Long-read RNA sequencing reveals extensive transcript isoform changes in a patient with IFAP syndrome with a recurrent intronic MBTPS2 variant

Abstract Hemizygous pathogenic variants in MBTPS2 located at Xp22. 12 cause IFAP syndrome, which is characterized by the triad of ichthyosis, alopecia and photophobia. Here we identified a hemizygous intronic variant in MBTPS2 (NM₀15884: c. 970+5G>A) in a patient with alopecia, follicular keratinization, developmental delay and epilepsy which were compatible with IFAP syndrome. The variant has been reported to cause skipping of 20 bases in exon 7, leading to the premature termination codon. To further investigate the consequence of the variant, we performed long-read RNA sequencing using RNA extracted from fibroblasts cultured from the patient’s skin. Long-read RNA sequencing revealed skipping of exons 6 and 7, in addition to the previously reported 20-base skipping in exon 7. Furthermore, the expression of normal transcripts, as observed in healthy skin, was markedly reduced. Long-read RNA sequencing is a powerful tool for simultaneously identifying diverse transcript isoforms, making it highly valuable for elucidating the effects of splice-altering variants.