TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis: further evidence supporting the compound inheritance and TBX6 gene dosage model

SAPHO syndrome is predominant in middle-age women, characterized by dermatological and osteoarticular manifestations with unknown aetiology. CT scan and bone scintigraphy are useful for diagnosis. There is still no standard treatment to control the disease.

IntroductionAlthough being debated for many years, the superiority of posterior cruciate-retaining (CR) total knee arthroplasty (TKA) and posterior-stabilized (PS) TKA remains controversial. We compare the knee scores, post-operative knee range of motion (ROM), radiological outcomes about knee kinematic and complications between CR TKA and PS TKA.MethodsLiterature published up to August 2015 was searched in PubMed, Embase and Cochrane databases, and meta-analysis was performed using the software, Review Manager version 5.3.ResultsTotally 14 random control trials (RCTs) on this topic were included for the analysis, which showed that PS and CR TKA had no significant difference in Knee Society knee Score (KSS), pain score (KSPS), Hospital for Special Surgery score (HSS), kinematic characteristics including postoperative component alignment, tibial posterior slope and joint line, and complication rate. However, PS TKA is superior to CR TKA regarding post-operative knee range of motion (ROM) [Random Effect model (RE), Mean Difference (MD) = -7.07, 95% Confidential Interval (CI) -10.50 to -3.65, p<0.0001], improvement of ROM (Fixed Effect model (FE), MD = -5.66, 95% CI -10.79 to -0.53, p = 0.03) and femoral-tibial angle [FE, MD = 0.85, 95% CI 0.46 to 1.25, p<0.0001].ConclusionsThere are no clinically relevant differences between CR and PS TKA in terms of clinical, functional, radiological outcome, and complications, while PS TKA is superior to CR TKA in respects of ROM, while whether this superiority matters or not in clinical practice still needs further investigation and longer follow-up.

With the recent advance in genome-wide association studies (GWAS), disease-associated single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) have been extensively reported. Accordingly, the issue of incorrect identification of recombination events that can induce the misannotation of multi-allelic or hemizygous variants has received more attention. However, the potential distorted calculation bias or significance of a detected association in a GWAS that may result due to the coexistence of CNVs and SNPs in the same genomic region may remain under-recognized. Here we performed the association study within a congenital scoliosis (CS) cohort whose genetic etiology was recently elucidated as a compound inheritance model including mostly one rare variant deletion CNV allele and one common variant noncoding hypomorphic haplotype of the TBX6 gene. We demonstrate that the existence of a deletion in TBX6 led to an overestimation of the contribution of the SNPs on the hypomorphic allele. Furthermore, we generalized a model to explain the calculation bias, or distorted significance calculation for an association study that can be ‘induced’ by CNVs at a locus. Meanwhile, overlapping between the disease-associated SNPs from published GWAS and common CNVs (overlap 10%) and pathogenic/likely pathogenic CNVs (overlap 99.69%) was significantly higher than the random distribution (p<1×10−6 and p=0.034, respectively), indicating that such locus co-existence of CNV and SNV alleles might generally influence data interpretation and potential outcomes of a GWAS. We also verified and assessed the influence of colocalizing CNVs to the detection sensitivity of disease-associated SNP variant alleles in another adolescent idiopathic scoliosis (AIS) genome-wide association study. We propose that detecting co-existent CNVs when evaluating the association signals between SNPs and disease traits may improve genetic model analyses and better integrate. GWAS with robust Mendelian principles