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Page 266 Lyulcheva-Bennett et al. J Transl Genet Genom 2023;7:259-73 https://dx.doi.org/10.20517/jtgg.2023.33

Notably, the influence of REV3L extends beyond MBS. Another study investigating chromosomal
[33]
imbalances in Poland Syndrome (PS) patients highlighted REV3L’s association with this condition . PS,
which usually presents with pectoralis muscle agenesis and upper limb malformation - a feature also
observed in MBS - revealed that REV3L might act as a PS risk factor. Adding another layer to REV3L’s
significance, a child, without classical MBS but exhibiting developmental delay, was identified with a rare
[34]
homozygous missense REV3L variant with residual protein function . Given that developmental delay
often coexists with MBS, this discovery emphasises the intertwined nature of these conditions.

Given the association of REV3L with intersecting phenotypes, a model emerges: abnormal REV3L function
during early embryonic development could lead to stochastic cell loss due to unrepaired DNA damage. This
could result in a spectrum of overlapping neurodevelopmental disorders. Moreover, given the hypothesis
that vascular disruptions are a primary cause of MBS, it is also possible that abnormal REV3L function
increases neuronal cell sensitivity to ischemic events during early development due to its role in maintaining
mitochondrial genome stability. Of note, unpublished work (Lylcheva-Bennett et al., personal
communication, unpublished work 2023) has identified two unrelated patients in the 100,000 Genomes
[35]
cohort with phenotypic features of “typical MBS” (see Table 1) and likely pathogenic REV3L variants.
Intriguingly, one of the patients showed evidence of mitochondrial depletion in the absence of a
mitochondrial disorder (personal communication).

In summary, while REV3L was initially associated with Moebius Syndrome, its broader role in various
overlapping neurodevelopmental disorders has become evident. Its central function in DNA repair and
mitochondrial genome stability positions it as a cornerstone in understanding the genetic foundations of
these conditions. Continued exploration of REV3L promises to offer invaluable insights, potentially paving
the way for stratified therapeutic strategies for those affected.

PLXND1: another potential contributor to MBS
PLXND1 is another MBS candidate gene reported by Tomas-Roca et al. Through exome sequencing of MBS
patients and their parents, de novo mutations in PLXND1 were identified in several patients . The
[29]
PLXND1 gene is a member of the plexin family that is expressed in various regions of the central nervous
system, including the cranial and spinal ganglia and cortical plate. Plexins are known to bind to
semaphorins, a large family of proteins that play a role in various developmental processes, including the
guidance of axons and the migration of cells [29,36] .

Notably, mice with mutations in Plxnd1 exhibited disruptions in neural pathways, particularly at the facial
branchiomotor nucleus . This disruption affected either the migration or proliferation of motoneurons.
[29]
The facial nerve phenotype observed in these mutant mice mirrored the facial nerve weakness seen in MBS
patients . Furthermore, PLXND1’s involvement in neural migration was highlighted by the observation
[29]
that deficiency in this gene affected the structures of neural fibres in the brain. In particular, there was
consistent hypoplasia of certain brain structures that are essential for neural communication .
[29]

Another study by Glass et al. identified a PLXND1 variant in a child with Moebius syndrome and
[37]
concurrent Poland anomaly . Although the variant was inherited from an unaffected parent, the authors
hypothesise that this may be the consequence of reduced penetrance or due to other variables modifying the
phenotypic expression in genetically predisposed individuals.

Interestingly, although PLXND1 had previously been considered a candidate gene for Hereditary
Congenital Facial Paresis (HCFP) , recent work by Tenney et al. demonstrated that HCFP is caused by
[29]