Microhomology-mediated mechanisms underlie non-recurrent disease-causing microdeletions of the FOXL2 gene or its regulatory domain.

Genomic disorders are often caused by recurrent copy number variations (CNVs), with nonallelic homologous recombination (NAHR) as the underlying mechanism. Recently, several microhomology-mediated repair mechanisms--such as microhomology-mediated end-joining (MMEJ), fork stalling and template switching (FoSTeS), microhomology-mediated break-induced replication (MMBIR), serial replication slippage (SRS), and break-induced SRS (BISRS)--were described in the etiology of non-recurrent CNVs in human disease. In addition, their formation may be stimulated by genomic architectural features. It is, however, largely unexplored to what extent these mechanisms contribute to rare, locus-specific pathogenic CNVs. Here, fine-mapping of 42 microdeletions of the FOXL2 locus, encompassing FOXL2 (32) or its regulatory domain (10), serves as a model for rare, locus-specific CNVs implicated in genetic disease. These deletions lead to blepharophimosis syndrome (BPES), a developmental condition affecting the eyelids and the ovary. For breakpoint mapping we used targeted array-based comparative genomic hybridization (aCGH), quantitative PCR (qPCR), long-range PCR, and Sanger sequencing of the junction products. Microhomology, ranging from 1 bp to 66 bp, was found in 91.7% of 24 characterized breakpoint junctions, being significantly enriched in comparison with a random control sample. Our results show that microhomology-mediated repair mechanisms underlie at least 50% of these microdeletions. Moreover, genomic architectural features, like sequence motifs, non-B DNA conformations, and repetitive elements, were found in all breakpoint regions. In conclusion, the majority of these microdeletions result from microhomology-mediated mechanisms like MMEJ, FoSTeS, MMBIR, SRS, or BISRS. Moreover, we hypothesize that the genomic architecture might drive their formation by increasing the susceptibility for DNA breakage or promote replication fork stalling. Finally, our locus-centered study, elucidating the etiology of a large set of rare microdeletions involved in a monogenic disorder, can serve as a model for other clustered, non-recurrent microdeletions in genetic disease.

A prospective randomised comparison of earlier function after total hip arthroplasty with a mini posterior approach or supercapsular percutaneously-assisted total hip approach: a gait analysis study.

BACKGROUND: The supercapsular percutaneously-assisted total hip (SuperPATH) approach is a muscle sparing surgical technique for total hip arthroplasty (THA). The literature reports good clinical and functional results of the SuperPATH technique in the short term. We aimed to compare early outcomes and gait analysis of THA using the mini posterior approach (MPA) and supercapsular percutaneously-assisted total hip (SuperPATH) approach. METHODS: 44 patients who underwent THA, were randomly allocated to either MPA or SuperPATH. The data were then collected prospectively (preoperatively and postoperatively at 6 weeks). Plain anteroposterior radiographs of the pelvis and instrumental gait analysis were obtained. The visual analogue scale (VAS), Harris Hip Score (HHS) and Hip disability and Osteoarthritis Outcome Scores (HOOS) were used to assess functional and clinical outcomes. RESULTS: No significant difference was found in patients' surgical outcomes. Patients in the SuperPATH group had less pain according to the VAS score at follow-up than the MPA group (p < 0.01). There was also a significant improvement in HHS and HOOS scores for all patients (p < 0.001) with the SuperPATH group showing superior changes. The comparison of mean differences in gait velocity between preoperative and 6 weeks postoperative result, revealed improvement in the SuperPATH group over the MPA group (p = 0.06). Limping was more persistent in the MPA group. Kinematic parameters demonstrated improved hip joint excursion slightly higher in the MPA group. There was no significant improvement in kinetic and kinematic parameters at different walking moments for all patients at 6 weeks compared to preoperative gait patterns. CONCLUSIONS: SuperPATH and MPA both show excellent results. This study reveals that the SuperPATH technique was associated with lower postoperative pain levels, and higher physical function and quality of life. Improved functional outcomes allowed earlier postoperative rehabilitation and faster recovery. Specific improvement in gait patterns were identified with nonsignificant differences between the 2 approaches at 6 weeks follow-up.