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[38]
noncoding variants affecting GATA2 expression . While PLXND1 has been shown to play an important
role in cardiac development, with biallelic variants in PLXND1 notably associated with congenital heart
[39]
defects , its likely pleiotropic role remains to be fully elucidated.

Future genomic studies
The genetic landscape of Moebius Syndrome is as intricate as its clinical presentation. The heterogeneous
clinical manifestations of MBS may represent the outcome of multiple distinct yet converging pathological
processes. While significant progress has been made in deciphering its genetic aetiology, myriad questions
remain. The inherent complexity of MBS suggests that disruptions in various developmental processes
might converge on a shared outcome. Consequently, multiple genes, each involved in distinct pathways,
might collectively contribute to MBS’s pathophysiology. Only a handful of patients with features of MBS
have been found to have de novo mutations in REV3L and PLXND1 and these findings have so far not been
replicated in other cohorts of MBS patients. It is possible that the interplay between genetic predispositions
and environmental factors might render certain individuals more susceptible to the environmental insults
that precipitate MBS. The potential involvement of multiple genes, each contributing to a shared clinical
outcome, underscores the need for further genetic analyses.

Despite recent advances in genomic medicine, it is estimated that over 6,000 monogenic disorders remain
[40]
unidentified . Therefore, there is a clear need to target research efforts towards candidate disease gene
discovery. One promising approach may be a reanalysis of existing genomic data from recent initiatives
such as the 100,000 Genomes Project, which aims to revolutionise the diagnostic landscape for rare
disorders. As the world’s most ambitious national sequencing initiative, it sought to sequence genomes from
[35]
85,000 patients, prioritising those with unresolved diagnostic needs .

However, the sheer volume of variants in each genome necessitated a focused approach. Analysis was
limited to panels of known disease genes, based on the patient’s phenotype. This method, while efficient,
had its drawbacks and is not suitable for the discovery of novel disease genes.

To delve deeper into MBS’s genetic landscape, we advocate for a meticulous review of the existing genomic
and phenotypic data from projects such as the 100,000 Genomes Project. By scrutinising data from parent-
offspring trios with phenotypic features of MBS, it may be possible to identify novel potential disease-
causing variants. Participation of specialist centres with extensive MBS disease registries would further
bolster such initiatives and other genomic studies. Upon identifying potential candidate genes, rigorous
functional analyses and case series studies will be paramount. Collaboration with research partners to enable
functional characterisation of any candidate genes/variants will further enhance such endeavours.

The analysis and reanalysis of genomic data, especially from initiatives like the 100,000 Genomes Project
and diagnostic Whole Genome or Exome Sequencing, presents a golden opportunity to unravel the genetic
intricacies of rare disorders, including MBS. Future efforts to elucidate the genetic determinants of MBS
should ultimately yield transformative discoveries that can enhance diagnostic capabilities and patient care.

A MULTIDISCIPLINARY APPROACH TO THE MOEBIUS PATIENT
Each patient presents a unique clinical picture, with variations in the challenges they face. As we advance
our understanding of the genomic landscape of MBS, we aspire to harness this knowledge for more precise
prognostication. This will enable us to tailor interventions, ensuring that treatments are promptly initiated
for those who stand to benefit the most.