Clinical variability in carriers of C1R gene variants: differential diagnosis of Ehlers-Danlos syndrome types

Ehlers-Danlos syndrome is a group of hereditary connective tissue disorders with pronounced clinical heterogeneity. Of particular interest is an extremely rare periodontal type caused by C1R and C1S gene variants and characterized primarily by dental disorders, skin manifestations, and joint hypermobility. This paper describes two families. In family F., the proband, a 35-yearold man, and his 6-year-old son were examined. The child had multiple spontaneous hematomas and ecchymoses. The father had pretibial plaques, joint hypermobility, early loss of permanent teeth, and gingival recession. Whole exome sequencing revealed a previously undescribed heterozygous variant NM_001733:c.1073G>A (p.Cys358Tyr) in the C1R gene. In family L., the proband, a 44-year-old woman, presented with chronic arthralgia, joint hypermobility and instability, and frequent infectious diseases. Her 20-year-old son has similar symptoms. Sequencing results also identified a previously undescribed heterozygous variant NM_001733:c.2066A>G (p.Lys689Arg) in the C1R gene. These observations highlight the need for early genetic testing when Ehlers-Danlos syndrome is suspected and demonstrate the importance of integrating clinical and molecular data for the accurate diagnosis of rare forms of the disease.