Diagnosis complexity of dentinogenesis imperfecta involving DSPP genetic variants

Pathogenic variants in the highly repetitive exon 5 region of DSPP (>200 tandem 9-bp repeats), undetectable by short-read sequencing, resolved by Oxford Nanopore Technology (ONT) long-read sequencing

In a cohort of 112 individuals (42 index cases, 70 relatives) with clinical signs of dentinogenesis imperfecta or dentin dysplasia, pathogenic DSPP variants were identified in 41 families, including 14 novel variants. Most pathogenic variants are located in the highly repetitive exon 5 region (>200 tandem 9-bp repeats) inaccessible to short-read methods. Oxford Nanopore (ONT) long-read sequencing resolved cases where conventional methods failed, with several variants showing intra-familial variability in expressivity.

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This article concretely illustrates a persistent technical limitation of short-read sequencing: highly repetitive regions remain a diagnostic blind spot. Using ONT as a targeted complement for refractory genes like DSPP is a pragmatic solution to integrate into dental diagnostic panels. The intra-familial variability in expressivity suggests as-yet-unidentified modifier factors.

Clinical impact: 2/3 · Evidence strength: 2/3 · Novelty: 1/2 · Sample size: 1/1 · Journal quality: 1/1 → Total: 7/10