Journal of medical genetics · 2026
Diagnosis complexity of dentinogenesis imperfecta involving DSPP genetic variants.
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Caravello Gaétan, Jiménez-Armijo Alexandra, Kawczynski Marzena, Rey Tristan, O-Rares Consortium, Antin Manuela, Roth Alison, Lamouche Jean-Baptiste, Gouronc Aurélie, Alioua Abdelmalek, Schluth-Bolard Caroline, Bloch-Zupan Agnès
Аннотация
BACKGROUND: Variants in the dentin sialophosphoprotein (DSPP) gene are associated with dentin dysplasia type II (DD-II; OMIM # 125420) and dentinogenesis imperfecta (DI) types II (OMIM # 125490) and III (OMIM # 125500). DSPP 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.
MATERIALS AND METHODS: 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 DSPP region.
RESULTS: Pathogenic or likely pathogenic DSPP 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.
CONCLUSION: This study demonstrates the value of long-read sequencing to resolve complex DSPP regions and expands the variant spectrum. The variability in clinical presentation suggests the influence of modifier factors, warranting further genotype-phenotype studies.
MATERIALS AND METHODS: 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 DSPP region.
RESULTS: Pathogenic or likely pathogenic DSPP 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.
CONCLUSION: This study demonstrates the value of long-read sequencing to resolve complex DSPP regions and expands the variant spectrum. The variability in clinical presentation suggests the influence of modifier factors, warranting further genotype-phenotype studies.