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