Biallelic truncating variants inVGLL2cause syngnathia in humans

Abstract

BackgroundSyngnathia is an ultrarare craniofacial malformation characterised by an inability to open the mouth due to congenital fusion of the upper and lower jaws. The genetic causes of isolated bony syngnathia are unknown.MethodsWe used whole exome and Sanger sequencing and microsatellite analysis in six patients (from four families) presenting with syngnathia. We used CRISPR/Cas9 genome editing to generatevgll2aandvgll4lgermline mutant zebrafish, and performed craniofacial cartilage analysis in homozygous mutants.ResultsWe identified homozygous truncating variants in vestigial-like family member 2 (VGLL2) in all six patients. Two alleles were identified: one in families of Turkish origin and the other in families of Moroccan origin, suggesting a founder effect for each. A shared haplotype was confirmed for the Turkish patients. TheVGLLfamily of genes encode cofactors of TEAD transcriptional regulators.Vgll2is regionally expressed in the pharyngeal arches of model vertebrate embryos, and morpholino-based knockdown ofvgll2ain zebrafish has been reported to cause defects in development of pharyngeal arch cartilages. However, we did not observe craniofacial anomalies invgll2aorvgll4lhomozygous mutant zebrafish nor in fish with double knockout ofvgll2aandvgll4l. InVgll2−/−mice, which are known to present a skeletal muscle phenotype, we did not identify defects of the craniofacial skeleton.ConclusionOur results suggest that although loss ofVGLL2leads to a striking jaw phenotype in humans, other vertebrates may have the capacity to compensate for its absence during craniofacial development.