PUBLICATION

Biallelic truncating variants in VGLL2 cause syngnathia in humans

Authors: Agostini, V., Tessier, A., Djaziri, N., Khonsari, R.H., Galliani, E., Kurihara, Y., Honda, M., Kurihara, H., Hidaka, K., Tuncbilek, G., Picard, A., Konas, E., Amiel, J., Gordon, C.T.
ID: ZDB-PUB-230905-55
Date: 2023
Source: Journal of Medical Genetics 60(11): 1084-1091 (Journal)
Registered Authors: Amiel, Jeanne, Gordon, Chris
Keywords: congenital, hereditary, and neonatal diseases and abnormalities
MeSH Terms: none
PubMed: 37666660 Full text @ J. Med. Genet.

Abstract

Background Syngnathia 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.

Methods We 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 generate vgll2a and vgll4l germline mutant zebrafish, and performed craniofacial cartilage analysis in homozygous mutants.

Results We 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. The VGLL family of genes encode cofactors of TEAD transcriptional regulators. Vgll2 is regionally expressed in the pharyngeal arches of model vertebrate embryos, and morpholino-based knockdown of vgll2a in zebrafish has been reported to cause defects in development of pharyngeal arch cartilages. However, we did not observe craniofacial anomalies in vgll2a or vgll4l homozygous mutant zebrafish nor in fish with double knockout of vgll2a and vgll4l. In Vgll2^-/- mice, which are known to present a skeletal muscle phenotype, we did not identify defects of the craniofacial skeleton.

Conclusion Our results suggest that although loss of VGLL2 leads to a striking jaw phenotype in humans, other vertebrates may have the capacity to compensate for its absence during craniofacial development.

Genes / Markers

Figures

Show all Figures

Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
vgll2a^ii101/ii101 (AB, TU)	standard conditions	Prim-5	whole organism vgll2a expression absent, abnormal	Fig. 4
vgll2a^ii101/ii101 (AB, TU)	standard conditions	Days 7-13	cranial cartilage morphology, normal	Fig. 4
vgll2a^ii101/ii101; vgll4l^ii103/ii103 (AB, TU)	standard conditions	Days 7-13	cranial cartilage morphology, normal	Fig. 4
vgll2a^ii102/ii102 (AB, TU)	standard conditions	Days 7-13	cranial cartilage morphology, normal	Fig. 4
vgll2a^ii102/ii102; vgll4l^ii103/ii103 (AB, TU)	standard conditions	Days 7-13	cranial cartilage morphology, normal	Fig. 4
vgll4l^ii103/ii103 (AB, TU)	standard conditions	Days 7-13	cranial cartilage morphology, normal	Fig. 4

1 - 6 of 6

Show

Mutations / Transgenics

Allele	Type	Affected Genomic Region
ii101	Small Deletion	vgll2a
ii102	Small Deletion	vgll2a
ii103	Small Deletion	vgll4l

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
cleft palate-lateral synechia syndrome			TAS

Sequence Targeting Reagents

Target	Reagent	Reagent Type
vgll2a	CRISPR3-vgll2a	CRISPR
vgll2a	CRISPR4-vgll2a	CRISPR
vgll2a	CRISPR5-vgll2a	CRISPR
vgll4l	CRISPR2-vgll4l	CRISPR

Fish

Fish
AB/TU
vgll2a^ii101/ii101 (AB, TU)
vgll2a^ii101/ii101; vgll4l^ii103/ii103 (AB, TU)
vgll2a^ii102/ii102 (AB, TU)
vgll2a^ii102/ii102; vgll4l^ii103/ii103 (AB, TU)
vgll4l^ii103/ii103 (AB, TU)

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Agostini et al., 2023 ZDB-PUB-230905-55 PMID:37666660

Biallelic truncating variants in VGLL2 cause syngnathia in humans

Agostini et al., 2023

ZDB-PUB-230905-55
PMID:37666660