A rare ACAN non-canonical splicing-site intron variant results in familial short stature

Objective ACAN gene variants, prevalent monogenic defects linked to short stature, are characterized by impaired cartilage generation in growth plates. We aimed to unravel the genetic basis of short stature in a specific pedigree by investigating the role of a novel non-canonical splicing-site variant, c.630-13G > A, within the ACAN gene. Method Sanger sequencing was used for pedigree verification, and the effects of this variant on mRNA splicing were analyzed through minigene assay. Results The study revealed that this variant led to the creation of a previously unreported splice site in the fourth intron, resulting in the incorporation of an 11-bp sequence from the intron into the final transcript. This alteration led to a frameshift and formation of a premature termination codon, impacting the structure of the aggrecan protein. Conclusions We document the pathogenicity of an ACAN non-canonical splicing-site variant, emphasizing the significance of considering intronic variants during genetic testing.