Peters. S.U., Fu. C., Suter,B., Marsh, E., Benke, T.A., Skinner, S.A., Lieberman, D.N., Stanbridge, S., Jones, M., Beisang, A., Feyma, T. Heydeman, P. Ryther, R., Kaufmann, W.F., Glaze, D.G., Neul, J.L., & Percy, A.K. (2019). Characterizing the Phenotypic Effect of Xq28 Duplication Size in MECP2 Duplication Syndrome. Clinical Genetics, doi.org/10.1111/cge.13521
It is great to see research on MECP2 duplication syndrome emerging from the NIH Rare Diseases Clinical Research Network Rett syndrome, MECP2 Duplication disorder, and Rett-related disorders Consortium, This research, published electronically on 20 February 2019, provides some important new insights into the role of additional genes in MECP2 duplication syndrome.
This is great news, both because it is good to see this research project starting to produce published results and because this study opens a new area for further study. Dr. Peters and her colleagues suggest that several other genes may contribute to the overall severity of MECP2 duplication. The authors use some existing measures of severity to determine the relationship between duplicated genes and overall severity. They go on to advocate for the creation of a comprehensive instrument for assessing severity of MECP2 duplication syndrome.
In addition to MECP2, some of the other genes suspected of contributing to severity are RAB39B, L1CAM, SRPK3, GDI1, and FLNA. Of these only RAB39B, was demonstrated to be a predictor of severity. Others did not reach statistical significance. While it is important to remember that both positive and negative findings regarding the significance of these genes need to be interpreted with caution due to inherent limitations of this study, such as a fairly small number of individuals studied and the natural sequence of genes which results in strong correlation between specific genes and their neighboring genes. Nevertheless, this study provides important evidence that it is at least likely that additional gene duplications play an important role, and it is consistent with previuos studies that report Xq28 syndromic findings in individuals with duplications of GDI1 and RAB39B without MECP2 duplication (see for example, Yamamoto, 2014; OMIM Xq28 duplication syndrome).
The researchers also suggest that length of duplication is correlated with severity. If we accept that the specific genes (in addition to MECP2) are relevant to severity, this is at least in part an inevitable outcome of the influence of additional genes. For example, if we accept that the researchers are correct that duplication of RAB39B increases severity, most of the shorter duplications are too short to include RAB39B because of its distance from MECP2. Since, RAB39B is located distally to MECP2, it remains possible that duplications of the same lengths but extending proximally will have entirely different effects. In fact, the figure included in the study shows one lengthy (approximately 4Mb) duplication associated with relatively mild effects. If length is treated as a variable in future research, it may be useful to consider length proximal to MECP2 and length distal to MECP2 as separate variables.
There are also examples of relatively short duplications with severe presentations and relative long duplications with mild presentations. In addition, two of the shortest duplications shown, involving the same genes and almost identical in length, were ranked in one case the most severe and the other near the mildest end of the spectrum. It would be very unfortunate if professionals began to assume prognoses and families based expectations on the length of the duplication.
It is also important to note that the the range of duplication sizes was very large in this sample. The longest was almost 70 times the length of the smallest and contained many more genes and the correlation between size and severity was statistically significant but weak (r=0.31 -0.36). Considering these concerns, the finding is important because it can help guide future research but has minimal predictive power, but it should not be overinterpreted to suggest that duplication length is a good clinical predictor of severity.
Larger samples will help clarify these results in future studies. As more families enroll in the Natural History Study, the power of forthcoming studies will improve. Families who want to see progress in research on MECP2 duplication syndrome can help move things forward by enrolling.
The authors point out the need to develop better and more comprehensive severity measures for MECP2 duplication syndrome. This is an important point since an appropriate scale may have clinical value as well as supporting future research. One of the challenges of creating a useful severity scale will be the diversity of symptoms associated with MECP2 duplication syndrome. A comprehensive scale may require multiple subdomains, each with its own score and a strategy for weighting them for an overall score. For example, one individual may have greater impact on developmental milestones but lesser impact on immune deficiency while a second may have more impact on immune deficiency but lesser on developmental milestones. If an overall severity score is measured how do we compare the two and weight each domain?