Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) Type 1 is a rare hereditary connective tissue disorder due to biallelic deleterious variants in PLOD1 and is mainly characterized by hypotonia, congenital kyphoscoliosis, eye fragility, hyperextensible skin, Marfanoid habitus, and joint hypermobility. In PLOD1-kEDS, deleterious variants are typically loss-of-function alleles. Therefore, the identification of private non-canonical splicing variants might deserve functional studies to refine their clinical interpretation. In a 7-year-old boy with congenital hypotonia, kyphoscoliosis, joint hypermobility, and arachnodactyly, exome sequencing revealed the homozygous variant c.1756-13C > A in PLOD1. This variant was previously annotated in public databases with conflicting pathogenicity criteria. In contrast to other EDS subtypes whose causative gene is not expressed in peripheral lymphocytes, whole blood RNA sequencing demonstrated a deleterious effect of the identified variant, which resulted in the incorporation of 11 intronic nucleotides and the generation of a premature stop codon. In this work, multi-OMIC analysis on peripheral blood was a rapid and reliable tool to clinically characterize a non-canonical splice site variant in PLOD1-kEDS.
Keywords: PLOD1; RNA sequencing; intronic variant; kyphoscoliotic Ehlers‐Danlos syndrome.
© 2025 Wiley Periodicals LLC.