Recurrent helical COL1A1 E678K variant in three families with an EDS-predominant phenotype expanding the clinical and molecular spectrum of COL1-related overlap disorder

Type I collagen, important for tissue integrity and strength, is comprised of two α1 chains and one α2 chain that form a triple helix. The collagen type 1 alpha 1 chain (COL1A1) gene encodes the pro-alpha 1 chains of type I collagen. Deleterious variants in COL1A1 are associated with multiple disorders, but most notably osteogenesis imperfecta (OI) types I–IV (MIM # 166200, 166210, 259420, 166220), arthrochalasia-type Ehlers-Danlos syndrome (aEDS) (MIM # 130060), combined osteogenesis imperfecta and Ehlers-Danlos syndrome (OI-EDS) (MIM # 130060) and the more recently recognised COL1-related overlap disorder (C1ROD).1 2 Other allelic disorders include Caffey disease (MIM # 114000) and postmenopausal osteoporosis (MIM # 166710).

Osteogenesis Imperfecta (OI) is characterised by frequent fractures, short stature, blue sclera, dentinogenesis imperfecta and hearing loss. Arthrochalasia-type Ehlers Danlos is characterised by congenital bilateral hip dislocation, severe generalised joint hypermobility and skin hyperextensibility. It was initially understood that…