Clinical Interpretations
As part of the IMPRESsion study, we included a list of clinical features associated with the different types of MPS, which clinicians were asked to fill out. The heatmap of the clinical features associated with each MPS type is depicted in Figure 2. In general, the trends and patterns observed in the heatmap are in line with previous findings. As with other literature reports, our analysis revealed that MPS I, MPS II, and MPS VI share a wide range of symptoms, and the heatmap indicates that symptoms are more concentrated in the same areas for these three types. However, there were no reports of corneal opacity, visual impairment, and cardiac valve defect among MPS II patients participating in our study, while these clinical features have been reported in previous studies (Martin et al. 2008; Montano et al. 2016; Muenzer et al. 2009, 2011). High occurrence of developmental and neurological problems among our MPS III patients was also suggested by the literature, as well as the rarity of skeletal abnormalities (M. J. Valstar et al. 2010). Moreover, the symptoms of MPS IV patients in our study fell in line with the known symptoms of this disease, with a high frequency of skeletal abnormalities and no cognitive impairment reported in our patients (Northover, Cowie, and Wraith 1996; Tomatsu et al. 2011).
Treatment of MPS is highly contingent on the type of the disease, which can be conclusively determined by molecular studies. While NGS provides a way to analyze all MPS genes with high specificity, it is an expensive technique, which requires well-equipped labs with high standards and specialized technicians. On the other hand, Sanger sequencing is a less complicated and more commonly available technique. By cross-referencing geographical patterns of frequent variants, it is possible to develop a stepwise diagnostic approach that can be used on clinically diagnosed MPS patients before they undergo costly biochemical assays or NGS analysis. This method can be helpful since we were able to identify variants that account for a significant proportion of the MPS patients originating from specific geographical regions as well as a few possible founder mutations. To illustrate, the c.430G>A in ARSB is concentrated in the southeastern regions of Iran, accounting for 88.2% of MPS VI patients, while c.962C>T is responsible for 85.7% of MPS VI cases in northwestern regions. Such patterns justify checking for c.430G>A and c.962C>T in MPS VI patients originating respectively from southeast or northwest before going through further diagnostic approaches, which could lead to a conclusive result at a fraction of the cost and effort. The same approach is suggested for MPS IV patients originating from East Azerbaijan, where c.319G>A in GALNS is responsible for 50% of MPS IV patients. Therefore, a stepwise genetic testing starting from c.319G>A analysis can be considered before performing a more comprehensive analysis.