Abstract
Simple SummarySkeletal connective tissue disorders represent a heterogeneous group of inherited disorders mostly monogenically inherited. Heritable connective tissue disorders such as osteogenesis imperfecta (OI) belong to this group. Herein, an affected calf showing congenital bone lesions such as intrauterine fractures, abnormally shaped long bones and localized arthrogryposis resembling OI type II is reported. Whole-genome sequencing (WGS) identified a most likely disease-causing mutation in the COL1A1 gene. The COL1A1 gene is known to be associated with dominant inherited OI type II forms in humans and sporadically in dogs and cattle, but so far, a variant in the fibrillar collagen NC1 domain has not been shown to cause a similar phenotype in domestic animals. We assume that the herein identified most-likely causative variant occurred either within the parental germlines or post-zygotically in the developing embryo. Rare lethal disorders such as OI in livestock are usually not diagnosed to the molecular level, mainly because of the lack of resources and diagnostic tools. WGS-based precision diagnostics allows understanding rare disorders and supports the value of surveillance of cattle breeding populations for harmful genetic disorders.Osteogenesis imperfecta (OI) type II is a genetic connective tissue disorder characterized by bone fragility, severe skeletal deformities and shortened limbs. OI usually causes perinatal death of affected individuals. OI type II diagnosis in humans is established by the identification of heterozygous mutations in genes coding for collagens. The purpose of this study was to characterize the pathological phenotype of an OI type II-affected neonatal Holstein calf and to identify the causative genetic variant by whole-genome sequencing (WGS). The calf had acute as well as intrauterine fractures, abnormally shaped long bones and localized arthrogryposis. Genetic analysis revealed a private heterozygous missense variant in COL1A1 (c.3917T>A) located in the fibrillar collagen NC1 domain (p.Val1306Glu) that most likely occurred de novo. This confirmed the diagnosis of OI type II and represents the first report of a pathogenic variant in the fibrillar collagen NC domain of COL1A1 associated to OI type II in domestic animals. Furthermore, this study highlights the utility of WGS-based precise diagnostics for understanding congenital disorders in cattle and the need for continued surveillance for rare lethal genetic disorders in cattle.
Highlights
Osteogenesis imperfecta (OI) encompasses a heterogeneous group of rare genetic connective tissue disorders characterized by skeletal abnormalities, leading to bone fragility, deformity, low bone mass and growth deficiency [1,2]
OI types I-IV are mainly associated with autosomal dominant variants in COL1A1 and COL1A2; OI type V is a less frequent dominantly inherited form associated with variants in the novel gene IFTM5
The identified missense variant in COL1A1 in an obvious candidate gene represents the most likely pathogenic variant associated with the observed OI phenotype
Summary
Osteogenesis imperfecta (OI) encompasses a heterogeneous group of rare genetic connective tissue disorders characterized by skeletal abnormalities, leading to bone fragility, deformity, low bone mass and growth deficiency [1,2]. Extra-skeletal manifestations of OI may include joint hypermobility, dentinogenesis imperfecta, blue sclera, hearing loss, and more rarely pulmonary and cardiovascular complications, and muscle weakness [2]. OI types I-IV are mainly associated with autosomal dominant variants in COL1A1 and COL1A2; OI type V is a less frequent dominantly inherited form associated with variants in the novel gene IFTM5. The remaining types of OI, which usually arise at much lower frequency are autosomal recessive diseases while OI type XVIII has an X-linked inheritance pattern [2,4]
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