A number sign (#) is used with this entry because of evidence that deafness, congenital heart defects, and posterior embryotoxon is caused by heterozygous mutation in the JAG1 gene (601920). One such family has been reported.

Heterozygous mutation in JAG1 can also cause Alagille syndrome-1 (118450) and tetralogy of Fallot (187500).

Le Caignec et al. (2002) described a large kindred with hearing loss, congenital heart defects, and posterior embryotoxon, segregating as autosomal dominant traits. Of the 7 affected patients available for study, 6 manifested mild to severe combined hearing loss, predominantly affecting middle frequencies. Two patients had vestibular pathology. All patients had congenital heart defects, including tetralogy of Fallot, ventricular septal defect, or isolated peripheral pulmonic stenosis. No history of hepatic dysfunction was noted for any of the patients. No individual in the family met diagnostic criteria for any previously described clinical syndrome.

The transmission pattern of DCHE in the family reported by Le Caignec et al. (2002) was consistent with autosomal dominant inheritance.

Using linkage analysis followed by direct sequencing of the JAG1 gene, Le Caignec et al. (2002) identified a novel JAG1 missense mutation, cys234 to tyr (C234Y; 601920.0012), in the first cysteine of the first epidermal growth factor-like repeat domain of the protein.

JAG1 is a transmembrane protein that serves as a ligand for the Notch (see 190198) transmembrane receptors. In functional studies, Bauer et al. (2010) determined that the C234Y mutation resulted in a JAG1 protein that was not present at the cell surface, was not properly posttranslationally modified, and could not initiate Notch signaling. Bauer et al. (2010) predicted that the C234Y mutation led to JAG1 haploinsufficiency, with only the wildtype allele in carriers of the mutation appearing on the cell surface.