COL12A1 Gene Variant and a Review of the Literature: A Case Report of Ullrich Congenital Muscular Dystrophy

Mutations in genes associated with collagen IV (COL6A1, COL6A2, and COL6A3) lead to Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) [1]. Patients affected by collagen VI-related myopathies can exhibit clinical manifestations of both a myopathy and a connective tissue disorder. Collagen XII is a member of the fibril-associated collagen family with interrupted triple helix domains on human chromosome 6q12-q13. It is intensively present in bones, tendons, ligaments, the dermis, cornea, vascular wall, and meninges [2]. Mutations in collagen XII have recently been reported to cause modifications in the connective tissue phenotypic manifestation similar to those of collagen VI-related myopathies. The typical manifestation of collagen XII-related myopathy includes distal joint hyperlaxity, mild muscular weakness, and joint contractures, with both age at onset and disease severity being variable [3]. This report describes a female patient aged 2 years and 10 months who presented to our outpatient clinic due to joint laxity and frequent falls, with findings of distal joint hyperlaxity, mild muscle weakness, and skin lesions, and whose genetic analysis revealed a variant in the COL12A1 gene that had previously been identified but about which there had been no clinical reports.

A girl aged 2 years and 10 months presented to the pediatric neurology clinic due to joint laxity and frequent falls. Developmental retardation was reported to have been present in the intrauterine period, and delivery was difficult, but through the normal spontaneous vaginal route. However, she had no history of admission to the neonatal intensive care unit. We learned that she lagged behind her peers in terms of neuromotor development, particularly in gross motor development. Third-degree consanguinity was present between the parents. Frequent falls were present in a sibling, and suspicion of osteogenesis imperfecta was present in a cousin of the mother. At physical examination, her mental state was good, curvature was present in the high palate, deep tendon reflexes were normoactive, the Babinski sign was negative, and muscle strength was 4/5 in all extremities. Hyperlaxity was present in the distal parts of the extremities in particular, with mild joint deformity in the fingers, pes planus, dry skin on the extensor surfaces of the upper and lower extremities, and hyperkeratosis pilaris (Fig. 1). Laboratory tests including complete blood count, electrolytes, liver and kidney function tests, creatine kinase, ferritin, folate, vitamins B12 and D, and thyroid function tests were all normal. Echocardiography, eye function, and hearing tests were also normal. The Denver developmental screening test was assessed as age-appropriate. Whole exome sequencing was performed on the patient, and then the segregation analysis was confirmed by next-generation sequencing of the target region on the parents. The whole exome of the patient was sequenced via Illumina Next-Seq NGS system (Illumina, California, USA) and analysis revealed a homozygous c.8903C>T (p.Pro2968Leu) missense variant in the collagen-like 4 domain of COL12A1 gene. This change is not included in population databases, and according to the American College of Medical Genetics and Genomics (ACMG) sequence variant classification guideline, the variant was classified as variant of unknown significance (PM2, PP3). This variant has previously been described in ClinVar but has not been linked to any disease (rs771010070). Segregation analysis of the patient’s parents showed that both were heterozygous carriers (see Fig. 2). No mutation was determined in the patient’s sibling. WES was performed at the genetic diseases diagnosis center of Dr. Ersin Arslan Training and Research Hospital (Gaziantep, Turkey). The genomic build number is GRch37/hg19.

Patients with UCMD with the COL6 mutation exhibit severe muscle weakness and distal joint hyperlaxity in addition to proximal joint contractures, while relatively mild proximal and distal joint contractures are present in BM. Cases with COL12A1 gene mutations have rarely been reported in patients with UCMD- and BM-like diseases not involving COL6 mutations [2, 4]. Very little is known about the spectrum of clinical symptoms deriving from mutations in collagen XII. However, to the best of our knowledge, there have been case reports of severe courses and a small number of studies involving mild cases. Zou et al. [2] reported two siblings with widespread joint hyperlaxity and muscle weakness preventing independent ambulation deriving from homozygous loss of function mutation in COL12A1 and another case with a de novo missense mutation with a milder impact in which the ability to walk was acquired. Coppens et al. [4] reported a case of a pediatric male patient with a de novo mutation in the COL12A1 exhibiting a severe clinical course with fetal hypokinesis, severe neonatal weakness, pronounced hyperlaxity, a high-arched palate, retrognathia, club feet, and pectus excavatum. In another case report, Punetha et al. [3] described a girl with a severe clinical course in the neonatal period who gradually developed a moderate phenotypic appearance. Neurological examination revealed a high-arched palate, tooth development disorder, mild muscle weakness in all extremities, kyphoscoliosis, and hyperlaxity. Although the deep tendon reflexes were normal, no contracture was observed. Araújo and Antunes [5] also reported that the clinical findings in a 14-year-old girl followed a mild course. The neurological examination of the 14-year-old patient revealed muscle strength of 4/5 in the upper extremities only, while in our patient, muscle strength was 4–5/5 in all extremities. Mild muscle weakness together with hyperkeratosis pilaris skin lesions and distal joint hyperlaxity were present in our case with a homozygous missense mutation in COL12A1. This clinical manifestation exhibited a milder phenotype than previously reported cases. However, joint hyperlaxity was pronounced in both cases, and the deep tendon reflexes were preserved. Creatine kinase values were also normal in both cases. Cutaneous abnormalities such as follicular hyperkeratosis and keloid formation can be observed in UCMD and BM involving COL6 mutations [6, 7]. Hicks et al. [8] reported a case with hyperkeratosis pilaris. The cutaneous lesion detected in the present case was also hyperkeratosis pilaris, a lesion emerging at a younger age associated with COL12A1 variant. This clinical variability suggests that disorders associated with collagen XII can exhibit a wide phenotype spectrum. Genetic analysis in the present case revealed a homozygous c.8903C>T (p.Pro2968Leu) missense variant in the COL12A1 gene. Homozygous variants in the COL12A1 gene are known to result in UCMD [2]. The compatibility of the clinical findings in our patient shows that change in the disease can be disease-producing. Confirming the diagnosis as early as possible is important in terms of symptomatic treatment and genetic counseling. A review of cases with the rare COL12A1 gene mutation based on their phenotype-genotype characteristics is shown in Table 1.

The variant affects the collagen-like 4 domain of the protein. However, there are not adequate functional studies about the functions or effects of the variations of the domains. The proline amino acid at localization 2,968 in the COL12A1 gene is located on the collagen-like 4 domain on the protein and is evolutionarily highly conserved. The pathogenicity of the variant detected in the case can be explained by the fact that it is in an important position for correct homotrimer formation. In silico prediction programs (MetaRNN, REVEL) also predict damaging effects. In the Genome Aggregation Database (gnomAD), this variant is not detected as a homozygote state. It needs to be supported by functional studies. Although the variant detected in our patient has not yet been clinically reported in the literature and is classified as variant of unknown significance, the clinical findings are compatible with COL12A1-related diseases. Therefore, we think that the variant is disease-causing, but it should be supported by further studies.

This report is presented in order to remind physicians of rare gene mutations associated with collagen XII in patients presenting at different ages with varying severities of distal joint hyperlaxity, mild muscle weakness, and cutaneous lesions. It is also intended to contribute to the literature by describing rare COL12A1 mutations affecting muscle and connective tissue. We think that this case report of a case with a known variant that had previously been described but which had not previously been the subject of any published phenotype-genotype report will broaden the phenotypic spectrum for COL12A1 disorders. In addition, it is suggested for future studies to carry out complementary studies that support the pathogenicity of the mutation.

Ethics approval was not required in accordance with local or national guidelines, and the study has been granted an exemption from requiring ethics approval since it contains only a presentation of two cases and written informed consent was obtained. Written informed consent was obtained from their parents (legal guardians) for publication of the details of their medical case and any accompanying images.

The authors have no conflicts of interest to declare.

This study was not supported by any funder.

Rojan İpek: conceptualization, methodology, investigation, writing – original Draft; Büşra Eser Çavdartepe: methodology, investigation, and writing – original draft; Sevcan Tuğ Bozdoğan: supervision, writing – original draft; Uluç Yiş: investigation, and writing – original draft.

All data generated or analyzed during this study are included in the present study. Further inquiries can be directed to the corresponding author.