A Novel Splice Variant in the COL1A1 Gene Leads to Exon 46 Skipping and Osteogenesis Imperfecta.

The intronic variant NM_000088.4:c.3423+5G>A in COL1A1 causes complete skipping of exon 46 and disrupts COL1A1 expression.

Ninety per cent of osteogenesis imperfecta cases are attributable to autosomal dominant variants in COL1A1 and COL1A2. Trio whole-exome sequencing identified a novel heterozygous variant in the C-terminal region of COL1A1, NM_000088.4:c.3423+5G>A, confirmed by Sanger sequencing in both the proband (II-2) and her foetus (III-1), who were clinically suspected of having osteogenesis imperfecta. A minigene splicing assay in HeLa and HEK293T cells showed that the variant causes complete skipping of exon 46, supporting its classification as likely pathogenic. The authors also retrieved 419 COL1A1 splicing variants from PubMed, excluded 15 without phenotypic data and 2 linked to Ehlers-Danlos syndrome, and stratified the remaining 402 into canonical splice site variants (77.8%, 313/402), mostly associated with mild phenotypes, other intronic variants including splice region variants (17.9%, 72/402) and deep intronic variants (0.4%, 2/402), and other variants such as exonic changes or fragment loss (3.7%, 15/402). They argue that variant location, particularly in the C-terminal region, provides a useful framework for prognostic prediction.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The functional demonstration of exon skipping is convincing, but it rests on a minigene assay outside the native tissue context and on a single family, with no transcript analysis in patient tissue. The stratification of 402 published variants is descriptive and subject to the publication bias favouring severe cases, so it does not yet support giving a prognosis based on variant position alone in the clinic. Its immediate practical value lies mainly in the classification of a +5 splice region variant, a position that remains hard to interpret in routine practice.

Analysis by Dr Thibaut Benquey