SMO mutation findings in HPE patients
We recently reported the results of a Targeted Capture analysis of 153
developmental genes (and a similar number of conserved non-coding
elements) among 333 HPE probands in an effort to identify both driver
mutations and potential modifiers (Roessler et al., 2018a). TheSMO gene was identified as a potential candidate gene based on
the identification of six families with gene variants of undetermined
significance. As described in Table 1, two of these families had a
detectable driver mutation with a co-morbid variant in SMO (see
summary Suppl. TableS7, and annotations for each proband Tables S8-13).
In order to better understand the potential roles of these variants we
developed functional studies.
Proband #1 has a maternal FGF8 driver mutation yet also
inherited a complex SMO variant with two variants of uncertain
significant (VOUS, in cis ) from the father (Hong et al., 2018).
We chose to investigate both SMO variants individually to better
determine the potential for digenic inheritance in this case. Similarly,
although proband #6 has a typical de novo driver mutation inSHH , we chose to directly examine the predicted “likely benign”
predictions for the co-inherited SMO variant. Our working
hypothesis continues to be that modifier genes need not meet the same
guideline considerations as more conspicuous driver mutations with
respect to allele frequency (Hong et al., 2017; Roessler et al., 2018a;
Roessler et al., 2018b).
Probands #2 and #3 present with findings that appear to reflect common
benign SMO variants inherited from otherwise healthy parents. In
neither case are the potentially co-morbid alterations predicted to be
functionally abnormal. In the case of proband #3, almost all of the
co-variants were inherited from the healthy father suggesting that even
if they had synergistic effects it would raise the question of why the
father was not similarly affected. Nevertheless, we included theseSMO variants as likely negative controls.
Probands #4 represents a similar case of exclusive maternal inheritance
of the potentially interacting loci. Although the SMO variant is
common in the general population it is predicted to be deleterious.
Thus, since we classified it as a rare VOUS we felt compelled to try to
determine its biological activity.
Perhaps the most interesting SMO variant was identified in
proband #5 as an initially novel alteration of p.V404M. Later it was
identified as a single detection in the gnomad data base. Its rarity and
location in the heptahelical domain suggested that of the seven variants
identified in HPE probands this missense alteration deserved closer
examination in functional studies.