COL1-related overlap disorder: An emerging phenotype linked to mono- and bi-allelic COL1A1/2 variants

Objectives

We describe the clinical, radiological, and oro-dental findings of four unrelated families with unusual skeletal phenotypes caused by mono- and bi- allelic COL1A1/2 variants.

Design

The study included five Arab patients with clinical manifestations resembling osteogenesis imperfecta in the presence of variable degrees of osteoporosis, bone deformities, gray sclera, Wormian bones in the skull, and oro-dental abnormalities. However, bone fractures, which are considered the cardinal feature in osteogenesis imperfecta patients, were not documented in any of the cases. In addition, they also lacked the characteristic features of Ehlers-Danlos syndrome. Exome sequence was used to identify the causative variants.

Results

A new homozygous missense variant in COL1A1: c.4340 T > G; p.(Val1447Gly) was identified in one family, while the remaining three families harbored two recurrent and one novel heterozygous variants in COL1A2: [c.1171 G>A; p.(Gly391Ser) and c.1253 G>C; p.(Gly418Ala)] and COL1A1: c.1678 G>A; p.(Gly560Ser), respectively.

Conclusions

We present a new patient harboring a homozygous COL1A1 variant with a distinctive skeletal phenotype in comparison to the few previously reported patients in the literature. In addition, we describe three families with osteogenesis imperfecta like phenotype harboring monoallelic COL1A1/2 variants, expanding the spectrum of COL1-related overlap disorder.