Molecular Diagnosis And Clinical Significance Of Early-onset Scoliosi

Background and ObjectivesEarly-onset scoliosis(EOS)refers to scoliosis whose onset age is earlier than ten years old.EOS can lead to progressive deformity in appearance and impair pulmonary function,conveying significant harm to children’s mobility and health.Given the complex etiology of EOS with the involvement of multiple genetic factors,identification of the underlying molecular cause is important for the clinical management and prenatal screening of EOS.With the rapid development of molecular techniques,exome sequencing(ES)has become one of the most important methods of genetic testing and has been used extensively in multiple hereditary diseases.However,the implementation of ES in large EOS cohort is still lacking.Materials and MethodsIn this study,we recruited 447 patients with EOS who underwent surgical treatment at Peking Union Medical College Hospital(PUMCH).We performed ES on the probands and available parents,totaling 670 subjects.In addition,ES results from 13 American patients with idiopathic EOS were also included in this study.The PUMCH Pipeline was used for bioinformatic analyses and variant interpretation.In addition to diagnostic variants,we also analyzed potential secondary findings in genes recommended by the ACMG.We then performed phenotypic analysis using the Random Forest algorithm.ResultsOf the 447 patients with EOS,92(20.6%)received molecular diagnoses.Fortyone of the patients were diagnosed as TBX6-associated congenital scoliosis.Forty-six patients received molecular diagnoses of various Mendelian diseases.We also found five patients solved by copy number variants,including two 16p13.1 duplication,one 22q11.2 deletion,one 5q35.3 deletion,and one 17q11.2 deletion.We identified nine clinical actionable secondary findings in the ACMG-recommended genes,including BRCA1,BRCA2,APC,RET,TSC2,COL3A1,and LDLR.Of the 92 patients with molecular diagnoses,84 patients were reclassified as syndromic scoliosis from other EOS groups.One of the thirteen patients with IEOS from the American cohort received a molecular diagnosis.The onset age,number of organs involved and Cobb angle are the three most important features predictive of a potential molecular diagnosis.ConclusionImplementation of ES yielded a considerable molecular diagnosis rate in patients with EOS.The genetic architecture of EOS is highly heterogeneous.The onset age,the number of organs involved and the Cobb angle could be used in determining whether genetic testing should be ordered for patients with EOS.