We presented the case of a 5-year-1-month-old boy who was referred to our outpatient clinic when he was 4-year-10-month-old (timeline of clinical course—Fig. illustrates the clinical course). The patient was examined because of prolonged unresolved pretibial haematoma that measured 6.5 × 6.5 cm2 after falling down to the floor with initial impression of cellulitis. Easy bruising, multiple ecchymoses, joint hypermobility and poly-arthralgia were noted since childhood; however, no specific medical advice was sought before the clinic visit. Clinical examination revealed body height 108 cm (23th percentile) and body weight 21 kg (75th percentile). The patient had joint hypermobility, Beighton score 7 (including bilaterally passive dorsiflexion of fifth finger beyond 90, score 2; bilaterally passive flexion of thumb to forearm, score 2; hyperextension of the elbow beyond 10 degree, score 0; bilateral hyperextension of the knee beyond 10 degree, score 2; forward flexion of the trunk with knees fully extended and palms resting on the floor, score 1) [], poly-arthralgia without inflammatory signs, mildly hyperextensible skin, and ecchymoses over multiple sites. Among the minor diagnostic criteria for cEDS, muscle hypotonia, delayed gross motor development, easy bruising without obvious causes, and positive family history (similar symptoms of joint hypermobility in his father and aunt) were also observed. Chest wall deformity, kyphoscoliotic posture, periodontal lesions were not observed during physical examination. No tumors and vasculopathy were observed on ultrasound and magnetic resonance imaging of the pretibial mass. Echocardiographic assessment revealed no mitral valve prolapse and aortic root dilatation. The myopathy was less likely due to normal range creatine kinase. Hematological studies for coagulation and platelet disorders and study for autoimmune diseases all provided normal results (Supplementary Table. ). With aforementioned presentation, the patient was suspected of having EDS. Skin biopsy was performed, and whitish subcutaneous fat spheroids were observed during the biopsy. Light microscopy revealed fibrosis in the subcutaneous fat and organizing haematoma without malignancy. Transmission electron microscopy of the skin biopsy revealed irregular interfibrillar spaces, collagen fibers with variable diameter, and collagen cauliflowers []. Molecular evaluation of genomic DNA extracted from a blood sample was performed. Whole exome sequencing and conventional Sanger sequencing were performed using the CytoOnearray sequencing panel (Phalanx Biotech, Taiwan). These analyses identified the frameshift mutation NM_000093.4(COL5A1):c.4211_4212delAG in exon 54, which resulted in a glutamine to arginine substitution at codon 1404 [NP_000084.3: p.Gln1404ArgfsTer77]. Based on disease-causing mutation databases, such as Leiden Open Variation Database (LOVD) [] and ClinVar [], this frameshift mutation identified in our patient is a novel finding. At least 45 pathologic variants of a frameshift mutation in cEDS have been found; however, no pathological variants and mutation loci were detected, as in our patient. This is a novel frameshift mutation in CO5A1 first identified in this patient with cEDS. This patient was regularly followed in the multidisciplinary team and accepted the rehabilitation program in outpatient clinic.