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First patient with bloom syndrome caused by a deep intronic variant leading to pseudoexon activation

Lynn Backers (UGent) , Bram Parton (UGent) , Stephanie Vermeulen (UGent) , Marieke De Bruyne (UGent) , Simon Tavernier (UGent) , Kris Van Den Bogaert, Anne Vral (UGent) , Ans Baeyens (UGent) , Filomeen Haerynck (UGent) , Bart Lambrecht (UGent) , et al.
(2020)
Author
Abstract
We report a Belgian boy presenting with severe growth delay, microcephaly and several immune defects suggestive of Bloom Syndrome, a rare genetic autosomal recessive disorder caused by germline mutations in the BLM/RECQL3 gene. This gene encodes the RecQL3 helicase, which plays a role in DNA damage repair. Mutations in this gene are associated with sensitivity to DNA damaging agents like mitomycin C. Increased sister chromatid exchanges (SCEs) were observed, indicating genomic instability, a pathognomonic sign for Bloom Syndrome. Molecular analysis of the coding region of BLM revealed heterozygosity for a, previously undescribed, nonsense variant (c.3379C>T, p.(Gln1127*)), but did not reveal a second variant. Here, we present the identification of a deep-intronic variant by cDNA analysis of the BLM gene. cDNA analysis revealed an aberrant transcript encompassing a part of intron 15 of the BLM gene and sequencing of the intron revealed a deep intronic substitution (c.3032-258A>G, p.(?)), predicted to create a cryptic donor splice site. This deep intronic substitution gives rise to two aberrant transcripts: r.[3019_3020ins3020-414_3020-259](in frame) and r.[3019_3020ins3020-424_3020-259](out-of-frame). We are currently evaluating residual protein levels and sensitivity to DNA damaging agents. In summary, we report a Belgian boy compound heterozygous for a novel nonsense variant and a deep intronic variant, a mechanism which has never been described before, in the BLM gene. Further functional validations are ongoing. This case highlights the role of non-coding variations associated with genetic syndromes and the added-value of RNA-based approaches in patients with a clear phenotype lacking a molecular diagnosis.
Keywords
Bloom syndrome, cDNA sequencing, deep-intronic variant, non-coding, BLM, RECQL3, RNA sequencing

Citation

Please use this url to cite or link to this publication:

MLA
Backers, Lynn, et al. First Patient with Bloom Syndrome Caused by a Deep Intronic Variant Leading to Pseudoexon Activation. 2020.
APA
Backers, L., Parton, B., Vermeulen, S., De Bruyne, M., Tavernier, S., Van Den Bogaert, K., … Claes, K. (2020). First patient with bloom syndrome caused by a deep intronic variant leading to pseudoexon activation. Presented at the Translational Immunology 2020, Ghent, Belgium.
Chicago author-date
Backers, Lynn, Bram Parton, Stephanie Vermeulen, Marieke De Bruyne, Simon Tavernier, Kris Van Den Bogaert, Anne Vral, et al. 2020. “First Patient with Bloom Syndrome Caused by a Deep Intronic Variant Leading to Pseudoexon Activation.” In .
Chicago author-date (all authors)
Backers, Lynn, Bram Parton, Stephanie Vermeulen, Marieke De Bruyne, Simon Tavernier, Kris Van Den Bogaert, Anne Vral, Ans Baeyens, Filomeen Haerynck, Bart Lambrecht, and Kathleen Claes. 2020. “First Patient with Bloom Syndrome Caused by a Deep Intronic Variant Leading to Pseudoexon Activation.” In .
Vancouver
1.
Backers L, Parton B, Vermeulen S, De Bruyne M, Tavernier S, Van Den Bogaert K, et al. First patient with bloom syndrome caused by a deep intronic variant leading to pseudoexon activation. In 2020.
IEEE
[1]
L. Backers et al., “First patient with bloom syndrome caused by a deep intronic variant leading to pseudoexon activation,” presented at the Translational Immunology 2020, Ghent, Belgium, 2020.
@inproceedings{8647567,
  abstract     = {We report a Belgian boy presenting with severe growth delay, microcephaly and several immune defects suggestive of Bloom Syndrome, a rare genetic autosomal recessive disorder caused by germline mutations in the BLM/RECQL3 gene. This gene encodes the RecQL3 helicase, which plays a role in DNA damage repair. Mutations in this gene are associated with sensitivity to DNA damaging agents like mitomycin C. Increased sister chromatid exchanges (SCEs) were observed, indicating genomic instability, a pathognomonic sign for Bloom Syndrome. Molecular analysis of the coding region of BLM revealed heterozygosity for a, previously undescribed, nonsense variant (c.3379C>T, p.(Gln1127*)), but did not reveal a second variant. Here, we present the identification of a deep-intronic variant by cDNA analysis of the BLM gene. cDNA analysis revealed an aberrant transcript encompassing a part of intron 15 of the BLM gene and sequencing of the intron revealed a deep intronic substitution (c.3032-258A>G, p.(?)), predicted to create a cryptic donor splice site. This deep intronic substitution gives rise to two aberrant transcripts: r.[3019_3020ins3020-414_3020-259](in frame) and r.[3019_3020ins3020-424_3020-259](out-of-frame). We are currently evaluating residual protein levels and sensitivity to DNA damaging agents.

In summary, we report a Belgian boy compound heterozygous for a novel nonsense variant and a deep intronic variant, a mechanism which has never been described before, in the BLM gene. Further functional validations are ongoing. This case highlights the role of non-coding variations associated with genetic syndromes and the added-value of RNA-based approaches in patients with a clear phenotype lacking a molecular diagnosis.},
  author       = {Backers, Lynn and Parton, Bram and Vermeulen, Stephanie and De Bruyne, Marieke and Tavernier, Simon and Van Den Bogaert, Kris and Vral, Anne and Baeyens, Ans and Haerynck, Filomeen and Lambrecht, Bart and Claes, Kathleen},
  keywords     = {Bloom syndrome,cDNA sequencing,deep-intronic variant,non-coding,BLM,RECQL3,RNA sequencing},
  location     = {Ghent, Belgium},
  title        = {First patient with bloom syndrome caused by a deep intronic variant leading to pseudoexon activation},
  year         = {2020},
}