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Page 20 Pascolini. J Transl Genet Genom 2020;4:17-21. I https://doi.org/10.20517/jtgg.2020.05

triangular face, long philtrum, large and protruding ears, ocular anomalies (hypertelorism, telecanthus, long
palpebral fissures), broad and thick eyebrows, an abnormal nose with anteverted nares and underdeveloped
alae nasi, and malformed teeth (macro-oligodontia, wide upper central or fused incisors, ridged teeth). On
the other hand, a long face with a broad forehead, broad chin, large and protruding ears with overfolded
helices, upslanted palpebral fissures, high and narrow palate with cleft lip/palate, everted lower lip vermilion,
small widely spaced teeth and typical nose morphology (tubular-pear shaped nose with broad nasal tip) define
[12]
KdVS. Interestingly, macrodontia is a frequently observed clinical sign in KBGS (> 80% of patients) ,
[13]
as well as an abnormal nose can also be considered a distinctive KdVS facial dysmorphism . Dental and
nasal malformations, such as a bulbous nose with broad nasal bridge, are also frequently identified in the
SETD5-syndrome, demonstrating a strong overlapping facial gestalt between these three conditions. These
observations could be explained by the common biological cause of the diseases, or mutations in genes
encoding key molecules for histones changes.

Results of the DeepGestalt experiment are in line with the above hypothesis. Specifically, the SETD5-KBGS
comparison analysis demonstrated AUC and ROC values compatible with a high degree of facial overlap, which
was shown by the two overlapping curves in the binary comparison and by the ROC graphic [Figure 1B]. A
minor facial similarity was registered in the SETD5-KdVS comparison. All three conditions were distinctly
recognized by the DeepGestalt technology and the obtained results seem to indicate that this group of
disorders are all characterized by distinctive dysmorphisms, confirming what has recently been illustrated in
[14]
a clinical phenotyping study on ID syndromes related to mutations in histones modifiers .

Furthermore, the DeepGestalt technology has been demonstrated to not be influenced by ethnicity,
according to previously published works, which analyzed the facial features of individuals with different
ancestries and affected by diverse genetic conditions [15-17] . These studies showed that the technology identifies
facial gestalt independently from an individual’s ancestry.

Craniofacial malformations are possibly related to mutations in SETD5, which could be involved in facial
morphogenesis, analogously to other chromatin remodeling genes. For example, ANKRD11 has been
[10]
[18]
demonstrated to influence bone development and facial morphogenesis . Interestingly, the nose and
mouth regions are often malformed in the SETD5-related phenotype. The possible connection between this
gene and the embryological pathways regulating nose and mouth formation could be an interesting area of
research. In this scenario, deregulation of embryonic structures controlling physiological facial development
such as the neural crests, could be further investigated in affected individuals. However, all these have to be
verified in future studies.

In conclusion, a novel study regarding the ID syndrome related to SETD5 mutations by using the
DeepGestalt technology has been here illustrated. The present results highlight the strong facial resemblance
between affected subjects and those with KBGS, suggesting to perform SETD5 analysis in negatives cases
for ANKRD11 mutations. Furthermore, nose and mouth abnormalities should be evaluated with careful
attention in ID individuals because distinctive dysmorphic facies is an important clinical handle. Finally,
a possible role of SETD5 in facial deformities could be hypothesized, based on the demonstrated action of
other histones modifiers on craniofacial development.

DECLARATIONS
Acknowledgments
The author would like to thank Nicole Fleischer who is an employee of FDNA Inc. (Boston, MA, USA), the
company providing Face2Gene, for her kind cooperation in this study.

Authors’ contributions
The author contributed solely to the article.