Aberrant splicing and transcriptional activity of TPP1 result in CLN2-like disorder

We describe an individual with a presentation suggestive of an attenuated CLN2 phenotype, including a history of regression, recent-onset microcephaly and spasticity from age five years. Exome sequencing revealed two variants inherited in trans in TPP1, NM_000391.4:c.225A>G; p.(Gln75 = ) and NM_000391.4:c.1012C>G; p.(Gln338Glu), both classified as variants of uncertain significance. TPP1 activity was found to be significantly reduced in fibroblasts of the affected individual. RNAseq was performed to assess the impact of compound heterozygous variants in TPP1 and enabled the identification of three aberrant splicing events. The c.225A>G variant introduces a 5 nucleotide truncation of exon 3 and a loss of reading frame. The majority of CLN2 transcripts exclude either exon 8 or exons 7-8, resulting in large in-frame deletions. Isoform specific RT-PCR confirmed the aberrant splicing events are mutually exclusive, suggesting that the paternal exon 8 c.1012C>G variant results in exon skipping. This case study demonstrates how RNAseq can be used as an orthogonal test to inform the interpretation of some variants of unknown significance and its particular importance in disorders where effective disease management requires early diagnosis.PMID:34126256 | DOI:10.1016/j.ejmg.2021.104259

Source: European Journal of Medical Genetics - June 14, 2021 Category: Genetics & Stem Cells Authors: Guy Helman Lauren E Taylor Marzena Walkiewicz Maelle Le Moing Stefanie Eggers Joy Yaplito-Lee Maria Fuller Gabriel Dabscheck Victoria Rodriguez-Casero Susan M White Cas Simons Source Type: research