INTRODUCTION
Rare diseases are defined as any disease or condition that affects less
than 200,000 people in the United States1. Because of
their rarity, these conditions are difficult to diagnose and therefore,
the time to diagnosis is prolonged and often involves extensive and
expensive work up (i.e. the diagnostic odyssey). With a prevalence of
< 1/1,000,0002, Schaaf-Yang Syndrome (SYS,
OMIM #615547) caused by pathogenic variants in the MAGEL2 gene, is a
rare disease with a very unspecific phenotype which overlaps with
numerous other more common conditions, hence, defaulting it’s diagnosis
even further. Nonetheless, with the advent of Next Generation Sequencing
(NGS) and with it, broad sequencing techniques, more individuals with
SYS have been identified and some phenotypic-genotypic associations have
been proposed3. However, diagnosis continues to be
delayed and achieved only after extensive work up has been done, without
significant impact in management once diagnosis has been achieved. The
rapid Whole Genome Sequencing (rWGS) protocol was developed at Nicklaus
Children’s Hospital to facilitate the early diagnosis of children with
rare genetic conditions to guide management strategies and improve
long-term outcomes. We report two, genotypically identical but
phenotypically distinct, cases of SYS diagnosed through the rWGS
protocol and propose the early utilization of WGS in patients with
poorly specific presentations to facilitate the diagnosis of patients
with rare genetic diseases. In turn, this will allow for better
understanding of these conditions and guide targeted management
approaches that can positively influence health care outcomes in the
acute and long term settings.
Keywords: MAGEL2, rapid Whole Genome Sequencing,
phenotype-genotype association, ICU