Diagnosis complexity of dentinogenesis imperfecta involving <i>DSPP</i> genetic variants

<h4>Background</h4>Variants in the dentin sialophosphoprotein (<i>DSPP</i>) gene are associated with dentin dysplasia type II (DD-II; OMIM # 125420) and dentinogenesis imperfecta (DI) types II (OMIM # 125490) and III (OMIM # 125500). <i>DSPP</i> encodes a precursor protein cleaved into three dentin matrix proteins: dentin sialoprotein (DSP), dentin phosphoprotein/phosphophoryn (DPP) and dentin glycoprotein (DGP). Exon 5 contains over 200 tandem 9-base pair repeats (DSS domain), complicating sequencing with standard methods.<h4>Materials and methods</h4>We studied 112 individuals (42 index cases and 70 relatives) with clinical signs of DI or DD. DNA extracted from saliva was analysed using the GenoDENT next-generation sequencing panel. For inconclusive cases, long-range PCR and Oxford Nanopore Technology (ONT) long-read sequencing were used to overcome limitations in analysing the repetitive <i>DSPP</i> region.<h4>Results</h4>Pathogenic or likely pathogenic <i>DSPP</i> variants were identified in 41 families, including 8 known and 14 novel variants. Most were in exon 5, causing frameshifts resulting in a -1 reading-frame shift with a hydrophobic C-terminal extension and termination at a downstream stop codon. ONT sequencing enabled detection in cases where short-read methods failed. Several variants showed familial segregation and variable expressivity.<h4>Conclusion</h4>This study demonstrates the value of long-read sequencing to resolve complex <i>DSPP</i> regions and expands the variant spectrum. The variability in clinical presentation suggests the influence of modifier factors, warranting further genotype-phenotype studies.