Missing heritability in Bloom syndrome: First report of a deep intronic variant leading to pseudo‐exon activation in the BLM gene. Issue 2 (19th October 2020)

• Record Type: Journal Article
• Authors: Backers, Lynn; Parton, Bram; De Bruyne, Marieke; Tavernier, Simon J.; Van Den Bogaert, Kris; Lambrecht, Bart N.; Haerynck, Filomeen; Claes, Kathleen B.M.
• Is Part Of: Clinical genetics. Volume 99:Issue 2(2021)
• Page Start: 292
• Page End: 297
• Publication Date: 2020-10-19
• Subjects: BLM -- Bloom syndrome -- cDNA analysis -- deep intronic variant -- missing heritability -- non‐coding variant -- pseudo‐exon activation -- RECQL3; Medical genetics -- Periodicals; 616.0420
• DOI: 10.1111/cge.13859
• Languages: English
• ISSNs: 0009-9163

Abstract

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. Abstract :