COL12A1: a diagnostic challenge

*Correspondence: [e-mail].

Abstract

Case Presentation: Male, 30 months old patient, is the second child from a non-consanguineous couple. Prenatal care was complete, and mother reported good intrauterine movement. Delivery was uneventful. The child sat without support at 6 months and walked without support at 11 months. Frequent falls and difficulty running have been observed. On examination, he had mild hypotonia, flat feet, genu valgum and walked with increased medial rotation of the legs. Mother reported that she always had a similar gait pattern and had never been athletic. Boy’s serum creatine kinase was slightly elevated (530). Muscle ultrasound was performed on boy and his mother, both showed mild hyperechogenicity without atrophy only in the posterior region of the thigh. Gene panel by next generation sequencing was performed on boy and identified a heterozygous variant of uncertain significance (VUS) in the COL12A1 gene (chr6:75.121.390C>T:p.Ser2333Asn), not previously reported. Segregation analysis revealed that the variant segregated in his mother. Cases were discussed in collaboration with NIH, which reported a child with the same phenotype, same ultrasound presentation and an immunocytochemical analysis of dermal fibroblasts that showed prominent reduction of the collagen XII matrix. This child had a VUS (p.Ile2334Thr) in COL12A1 gene.

Discussion: COL12A1 is a large gene, which encodes the alpha chain type XII collagen family that interacts with other extracellular matrix proteins. There are few described pathogenic variants that may lead to Collagen XII related disorders (COL12-RD) and inheritance pattern may be either autosomal dominant or recessive. COL12-RD presents an overlap syndrome involving muscle and connective tissue. The phenotype includes mild hypotonia, limbs deformities, Myopathic Ehlers-Danlos Syndrome, Bethlem Myopathy 2 and Ullrich congenital muscular dystrophy-2. Our cases have clinical signs and complementary exams compatible with COL12-RD and clinical discussion with other specialists reported another child with the same presentation and a close missense variant. Although VUS should be evaluated carefully, these informations support COL12-RD diagnosis.

Final Comments: The limited number of patients with pathogenic COL12A1 variants described to date and the broad phenotype makes COL12-RD diagnosis complex. The importance of this report is to draw attention to the need for exchanging information between specialists in the face of a VUS finding, especially when dealing with rare diseases such as COL12-RD.

Publication History

Article published online:
12 May 2025