Out-of-Frame Transcript and in-Frame Deletion owing to a Novel Splice Mutation of COL2A1 (c.1266+2T>A) in an Adult with Kniest Dysplasia: A Case Report.

INTRODUCTION

Kniest dysplasia is a severe form of type II collagenopathy caused by mutations in collagen II alpha 1 chain (COL2A1) gene. It can be diagnosed in early childhood based on the clinical findings of short stature, splayed epiphysis, narrowed joint spaces and platyspondyly associated with maxillofacial, ophthalmological, and otolaryngological complications. Missense mutations and small deletions owing to exon skipping in the triple-helical region of COL2A1 have been reported in most cases of Kniest dysplasia.

CASE PRESENTATION: We describe a female patient aged 39 years with difficulty in walking, back pain, and limited movement of the lower extremities. She had experienced neck pain during adolescence; however, it gradually decreased with age. She also showed markedly short stature (-4.37 SD), cleft palate, cataract, retinal detachment, and serous otitis media. Radiographic analyses revealed epiphyseal enlargement of the longitudinal bones, kyphoscoliosis, and flat vertebrae in the thoracolumbar spine. The cervical spinal bodies were fused but not at the age of 19 years. Genetic analysis revealed a novel heterozygous mutation, c.1266+2T>A, in intron 20 of COL2A1. In silico predictive tools indicated that this mutation was pathological. Exon-trapping assay showed that this splice mutation led to both intron retention and exon skipping in the triple-helical region. These clinical findings and genetic tests confirmed the diagnosis of Kniest dysplasia.

DISCUSSION: The diagnosis of Kniest dysplasia is sometimes difficult based on clinical findings in adulthood owing to progressive skeletal changes. The current novel splice mutation in COL2A1 demonstrates both out-of-frame transcript and in-frame deletion in Kniest dysplasia.