Description of Joint Alterations Observed in a Family Carrying p.Asn453Ser COMP Variant: Clinical Phenotypes, In Silico Prediction of Functional Impact on COMP Protein and Stability, and Review of the Literature

The role of genetics in the development of osteoarthritis is well established but the molecular bases are not fully understood. Here, we describe a family carrying a germline mutation in COMP (Cartilage Oligomeric Matrix Protein) associated with three distinct phenotypes. The index case was enrolled for a familial form of idiopathic early-onset osteoarthritis. By screening potential causal genes for osteoarthritis, we identified a heterozygous missense mutation of COMP (c.1358C>T, p.Asn453Ser), absent from genome databases, located on a highly conserved residue and predicted to be deleterious. Molecular dynamics simulation suggests that the mutation destabilizes the overall COMP protein structure and consequently the calcium releases from neighboring calcium binding sites. This mutation was once reported in the literature as causal for severe multiple epiphyseal dysplasia (MED). However, no sign of dysplasia was present in the index case. The mutation was also identified in one of her brothers diagnosed with MED and secondary osteoarthritis, and in her sister affected by an atypical syndrome including peripheral inflammatory arthritis of unknown cause, without osteoarthritis nor dysplasia. This article suggests that this mutation of COMP is not only causal for idiopathic early-onset osteoarthritis or severe MED, but can also be associated to a broad phenotypic variability with always joint alterations.

A novel homozygous variant of COL2A1 in a Chinese male with type II collagenopathy: a case report

Background Type II collagenopathies are a spectrum of diseases and skeletal dysplasia is one of the prominent features of collagenopathies. Molecular defects of the COL2A1 gene cause type II collagenopathies that is mainly an autosomal dominant disease, whereas some rare cases with autosomal recessive inheritance of mode have also been identified. Case presentation The patient was a 5-year-old male with a short neck, flat face, epiphyseal dysplasia, irregular vertebral endplates, and osteochondritis. Sequencing result indicated NM_001844.4: c.3662C > T; p. (Ser1221Phe) a novel missense variant, leading to a serine-to-phenylalanine substitution. Sanger sequencing confirmed the variant compared to his parents and brother. Conclusions We identified a novel homozygous variant of the COL2A1 gene as the cause of type II collagenopathies in a Chinese male, enriching the spectrum of genotypes. This is the first case of type II collagenopathies inherited in an autosomal recessive manner in China and East Asia, and it is the first case that resulted from serine substitution in the world.

The Early Outcome Of the Bernese Periacetabular Osteotomy For Hip Dysplasia In Multiple Epiphyseal Dysplasia

Background:Multiple epiphyseal dysplasia (MED) is a rare congenital bone dysplasia. Patients with MED develop secondary hip osteoarthritis as early as third to the fourth decade. Currently, there is no consensus on how to prevent or slow the process of secondary hip osteoarthritis.The Bernese periacetabular osteotomy is a joint preserving surgery to reshape acetabulum and extend coverage for the hip, however, there is no established evidence of the effectiveness for the MED hips.Patients and methods:A retrospective series of 6 hips in 3 patients with multiple epiphyseal dysplasia treated with the Bernese periacetabular osteotomy were reviewed. The average age at the time of surgery was 14.3 years (range: 11.4 to 17.2 y). Radiographic parameters were analyzed preoperatively and 1-year postoperatively. The hip function was evaluated by the Harris Hip Score (HHS) before and after surgery. Results:The mean follow-up time was 1.7 years. The mean LCEA increased from 3.8° to 47.1° (p = .02), ACEA increased from 7.3° to 35.1° (p = .02), and AI decreased from 27.8° to 14.6° (p=.04). The femoral head coverage ratio increased from 66.8% to 100% (p= .02). The procedure achieved femoral head medialization by decreasing central head distance from 86.7mm preoperatively to 82.7mm postoperatively, however, without statistical significance. (p = .699). The improvement of clinical outcomes by mean HHS was significant from 67.3 preoperatively to 86.7 postoperatively (p=0.05).Conclusion:Bernese PAO is a feasible option for treatment of the hip problems in MED patients. It reshapes acetabular and femoral morphology 3-dimensionally. In our study, the short-term follow-up results showed obvious functional and radiographic improvement. A long-term follow-up is necessary in the future.

SLC26A2-Associated Diastrophic Dysplasia and rMED—Clinical Features in Affected Finnish Children and Review of the Literature

Diastrophic dysplasia (DTD) is a rare osteochondrodysplasia characterized by short-limbed short stature and joint dysplasia. DTD is caused by mutations in SLC26A2 and is particularly common in the Finnish population. However, the disease incidence in Finland and clinical features in affected individuals have not been recently explored. This registry-based study aimed to investigate the current incidence of DTD in Finland, characterize the national cohort of pediatric subjects with DTD and review the disease-related literature. Subjects with SLC26A2-related skeletal dysplasia, born between 2000 and 2020, were identified from the Skeletal dysplasia registry and from hospital patient registry and their clinical and molecular data were reviewed. Fourteen subjects were identified. Twelve of them were phenotypically classified as DTD and two, as recessive multiple epiphyseal dysplasia (rMED). From the subjects with available genetic data, 75% (9/12) were homozygous for the Finnish founder mutation c.-26+2T>C. Two subjects with rMED phenotype were compound heterozygous for p.Arg279Trp and p.Thr512Lys variants. The variable phenotypes in our cohort highlight the wide spectrum of clinical features, ranging from a very severe form of DTD to milder forms of DTD and rMED. The incidence of DTD in Finland has significantly decreased over the past decades, most likely due to increased prenatal diagnostics.

New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform

This study aims to genetically characterize a two-year-old patient suffering from multiple systemic abnormalities, including skeletal, nervous and developmental involvements and Leber congenital amaurosis (LCA). Genetic screening by next-generation sequencing identified two heterozygous pathogenic variants in nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) as the molecular cause of the disease: c.439+5G>T and c.299+526_*968dup.This splice variant has never been reported to date, whereas pathogenic duplication has recently been associated with cases displaying an autosomal recessive disorder that includes a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and LCA (SHILCA), as well as some brain anomalies. Our patient presented clinical manifestations which correlated strongly with this reported syndrome. To further study the possible transcriptional alterations resulting from these mutations, mRNA expression assays were performed in the patient and her father. The obtained results detected aberrant alternative transcripts and unbalanced levels of expression, consistent with severe systemic involvement. Moreover, these analyses also detected a novel NMNAT1 isoform, which is variably expressed in healthy human tissues. Altogether, these findings represent new evidence of the correlation of NMNAT1 and SHILCA syndrome, and provide additional insights into the healthy and pathogenic expression of this gene.