Abstract:
:Pathogenic biallelic variants in the BLM/RECQL3 gene 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 the BLM gene. 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.
journal_name
Clin Genetjournal_title
Clinical geneticsauthors
Backers L,Parton B,De Bruyne M,Tavernier SJ,Van Den Bogaert K,Lambrecht BN,Haerynck F,Claes KBMdoi
10.1111/cge.13859subject
Has Abstractpub_date
2021-02-01 00:00:00pages
292-297issue
2eissn
0009-9163issn
1399-0004journal_volume
99pub_type
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