A novel COL1A1 variant in a family with clinical features of hypermobile Ehlers-Danlos syndrome that proved to be a COL1-related overlap disorder

Abstract

COL1-related overlap disorder is a condition, which is not yet considered as part of the 2017 EDS classification. However, it should be investigated as an alternative diagnosis for any patient with hypermobile EDS. This could allow providing appropriate genetic counseling.

Keywords: COL1A1; Ehlers‐Danlos Syndrome; connective tissue; hypermobile EDS; joint laxity.

FIGURE 1

Family pedigree, clinical presentation of the patients, and genomic structure of the COL1A1 gene. (A) Family pedigree. Circles indicate females, and squares indicate males. Symbols in black indicate individuals affected with a hEDS. Individual I.2 died in a motorcycle accident at age 25. His medical history is unknown. Individuals I.3, II.4, II.5, and III.1 are healthy. I.1 has not been reevaluated by the referral center. (B) Clinical presentation of the patients. Laxity of the thumb (a), swan‐neck deformity of the fingers (b), laxity of the ankle (c, d) and bruising (d, arrow), piezogenic papules of the heel and mildly flat feet (e), hyperextensible skin (f, g), large scars (h), high and narrow palate (i), hyperlaxity of the fifth and third fingers (j, k), and blue sclerae (l). (C) Genomic structure of the COL1A1 gene including exons (white rectangles) and introns (black horizontal line). Adapted from Morlino et al, 2019. Previously identified variants associated with C1ROD are noted in black. The variant identified in patients II.2, II.3, and III.2 is indicated in red. The previously identified variant associated with COL1A1‐cEDS is noted in green for the missense c.934C>T p.(Arg312Cys). , The α1(I) collagen chain is characterized by a signal peptide (black box), procollagen N‐ and C‐ proteinase cleavage sites (little red and purple boxes), N‐ and C‐propeptides (green and orange boxes), a large helical domain composed of Gly‐X‐Y triplets (blue box)

FIGURE 2

Collagen I and fibronectin secretion by dermal fibroblasts in culture visualized by confocal imaging. (A) COLI (red) was detected with a recombinant antibody (ab138492, Abcam) on PFA‐fixed cells from patient II.3 (II.3) and a control individual (CT). Inserts are 200X zooms. (B) Co‐immunolabeling with a monoclonal antibody (HFN7.1, DSHB) against fibronectin (green). Nuclei are identified by DAPI staining (blue). Scale bars: 50µm