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Comment
. 2023 Jul;31(7):730-732.
doi: 10.1038/s41431-023-01350-8. Epub 2023 Apr 10.

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

Abderaouf Hamza  1 , Carine El-Sissy  2 , Nadhir Yousfi  3 , Paula Vieira Martins  2 , Cédric Rafat  4   5 , Julien Masliah-Planchon  1 , Véronique Frémeaux-Bacchi  2   6 , Laurent Mesnard  7   8   9   10
Affiliations
Comment

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

Abderaouf Hamza et al. Eur J Hum Genet. 2023 Jul.
No abstract available

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Conflict of interest statement

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

Figures

Fig. 1
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.
A MANE-Select transcripts [15] in the CFHR-Factor H gene cluster region in GRCh38 (top) and T2T-CMH13 (bottom). The CFHR3 and CFHR1 genes (red) are absent from T2T-CMH13. Blue and red boxes represent exons and gray lines introns. B Using GRCh38 as a reference genome, split reads mapping both to the CFH and CFHR1 loci are indicative of the presence of a structural variant responsible for the CFH::CFHR1 gene fusion, enabling the molecular diagnosis of aHUS. Control 1 and control 2 show no such alignment pattern; the absence of reads aligning on the CFHR3 and CFHR1 in control 3 suggests that this individual is a carrier of a polymorphic CFHR3-CFHR deletion [12]. Note that all three alignment patterns are easily interpretable; the aHUS patient data have been aligned with specific parameters to better visualize SV breakpoints with split reads. On this Integrative Genomics Viewer (IGV) visualization, blue lines and boxes represent gene introns and exons, respectively, and gray rectangles represent aligned reads. Thin horizontal light blue lines connecting two portions of aligned reads indicate discontinuous alignment (“split reads”).
Fig. 2
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.
Alignment of control 1, control 2, and the aHUS patient’s long-read sequencing data shows split reads mapped to the T2T-CMH13 CFHR-Factor H region that cannot be resolved into structural variants, obscuring any relevant variation, and making the region extremely challenging to analyze. In particular, the CFH::CFHR1 gene fusion found in the aHUS patient’s sequencing data aligned against GRCh38 (Fig. 1) is not discernible anymore. Alignment data of control 3 show no such aberrant pattern, suggesting that the subject carries the same haplotype as the CHM13hTERT cell line used to generate T2T-CMH13. On this IGV visualization, colored lines and boxes represent gene introns and exons, respectively, and gray rectangles represent aligned reads.
See this image and copyright information in PMC

Comment on

  • The complete sequence of a human genome.
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References

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