A novel JAG1 frameshift variant with incomplete penetrance was identified in a female fetus diagnosed with Alagille syndrome (ALGS) in China, as recently published in Clinical Biochemistry.

The heterozygous frameshift variant, c.1794_1797del/p.Cys599ValfsTer143, located at the exon 14 of the JAG1 gene, was inherited from the mother, a 26-year-old female. She presented at the Prenatal Diagnosis and Screening Center, Hangzhou Maternity and Child Health Care Hospital in Zhejiang, China after an abnormal ultrasound result at 26 weeks of gestation.

The fetus showed signs of cardiovascular abnormalities. These included narrow inner diameters of the fetal aorta and the pulmonary artery, with fast blood flow, as well as persistent left superior vena cava and aberrant right subclavian artery. Neither of the parents showed an altered clinical phenotype.

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Karyotype and chromosomal microarray analysis of the amniotic fluid returned normal. However, whole-exome sequencing (WES) of the amniotic fluid and parents’ blood revealed a novel JAG1 variant and disclosed a maternal origin.

The variant was classified as likely pathogenic, according to the American College of Medical Genetics and Genomics guidelines. The results of WES together with the fetus’ clinical phenotype confirmed the diagnosis of ALGS. The parents decided to terminate the pregnancy.

“The identical variant in the mother exhibited incomplete penetrance, but displayed high penetrance in the proband,” the authors said. “The mechanism of this phenomenon is not clear yet, but some researchers propose that additional genes may be involved in the modification of the phenotypes of [ALGS].”

Additionally, WES revealed missense variants of ECE1, MYPN, ROBO4, SCUBE3, and ZIC3 in the fetus. SCUBE3 and ZIC3 may have also contributed to the fetus’ phenotype, albeit the inheritance patterns were not consistent with the associated disorders, they concluded.


Yang Y, Wang H. A novel JAG1 frameshift variant causing Alagille syndrome with incomplete penetrance. Clin Biochem. Published online February 10, 2022. doi:10.1016/j.clinbiochem.2022.02.004