Confirmation of frameshift variants in the last exon of FGFR1 as a cause of multiple epiphyseal dysplasia.

Multiple epiphyseal dysplasia (MED) is a genetically diverse skeletal disorder characterized by abnormal and delayed epiphyseal ossification, early-onset osteoarthritis, joint pain and mild short stature. MED is primarily caused by pathogenic variants in genes involved in cartilage and bone development, including COMP, MATN, COL9A1-3, CANT1 and SLC26A2. FGFR1 was suggested as a cause of MED in a study published in 2020, which reported a frameshift variant in the last exon of this gene. We assembled an international cohort of 13 individuals with MED carrying C-terminal frameshift variants in FGFR1 (NM_023110.3: c.2424_2425del, c.2436_2440del, and c.2460dup). In all three families, the frameshift variants are predicted to result in the same 164-amino acid C-terminal elongation tail. The cohort includes two families (three affected individuals in one, nine in the other) and one previously reported individual. All affected individuals presented with MED without vertebral involvement. Age of symptom onset ranged from 3 to 13 years, with complete penetrance. Genu valgum was very frequent, and most affected patients required its surgical correction. Hypogonadotropic hypogonadism was present in approximately half of the cases. Adult height was mildly reduced, with an median of 164.0 cm in males (-1.7 SDS) and 153.1 cm in females (-1.6 SDS). Structural modeling for the novel C-terminal stretch as a result of the variants could acquire secondary structures, including an α-helix and a β-sheet domain, and could bring a potential antimorphic effect. Our findings confirm FGFR1 C-terminal frameshift variants as a cause of MED and provide further clinical characterization of this disorder.