Relevance of Extending FGFR3 Gene Analysis in Osteochondrodysplasia to Non-Coding Sequences: A Case Report

• Published in: Genes 2024-02, Vol.15 (2), p.225
• Main Authors: Ouedraogo, Zangbéwendé Guy, Janel, Caroline, Janin, Alexandre, Millat, Gilles, Langlais, Sarah, Pontier, Bénédicte, Biard, Marie, Lepage, Mathis, Francannet, Christine, Laffargue, Fanny, Creveaux, Isabelle
• Format: Article
• Language: English
• Subjects: Achondroplasia; Achondroplasia - diagnosis; Achondroplasia - genetics; Achondroplasia - pathology; Adult; Bone dysplasia; Child; Cloning; Development and progression; DNA polymerase; Drug development; Exons; Fibroblast growth factor receptor 3; Fibroblast growth factor receptors; Fibroblast growth factors; Genes; Genetic testing; Genomics; Genotype & phenotype; Glycine; Humans; Hypochondroplasia; Mutation; Osteochondrodysplasia; Osteochondrodysplasias - diagnosis; Osteochondrodysplasias - genetics; Pathogenicity; Phenotype; Phenotypes; Receptor, Fibroblast Growth Factor, Type 3 - genetics; Scoliosis; Skeleton
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes15020225

Skeletal dysplasia, also called osteochondrodysplasia, is a category of disorders affecting bone development and children's growth. Up to 552 genes, including fibroblast growth factor receptor 3 ( ), have been implicated by pathogenic variations in its genesis. Frequently identified causal mutations in osteochondrodysplasia arise in the coding sequences of the gene: c.1138G>A and c.1138G>C in achondroplasia and c.1620C>A and c.1620C>G in hypochondroplasia. However, in some cases, the diagnostic investigations undertaken thus far have failed to identify the causal anomaly, which strengthens the relevance of the diagnostic strategies being further refined. We observed a Caucasian adult with clinical and radiographic features of achondroplasia, with no common pathogenic variant. Exome sequencing detected an (NM_000142.4):c.1075+95C>G heterozygous intronic variation. In vitro studies showed that this variant results in the aberrant exonization of a 90-nucleotide 5' segment of intron 8, resulting in the substitution of the alanine (Ala359) for a glycine (Gly) and the in-frame insertion of 30 amino acids. This change may alter FGFR3's function. Our report provides the first clinical description of an adult carrying this variant, which completes the phenotype description previously provided in children and confirms the recurrence, the autosomal-dominant pathogenicity, and the diagnostic relevance of this intronic variant. We support its inclusion in routinely used diagnostic tests for osteochondrodysplasia. This may increase the detection rate of causal variants and therefore could have a positive impact on patient management. Finally, alteration via non-coding sequence exonization should be considered a recurrent disease mechanism to be taken into account for new drug design and clinical trial strategies.