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Missing heritability in Bloom syndrome : first report of a deep intronic variant leading to pseudo‐exon activation in the BLM gene

Lynn Backers (UGent) , Bram Parton (UGent) , Marieke De Bruyne (UGent) , Simon Tavernier (UGent) , Kris Van Den Bogaert, Bart Lambrecht (UGent) , Filomeen Haerynck (UGent) and Kathleen Claes (UGent)
(2021) CLINICAL GENETICS. 99(2). p.292-297
Author
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Abstract
Pathogenic biallelic variants in theBLM/RECQL3gene cause a rare autosomal recessive disorder called Bloom syndrome (BS). This syndrome is characterized by severe growth delay, immunodeficiency, dermatological manifestations and a predisposition to a wide variety of cancers, often multiple and very early in life. Literature shows that the main mode of BLM inactivation is protein translation termination. We expanded the molecular spectrum of BS by reporting the first deep intronic variant causing intron exonisation. We describe a patient with a clinical phenotype of BS and a strong increase in sister chromatid exchanges (SCE), who was found to be compound heterozygous for a novel nonsense variant c.3379C>T, p.(Gln1127Ter) in exon 18 and a deep intronic variant c.3020-258A>G in intron 15 of theBLMgene. The deep intronic variant creates a high-quality de novo donor splice site, which leads to retention of two intron segments. Both pseudo-exons introduce a premature stop codon into the reading frame and abolish BLM protein expression, confirmed by Western Blot analysis. These findings illustrate the role of non-coding variation in Mendelian disorders and herewith highlight an unmet need in routine testing of Mendelian disorders, being the added value of RNA-based approaches to provide a complete molecular diagnosis.
Keywords
Genetics(clinical), Genetics, BLM, Bloom syndrome, cDNA analysis, deep intronic variant, missing heritability, non-coding variant, pseudo-exon activation, RECQL3, SISTER-CHROMATID EXCHANGES, BLM GENE, FRAMESHIFT MUTATION, CANCER, RECOMBINATION, FAMILY

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MLA
Backers, Lynn, et al. “Missing Heritability in Bloom Syndrome : First Report of a Deep Intronic Variant Leading to Pseudo‐exon Activation in the BLM Gene.” CLINICAL GENETICS, vol. 99, no. 2, 2021, pp. 292–97, doi:10.1111/cge.13859.
APA
Backers, L., Parton, B., De Bruyne, M., Tavernier, S., Van Den Bogaert, K., Lambrecht, B., … Claes, K. (2021). Missing heritability in Bloom syndrome : first report of a deep intronic variant leading to pseudo‐exon activation in the BLM gene. CLINICAL GENETICS, 99(2), 292–297. https://doi.org/10.1111/cge.13859
Chicago author-date
Backers, Lynn, Bram Parton, Marieke De Bruyne, Simon Tavernier, Kris Van Den Bogaert, Bart Lambrecht, Filomeen Haerynck, and Kathleen Claes. 2021. “Missing Heritability in Bloom Syndrome : First Report of a Deep Intronic Variant Leading to Pseudo‐exon Activation in the BLM Gene.” CLINICAL GENETICS 99 (2): 292–97. https://doi.org/10.1111/cge.13859.
Chicago author-date (all authors)
Backers, Lynn, Bram Parton, Marieke De Bruyne, Simon Tavernier, Kris Van Den Bogaert, Bart Lambrecht, Filomeen Haerynck, and Kathleen Claes. 2021. “Missing Heritability in Bloom Syndrome : First Report of a Deep Intronic Variant Leading to Pseudo‐exon Activation in the BLM Gene.” CLINICAL GENETICS 99 (2): 292–297. doi:10.1111/cge.13859.
Vancouver
1.
Backers L, Parton B, De Bruyne M, Tavernier S, Van Den Bogaert K, Lambrecht B, et al. Missing heritability in Bloom syndrome : first report of a deep intronic variant leading to pseudo‐exon activation in the BLM gene. CLINICAL GENETICS. 2021;99(2):292–7.
IEEE
[1]
L. Backers et al., “Missing heritability in Bloom syndrome : first report of a deep intronic variant leading to pseudo‐exon activation in the BLM gene,” CLINICAL GENETICS, vol. 99, no. 2, pp. 292–297, 2021.
@article{8678681,
  abstract     = {{Pathogenic biallelic variants in theBLM/RECQL3gene cause a rare autosomal recessive disorder called Bloom syndrome (BS). This syndrome is characterized by severe growth delay, immunodeficiency, dermatological manifestations and a predisposition to a wide variety of cancers, often multiple and very early in life. Literature shows that the main mode of BLM inactivation is protein translation termination. We expanded the molecular spectrum of BS by reporting the first deep intronic variant causing intron exonisation. We describe a patient with a clinical phenotype of BS and a strong increase in sister chromatid exchanges (SCE), who was found to be compound heterozygous for a novel nonsense variant c.3379C>T, p.(Gln1127Ter) in exon 18 and a deep intronic variant c.3020-258A>G in intron 15 of theBLMgene. The deep intronic variant creates a high-quality de novo donor splice site, which leads to retention of two intron segments. Both pseudo-exons introduce a premature stop codon into the reading frame and abolish BLM protein expression, confirmed by Western Blot analysis. These findings illustrate the role of non-coding variation in Mendelian disorders and herewith highlight an unmet need in routine testing of Mendelian disorders, being the added value of RNA-based approaches to provide a complete molecular diagnosis.}},
  author       = {{Backers, Lynn and Parton, Bram and De Bruyne, Marieke and Tavernier, Simon and Van Den Bogaert, Kris and Lambrecht, Bart and Haerynck, Filomeen and Claes, Kathleen}},
  issn         = {{0009-9163}},
  journal      = {{CLINICAL GENETICS}},
  keywords     = {{Genetics(clinical),Genetics,BLM,Bloom syndrome,cDNA analysis,deep intronic variant,missing heritability,non-coding variant,pseudo-exon activation,RECQL3,SISTER-CHROMATID EXCHANGES,BLM GENE,FRAMESHIFT MUTATION,CANCER,RECOMBINATION,FAMILY}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{292--297}},
  title        = {{Missing heritability in Bloom syndrome : first report of a deep intronic variant leading to pseudo‐exon activation in the BLM gene}},
  url          = {{http://dx.doi.org/10.1111/cge.13859}},
  volume       = {{99}},
  year         = {{2021}},
}

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