In this family, whole-exome sequencing yielded rare, simultaneously heterozygous variants in the Aicardi-Goutières syndrome (AGS) genes ADAR and RNASEH2B co-segregating with the tumor phenotype.
To estimate the frequency of JAG1 mutations in cases with right-sided cardiac defects not otherwise diagnosed with AGS, we screened 94 cases with tetralogy of Fallot (TOF) and 50 with pulmonic stenosis/peripheral pulmonary stenosis (PS/PPS) or pulmonary valve atresia with intact ventricular septum (PA) for mutations.
Alagille syndrome (AGS) is caused by heterozygous mutations in JAG1, and mutations have been previously reported in about 70% of patients who meet clinical diagnostic criteria.
To identify the cause of disease in patients without JAG1 mutations, we screened 11 JAG1 mutation-negative probands with AGS for alterations in the gene for the Notch2 receptor (NOTCH2).
Here, we show that TREX1, encoding the major mammalian 3' --> 5' DNA exonuclease, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity.
In conclusion, mutant JAG1 transcripts are present in LCLs, livers and tissues of AGS patients, whatever the mutation type, and mutant proteins can be produced, suggesting a dominant negative effect of some mutant proteins as another molecular mechanism of AGS.
We have studied a JAG1 missense mutation (JAG1-G274D) that was previously identified in 13 individuals from an extended family with cardiac defects of the type seen in patients with AGS (e.g., peripheral pulmonic stenosis and tetralogy of Fallot) in the absence of liver dysfunction.
The results of this study are consistent with the proposal that either haploinsufficiency for wild-type JAG1 and/or dominant negative effects produced by mutated JAG1 are responsible for the AGS phenotype.