Current needs in the SYS research world
The current knowledge available about the natural presentation and course of SYS is limited. In January 2019, the SYS/MAGEL2 Advisory Group outlined the needs of SYS research, which include identifying the full phenotypic spectrum of SYS, establishing standards of care for individuals with SYS, and understanding the SYS patient’s perspective to improve outcomes 17.
While patient 1 and patient 2 presented close in time with similar clinical presentation, enough differences existed to keep the patients distinct. It was the utilization of rapid whole genome sequencing that found the commonality between these two patients, which might have not been achieved based on clinical criteria only. McCarthy et al, 2018 noted that based on clinical presentation, several different conditions may be caused by truncating mutations in MAGEL2 . In fact, individuals initially diagnosed with Opitz Trigonocephaly C syndrome, Chitayat-Hall syndrome, and Arthrogryposis Multiplex Complex diagnoses were found to have truncating mutations in MAGEL2.18-21 Thus, many more cases of SYS may exist that can add to the variable phenotypic picture that exists today. Nevertheless, this wide phenotypic spectrum that is characteristic of SYS represents an obstacle for reaching a diagnosis as patients typically undergo extensive workup prior to achieving the diagnosis of SYS. This is especially important considering that the MAGEL2gene is not included in many gene panels and is, therefore, typically only identified through broad testing options (i.e. expanded panels, whole exome sequencing (WES ) and WGS). For both of our patients, early diagnosis was achieved through the rWGS protocol, which allowed for rapid turnaround of results in the acute setting.
With whole genome sequencing becoming more accessible22, this diagnostic odyssey can be shortened, saving both time and other valuable resources for families and the community. An earlier diagnosis can also have a significant impact in care outcomes by guiding decision-making in the acute care setting, especially now with some available knowledge about certain phenotype-genotype associations that could influence those decisions. An example of this would be earlier tracheostomy placement based on the expected prognosis associated with the p.Gln666ProfsTer47 MAGEL2variant, as multiple studies (in both children and adults) have reported improved medical outcomes associated with earlier tracheostomy in critically ill patients.23-25