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The absence of CFHR3 and CFHR1 genes from the T2T-CHM13 assembly can limit the molecular diagnosis of complement-related diseases

European Journal of Human Genetics volume 31, pages 730–732 (2023)Cite this article

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The CFHR-Factor H gene cluster is medically relevant. It is associated with complement disorders like atypical hemolytic and uremic syndrome (aHUS) [3, 4]. Structural variants (SV) genes leading to the formation of gene fusions between CFH and its paralogs could be the cause of up to 5% of aHUS cases. In one such genomic rearrangement (CFH::CFHR1) the C-terminal SCR region of the CFH protein is replaced by the C-terminal portion of CFHR1 [5,6,7], leading to the partial loss of SCR function [8]. C3 glomerulopathy, another human kidney disease that shares complement over-activation as a common pathophysiological pathway with aHUS, has also been connected to sequence variations of the CFHR-Factor H gene cluster [9, 10].

The molecular diagnosis of these diseases is complicated by the highly repetitive nature of the CFHR-Factor H gene cluster locus sequence. On the one hand, short-read NGS can detect various types of rearrangement, but their detection can be impaired by read mapping issues caused by the numerous segmental duplications at this locus; on the other hand, multiplex ligation-dependent probe amplification (MLPA) can only detect copy number variants [4]. The performance of SV detection with long-read sequencing methods and their increasing accessibility make them a promising alternative. As such, long-read sequencing paired with an improved reference could revolutionize the diagnosis of aHUS and other CFH-related diseases, but the impact of the absence of relevant genes from T2T-CHM13 needs to be evaluated.

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Fig. 1: Long-read sequencing and mapping against the GRCh38 reference genome reveal a structural variant in the CFHR-Factor H cluster region, allowing the precise molecular diagnosis of aHUS.
Fig. 2: The T2T-CMH13 reference genome generates aberrant patterns of alignment in the CFHR-Factor H cluster region, hindering the molecular diagnosis of aHUS.

Data availability

The FASTQ files of reads aligning on the CFH-gene cluster region (GRCh38 coordinates: chr1:196598161-197040250) are available on the Sequence Read Archive under the accession number PRJNA916871. The complete sequencing data files are available from the corresponding author upon reasonable request.

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Funding

No specific funding was received for the study.

Author information

Authors and Affiliations

  1. Department of Genetics, Institut Curie, PSL Research University, Paris, France

    Abderaouf Hamza & Julien Masliah-Planchon

  2. Department of Biological Immunology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France

    Carine El-Sissy, Paula Vieira Martins & Véronique Frémeaux-Bacchi

  3. Unité Mixte de Recherche S1155, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France

    Nadhir Yousfi & Laurent Mesnard

  4. Service de Soins Intensifs Néphrologiques et Rein Aigu (SINRA), French Intensive Renal Network, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Paris, France

    Cédric Rafat & Laurent Mesnard

  5. Faculté de Médecine, Sorbonne Université, Paris, France

    Cédric Rafat & Laurent Mesnard

  6. Unité Mixte de Recherche S1138, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers, Paris, France

    Véronique Frémeaux-Bacchi

  7. Institut des Sciences du Calcul et des Données, Sorbonne Université, Paris, France

    Laurent Mesnard

Authors
  1. Abderaouf Hamza
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  8. Laurent Mesnard
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Contributions

Conceptualization: LM. Methodology: AH, LM. Investigation: AH. Visualization: AH. Funding acquisition: not applicable. Project administration: not applicable. Supervision: LM, VF-B. Writing—original draft: AH, LM. Writing—review and editing: AH, LM, CE-S, PVM, CR, JM-P, VF-B.

Corresponding author

Correspondence to Laurent Mesnard.

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Competing interests

VF-B manages a genetic testing facility that uses MLPA in the diagnosis of aHUS. The other authors declare no competing interests.

Ethics approval

The study was performed in accordance with the ethical standards of the Declaration of Helsinki. Written informed consent was obtained regarding de-identified clinical and personal patient data collection, analysis and publication. The study has been approved by an Institutional Review Board (Direction de la Recherche Clinique et de l’Innovation (APHP220461)) and the Ethic board of Sorbonne Université (CER-2022-009).

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Hamza, A., El-Sissy, C., Yousfi, N. et al. The absence of CFHR3 and CFHR1 genes from the T2T-CHM13 assembly can limit the molecular diagnosis of complement-related diseases. Eur J Hum Genet 31, 730–732 (2023). https://doi.org/10.1038/s41431-023-01350-8

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