic Vision's Molecular Combing Technology, to detect and visualize SVs within the CFH gene cluster and resolve its structural haplotypes completely. This approach was tested in three patients with atypical hemolytic uremic syndrome (aHUS) and known SVs, and 18 patients with aHUS or complement factor 3 glomerulopathy with unknown CFH gene cluster haplotypes. Three SVs, a CFH/CFHR1 hybrid gene in two patients and a rare heterozygous CFHR4/CFHR1 deletion in trans with the common CFHR3/CFHR1 deletion in a third patient were newly identified. For the latter, the breakpoints were determined using a targeted enrichment approach for long DNA fragments (Samplix Xdrop) in combination with Oxford Nanopore sequencing. Molecular combing in addition to NGS was able to improve the molecular genetic yield in this pilot study. This (cost-)effective approach warrants validation in larger cohorts with CFH/CFHR-associated disease.
Keywords:Atypical Hemolytic Uremic Syndrome, Complement C3b Inactivator Proteins, Haplotypes, Multigene Family, Pilot Projects
Source:Journal of Molecular Diagnostics
ISSN:1525-1578
Publisher:Elsevier
Volume:24
Number:6
Page Range:619-631
Date:June 2022
Official Publication:https://doi.org/10.1016/j.jmoldx.2022.02.006
PubMed:View item in PubMed

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