Mucopolysaccharidosis VI (MPS VI)
MPS VI is known as one of the rare types with prevalence ranging from 0.7% to 15% in most of the studied populations. The only exceptions are Brazil with 30% prevalence, and Saudi Arabia where MPS VI is the most common type, accounting for 46.4% of the MPS patients. The demographics of our study were similar to that of Brazil and Saudi Arabia concerning the frequency of MPS VI patients. MPS VI was the third most common type among the Iranian patients, accounting for 22.5% (58/258) of the total number of patients. The high prevalence of MPS VI in this cohort, may be attributed to the high level of consanguinity, which results in the expression of otherwise rare recessive disorders (Costa-Motta et al. 2014). It is also noteworthy that the five frequent variants in ARSB accounted for 55.2% (32/58) of our MPS VI patients, which can support the possible role of founder variants in reinforcing MPS VI in the iranian population.
Geolocalization of the three most common variants in the ARSBgene, c.430G>A, c.962T>C, and c.281C>A, revealed that they are concentrated in certain regions or provinces of Iran, likely to be founder variants (Figure 6). c.430G>A was the most common variant across all MPS types in this study, discovered in 15 patients, whose parents were from the southeastern provinces of Iran. Also, 88.2% (15/17) of MPS VI patients in this region harbored this variant (Supp. Table 1). As a result, a tailored diagnostic approach to MPS VI patients originating from southeast of Iran is hereby suggested, beginning with genetic testing of c.430G>A before employing more comprehensive genetic analysis to decrease the total cost and improve the diagnostic yield.
Six patients diagnosed with c.962C>T, the second most common MPS VI variant, were originally from the northwestern provinces, which are neighboring Turkey and Azerbaijan. This variant has also been reported in the Turkish population with a high prevalence and is believed to be a founder variant in that area (Kantaputra et al. 2014), suggesting the possibility that the origin of this variant in the Iranian and Turkish patients track back to the same ancestor. Moreover, 85.7% (6/7) of MPS VI patients from this region were harboring c.962C>T (Supp. Table 1). The significant prevalence of c.962C>T in the northwestern region justifies checking for this variant in MPS VI patients whose origin track back to these provinces before employing more labor-intensive and demanding techniques.
Four patients with c.281C>A participating in our cohort, were all previously reported in a study carried out on 10 MPS VI Iranian families (Aminzadeh et al. 2019). They suggested that c.281C>A can be “the most common mutation in the Arab Iranian patients with MPS VI”. These patients were born in the Khuzestan province in the southwest of Iran in villages within the same county, and beside the Karun River. These findings are in favor of a founder mutation, especially because this variant has not been reported in other regions of Iran, or other countries. Additionally, genetic analysis of c.281C>A can prove helpful in making a final diagnosis for patients suspected of MPS VI in Khuzestan province using less resources and less-demanding techniques due to the 66.7% (4/6) prevalence of this variant among MPS VI patients in Khuzestan.