CLN2 disease resulting from a novel homozygous deep intronic splice variant in TPP1 discovered using long-read sequencing

Neuronal ceroid lipofuscinosis type 2 (CLN2) is an autosomal recessive neurodegenerative disorder with enzyme replacement therapy available. We present two siblings with a clinical diagnosis of CLN2 disease, but no identifiable TPP1 variants after standard clinical testing. Long-read sequencing identified a homozygous deep intronic variant predicted to affect splicing, confirmed by clinical DNA and RNA sequencing. This case demonstrates how traditional laboratory assays can complement emerging molecular technologies to provide a precise molecular diagnosis.

Automated summary

This study presents two siblings with a clinical diagnosis of CLN2 disease but no identifiable TPP1 variants after standard clinical testing. Long-read sequencing identified a homozygous deep intronic variant predicted to affect splicing, which was confirmed by clinical DNA and RNA sequencing. This case demonstrates the complementarity of traditional laboratory assays and emerging molecular technologies in providing precise molecular diagnosis.