Universität zu Köln

Tschernoster, Nikolai ORCID: 0000-0002-6058-9342, Erger, Florian ORCID: 0000-0002-2768-1702, Walsh, Patrick R., McNicholas, Bairbre, Fistrek, Margareta, Habbig, Sandra, Schumacher, Anna-Lena ORCID: 0000-0001-7739-486X, Folz-Donahue, Kat, Kukat, Christian ORCID: 0000-0003-1508-0229, Toliat, Mohammad R., Becker, Christian, Thiele, Holger, Kavanagh, David, Nuernberg, Peter, Beck, Bodo B. and Altmueller, Janine (2022). Unraveling Structural Rearrangements of the CFH Gene Cluster in Atypical Hemolytic Uremic Syndrome Patients Using Molecular Combing and Long-Fragment Targeted Sequencing. J. Mol. Diagn., 24 (6). S. 619 - 632. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1943-7811

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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 because of its high degree of sequence homology. Following first-line next-generation sequencing 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 and known SVs and 18 patients with atypical hemolytic uremic syndrome 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 next-generation sequencing was able to improve the molecular genetic yield in this pilot study. This (cost-)effective approach warrants validation in larger cohorts with CFH/ j.jmoldx.2022.02.006)

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Tschernoster, Nikolai UNSPECIFIED orcid.org/0000-0002-6058-9342 UNSPECIFIED Erger, Florian UNSPECIFIED orcid.org/0000-0002-2768-1702 UNSPECIFIED Walsh, Patrick R. UNSPECIFIED UNSPECIFIED UNSPECIFIED McNicholas, Bairbre UNSPECIFIED UNSPECIFIED UNSPECIFIED Fistrek, Margareta UNSPECIFIED UNSPECIFIED UNSPECIFIED Habbig, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Schumacher, Anna-Lena UNSPECIFIED orcid.org/0000-0001-7739-486X UNSPECIFIED Folz-Donahue, Kat UNSPECIFIED UNSPECIFIED UNSPECIFIED Kukat, Christian UNSPECIFIED orcid.org/0000-0003-1508-0229 UNSPECIFIED Toliat, Mohammad R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Becker, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Thiele, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Kavanagh, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Beck, Bodo B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-691711
DOI:	10.1016/j.jmoldx.2022.02.006
Journal or Publication Title:	J. Mol. Diagn.
Volume:	24
Number:	6
Page Range:	S. 619 - 632
Date:	2022
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1943-7811
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language COMPLEMENT FACTOR-H; C3 GLOMERULOPATHY; MACULAR DEGENERATION; DELETION; AUTOANTIBODIES; FAMILY; ASSOCIATION; ECULIZUMAB; DEFICIENCY; ACTIVATION Multiple languages Pathology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69171