Genetically inactivating 1 allele of either Ednra or Bmp4 significantly reduced the penetrance of maxillary malformation in both Six1 <sup>-/-</sup> and Six1 <sup>-/-</sup> Six2 <sup>+/-</sup> embryos, indicating that Six1 and Six2 regulate both endothelin and bone morphogenetic protein-4 signaling pathways to pattern the facial structures.
In conclusion, we show that a de novo variant in SIX1 in a patient with sensorineural hearing loss leads to cochleovestibular malformations and abnormalities of the CVN, without any other abnormalities.
Nevertheless, further studies are necessary to understand if altered SIX1 expression may play a role in human development of kidney and urinary tract congenital anomalies.
These findings uncover an essential role for Six1 in establishing a functionally normal ureter and provide new insights into the molecular basis of urinary tract malformations in BOR patients.
The present, yet preliminary, observation that renal and temporal bone malformations are less frequent in SIX1-related disease suggests a slightly different clinical profile compared to EYA1-related disease.