Publication on NF1 deep intronic pathogenic variants

5.05.2023

Magdalena Koczkowska, PhD, a senior postdoc from the Research Group “Mosaicism for autosomal post-zygotic mutation”, recently co-authored a groundbreaking paper with Prof. Ludwine M. Messiaen from the University of Alabama at Birmingham, USA.

The paper Analysis of 200 unrelated individuals with a constitutional NF1 deep intronic pathogenic variant reveals that variants flanking the alternatively spliced NF1 exon 31 [23a] cause a classical neurofibromatosis type 1 phenotype while altering predominantly NF1 isoform type II, published in Human Genetics by Springer Nature, provides a state-of-the-art description and summary of currently known NF1 deep intronic pathogenic variants that have a well-documented effect on splicing. The authors retrospectively investigated a cohort of over 8,000 patients with molecularly confirmed neurofibromatosis type 1 (NF1) from the University of Alabama at Birmingham (UAB) dataset and identified 68 distinct pathogenic deep intronic variants within the NF1 gene in 2.5% of these individuals. Among these, nine different pathogenic splicing variants in 20 probands led to exonization of different parts of intron 30 [23.2] and 31 [23a] of this gene. The authors found that the exonization of intron 31 [23a] sequences due to these deep intronic variants predominantly affects the NF1 isoform II, not isoform I, but still results in a classic NF1 phenotype. The observed effect of the deep intronic variants flanking exons 31 [23a] may provide further insights into the alternative splicing and the DNA sequences that are essential to this process. Furthermore, the authors curated all available records of deep intronic variants from the literature and/or publicly available databases and identified seven additional pathogenic NF1 deep intronic variants not observed in the UAB dataset.