New JAG1 mutation seen as likely cause of Alagille case
Researchers note 18-year-old's rare eye condition
Researchers have identified a new mutation in the JAG1 gene as the likely cause of Alagille syndrome in an 18-year-old man who also had persistent fetal vasculature (PFV), a rare eye disorder present at birth.
While the patient had several clinical features commonly associated with Alagille syndrome, including heart defects and skeletal anomalies, PFV had not previously been recognized as part of the syndrome’s spectrum.
“Our findings suggest that [eye manifestations] of ALGS [Alagille syndrome] may potentially include PFV,” the researchers wrote.
The study, “A Novel Heterozygous Likely Pathogenic JAG1 Germline Variant in an Adult With Unilateral Persistent Fetal Vasculature,” was published as a research letter in American Journal of Medical Genetics Part A.
Alagille syndrome is a rare genetic disorder most often caused by mutations in the JAG1 gene, which provides instructions for making a protein, called Jagged-1. This protein is part of the Notch signaling pathway, which is essential to guide the development of body structures in a growing embryo.
Bile duct scarcity leads to liver issues
When mutations hit JAG1, the resulting Jagged-1 protein may not work properly, causing errors during early development and ultimately leading to Alagille symptoms.
A hallmark of Alagille is the presence of fewer than normal bile ducts inside the liver. Bile ducts are the series of tubes that transport bile, a digestive fluid, from the liver to the small intestine.
This bile duct paucity causes slowed bile flow, or cholestasis, which in turn leads to toxic accumulation of bile in the liver, damaging the organ and causing symptoms including jaundice (yellowing of the skin and whites of the eyes) and failure to thrive in infancy.
Alagille can also cause heart defects, skeletal and eye abnormalities, blood vessel and kidney issues, along with characteristic facial features.
The full range of symptoms associated with Alagille, especially those involving the eyes and skeleton, is still being defined, the researchers noted.
The team of researchers in the U.S. and U.K. described the case of an 18-year-old man with PFV who was found to carry a previously unreported mutation in the JAG1 gene, which was likely the cause of his Alagille syndrome.
PFV is a rare eye condition in which the blood vessels that are supposed to disappear after birth fail to regress, potentially leading to vision problems and blindness.
“PFV … has been associated with some genetic disorders … but has not been previously linked with the Notch signaling pathway and ALGS [Alagille syndrome],” the researchers wrote.
From birth, the boy showed signs of liver dysfunction, including jaundice and poor growth, though he was never formally diagnosed with cholestasis. He also lost his hearing, showed delays in speech development, had skin and nighttime breathing problems, a curved spine, and PFV in his right eye.
He had other symptoms characteristic of Alagille, including severe heart defects that required surgery during infancy, structural abnormalities in the arteries that carry blood from the heart to the lungs, and butterfly-shaped bones in the spine. He also had distinct facial features, but not the typical ones seen in Alagille.
Genetic testing revealed a new mutation, called c.812G>A (p.Cys271Tyr), in one of the two copies of the JAG1 gene. This mutation was not inherited from either parent, meaning it arose spontaneously in the patient.
The c.812G>A mutation affects a region of the Jagged-1 protein that is critical to maintain the protein’s proper shape and activate the Notch pathway. Based on its novelty, location in a functionally important region, and predicted damaging effect, the variant was classified as likely disease-causing, or pathogenic.
Following the genetic diagnosis, further clinical assessments were conducted, including detailed eye examinations that confirmed PFV and revealed posterior embryotoxon, the most common eye abnormality seen in Alagille patients. However, imaging of the liver did not show the classic scarcity of bile ducts.
“This is the first report of PFV in a patient with a germline likely pathogenic JAG1 variant,” the researchers wrote.
Germline mutations are genetic changes occurring in the in reproductive cells (sperm or egg) that become present in every cell of the body from birth and can be passed to future generations.
“Our observations not only complement the pre-existing body of evidence supporting a crucial role for JAG1 in ocular [eye] development, but also provide evidence for a possible role for JAG1 in patients with PFV,” the researchers wrote.
The findings also “broaden the [clinical] spectrum of ALGS to include PFV, while also underscoring the need for an improved understanding of the molecular mechanisms underpinning the multisystemic manifestations of JAG1-related disorders,” the team concluded.
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