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Background：Congenital scoliosis (CS) is a spinal deformity due to vertebral malformations. Although insufficiency of TBX6 dosage contributes to a substantial proportion of CS, the molecular etiology for the majority of CS remains largely unknown. TBX6‐mediated genes involved in the process of somitogenesis represent promising candidates.Methods：Individuals affected with CS and without a positive genetic finding were referred to this study. Proband‐only exome sequencing (ES) were performed on the recruited individuals, followed byanalysis of TBX6‐mediated candidate genes, namely MEOX1, MEOX2, MESP2, MYOD1, MYF5, RIPPLY1, and RIPPLY2.Results：A total of 584 patients with CS of unknown molecular etiology were recruited. After ES analysis, protein‐truncating variants in RIPPLY1 and MYF5 were ：identified from two individuals, respectively. In addition, we identified five deleterious missense variants (MYOD1, n = 4; RIPPLY2, n = 1) in TBX6‐mediated genes. We observed a significant mutational burden of MYOD1 in CS (p = 0.032) compared with the in‐house controls (n = 1854). Moreover, a potential oligogenic disease‐causing mode was proposed based on the observed mutational co‐existence of MYOD1/MEOX1 and MYOD1/RIPPLY1.Conclusion：Our study characterized the mutational spectrum of TBX6‐mediated genes, prioritized core candidate genes/variants, and provided insight into a potential oligogenic disease‐causing mode in CS.
Background：Multiple epiphyseal dysplasia (MED) is a skeletal disorder characterized by delayed and irregular ossification of the epiphyses and early-onset osteoarthritis. At least 66% of the reported autosomal dominant MED (AD-MED) cases are caused by COMP mutations.Methods：We recruited a four-generation Chinese family with early-onset hip osteoarthritis, flatfoot, brachydactyly, and mild short stature. An assessment of the family history, detailed physical examinations, and radiographic evaluations were performed on the proband and other family members, followed by the performance of whole-exome sequencing (WES). The pathogenicity of the candidate mutation was also analyzed.Results：An AD-MED family with 10 affected members and 17 unaffected members was recruited. The main radiographic findings were symmetrical changes in the dysplastic acetabulum and femoral heads, irregular contours of the epiphyses, a shortened femoral neck, and flatfoot. Lower bone density was also observed in the ankle joints, wrist joints, and knees, as well as irregular vertebral end plates. In the proband, we identified the missense mutation c.1153G > T (p. Asp385Tyr), located in exon 11 of the COMP gene. This mutation was assessed as 'pathogenic' because of its low allele frequency and its high likelihood of co-segregation with disease in the reported family. Sanger sequencing validated the novel heterozygous mutation c.1153G > T (p. Asp385Tyr) in exon 11 of COMP in all affected individuals in the family.Conclusions：Our results underlined a key role of the Asp385 amino acid in the protein function of COMP and confirmed the pathogenicity of the COMP (c.1153G > T; p. Asp385Tyr) mutation in AD-MED disease. We have therefore expanded the known mutational spectrum of COMP and revealed new phenotypic information for AD-MED.
Background：Klippel-Feil syndrome (KFS) represents a rare anomaly characterized by congenital fusion of the cervical vertebrae. The underlying molecular etiology remains largely unknown because of the genetic and phenotypic heterogeneity.Methods：We consecutively recruited a Chinese cohort of 37 patients with KFS. The clinical manifestations and radiological assessments were analyzed and whole-exome sequencing (WES) was performed. Additionally, rare variants in KFS cases and controls were compared using genetic burden analysis.Results：We primarily examined rare variants in five reported genes (GDF6, MEOX1, GDF3, MYO18B and RIPPLY2) associated with KFS and detected three variants of uncertain significance in MYO18B. Based on rare variant burden analysis of 96 candidate genes related to vertebral segmentation defects, we identified BAZ1B as having the highest probability of association with KFS, followed by FREM2, SUFU, VANGL1 and KMT2D. In addition, seven patients were proposed to show potential oligogenic inheritance involving more than one variants in candidate genes, the frequency of which was significantly higher than that in the in-house controls.Conclusions：Our study presents an exome-sequenced cohort and identifies five novel genes potentially associated with KFS, extending the spectrum of known mutations contributing to this syndrome. Furthermore, the genetic burden analysis provides further evidence for potential oligogenic inheritance of KFS.
Background：Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity, but its etiology is unclear. Multiple genetic mutations have been reported to be associated with AIS.Material/Methods：We enrolled a cohort of 113 surgically treated AIS patients with available parental subjects from the Peking Union Medical College Hospital. We performed whole-exome sequencing in 10 trio families and whole-genome sequencing in 103 singleton patients. Luciferase assay was used to detect the functional alterations of candidate ESR1 and ESR2 variants.Results：Using a de novo strategy, a missense variant in ESR1 (c.868A>G) was selected as a candidate gene for AIS. The main Cobb angle of this patient was 41° (T6–T10). Another potential pathogenic variant in ESR2 (c.236T>C) was identified. The main curve of the patient was 45° at T10–L3. The transactivation capacities of the mutated ESR1 and ESR2 protein were both significantly decreased (p=0.026 and 0.014, respectively).Conclusions：Potential pathogenic variants in ESR1 and ESR2 were identified in 113 AIS patients, suggesting that genetic mutations in ESR1/2 were associated with the risk of AIS.
Objective：Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome encompasses heterogeneous dermatological manifestations, mainly palmoplantar pustulosis (PPP) and severe acne (SA). This study aims to explore the necessity of stratified management according to skin lesions. Methods：In a cohort of SAPHO patients, we compared the demographic, clinical, and scintigraphic characteristics of the SAPHO patients whose skin lesion was PPP or SA. Results： A total of 249 patients were included (227 affected by PPP and 22 affected by SA). Patients with SA were younger at onset (20, interquartile ranges (IQR) 15–30 vs. 37, IQR 30–46 years old; p < 0.001) and enrollment (35, IQR 25–38 vs. 41, IQR 33–50 years old; p = 0.001), and they had a prolonged disease duration (88.5 months, IQR 18.7–216.0 vs. 16.0, IQR 7.0– 48.0 months; p < 0.001) and time needed for diagnosis (7.5, IQR 2.0–19.0 vs. 1.0, IQR 1.0–4.0 years; p < 0.001). Adjusted by age, sex, and disease duration, SA was significantly associated with more disease-modifying anti-rheumatic drug (DMARD) use (adjusted odds ratio (OR) 3.72; 95% confidence interval (CI) 1.23, 12.62; p = 0.019) and more sternoclavicular joint involvement (adjusted OR 5.91; 95% CI 1.17, 61.3; p = 0.030) in two separate Firth's logistic regression models. Conclusion： SAPHO patients affected by PPP or SA as the only skin lesion may have different epidemiologic features, osteoarticular manifestations, and treatment history.
Abstract: Tumour‐induced osteomalacia (TIO) is a very rare paraneoplastic syndrome with bone pain, fractures and muscle weakness, which is mostly caused by phosphaturic mesenchymal tumours (PMTs). Cell‐free DNA (cfDNA) has been regarded as a non‐invasive liquid biopsy for many malignant tumours. However, it has not been studied in benign tumours, which prompted us to adopt the targeted next‐generation sequencing approach to compare cfDNAs of 4 TIO patients, four patients with bone metastasis (BM) and 10 healthy controls. The mutational landscapes of cfDNA in TIO and BM groups were similar in the spectrum of allele frequencies and mutation types. Markedly, deleterious missense mutations in FGFR1 and loss‐of‐function mutations in MED12 were found in 3/4 TIO patients but none of BM patients. The gene ontology analysis strongly supported that these mutated genes found in TIOs would play a potential role in PMTs' process. The genetic signatures and corresponding change in expression of FGFR1 and FGF23 were further validated in PMT tissues from a test cohort of another three TIO patients. In summary, we reported the first study of the mutational landscape and genetic signatures of cfDNA in TIO/PMTs.
Abstract:Vertebral malformations (VMs) are caused by alterations in somitogenesis and mayoccur in association with other congenital anomalies. The genetic etiology of mostVMs remains unknown and their identification may facilitate the development ofnovel therapeutic and prevention strategies. Exome sequencing was performed onboth the discovery cohort of nine unrelated probands from the USA with VMs andthe replication cohort from China (Deciphering Disorders Involving Scoliosis &COmorbidities study). The discovery cohort was analyzed using the PhenoDB analysis tool.Heterozygous and homozygous, rare and functional variants were selected and evaluated for their ClinVar, HGMD, OMIM, GWAS, mouse model phenotypes, and otherannotations to identify the best candidates. Genes with candidate variants in three ormore probands were selected. The replication cohort was analyzed by another inhouse developed pipeline. We identified rare heterozygous variants in KIAA1217 infour out of nine probands in the discovery cohort and in five out of 35 probandsin the replication cohort. Collectively, we identified 11 KIAA1217 rare variants in10 probands, three of which have not been described in gnomAD and one of which isa nonsense variant. We propose that genetic variations of KIAA1217 may contributeto the etiology of VMs.
Please find at: ((((Nan Wu[Author]) OR Zhihong Wu[Author]) OR Guixing Qiu[Author])) AND peking union medical college hospital
Department of orthopedic surgery, Peking Union Medical College Hospital (PUMCH), Peking Union Medical College (PUMC) & Chinese Academy of Medical Sciences (CAMS)
Beijing Key Laboratory for Genetic Research of Skeletal Deformity
Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences
Address: Department of orthopedic surgery, Peking Union Medical College Hospital, No.1 Shuaifuyuan, Dongcheng District, Beijing 100730, China