Clinical characterization of Collagen XII-related disease caused by biallelic COL12A1 variants

While there have been several reports of patients with dominantly acting COL12A1 variants, few cases of the more severe recessive Collagen XII-related disorders have previously been documented.

We present detailed clinical, immunocytochemical, and imaging data on eight additional patients from seven families with biallelic pathogenic variants in COL12A1.

All patients presented with a consistent constellation of congenital onset clinical features: hypotonia, dysmorphic features, most notably gingival hypertrophy, prominent distal joint hyperlaxity, with co-occurring contractures of large joints, and variable muscle involvement, evident both clinically and on muscle imaging. Five patients presented with a severe congenital phenotype manifesting with profound weakness, significantly delayed or minimal attainment of motor milestones, respiratory insufficiency, and feeding difficulties. Three patients presented with mild-to-moderate muscle weakness and delayed milestones but were able to achieve independent ambulation. Patients were found to have biallelic loss-of-function COL12A1 variants, except for one family (p.I1393Ffs*11/p.A1110D). Consistent with the variable clinical spectrum, in vitro immunocytochemistry analysis in fibroblasts ranged from complete absence of Collagen XII expression in a patient with severe disease, to a mild reduction in a patient with milder disease.

Here we characterize the clinical presentation, muscle imaging, and dermal fibroblast immunostaining findings associated with biallelic variants in COL12A1, further establishing COL12A1 as a recessive myopathic Ehlers-Danlos syndrome (mEDS) gene, and expanding the clinical spectrum to include a milder EDS phenotype.