New JAG1 mutations seen as likely cause of Alagille in 2 young boys

Researchers have identified two new mutations in JAG1, a gene linked to Alagille syndrome, that each resulted in a unique clinical profile for two young boys diagnosed with the disease after genetic testing.

“This study highlights the significance of genetic testing and comprehensive clinical assessments in improving the time to diagnosis and the clinical management and treatment of this complex syndrome,” the researchers wrote.

The variable nature of Alagille symptoms “can lead to challenges in accurately diagnosing affected infants, potentially resulting in misdiagnoses or underdiagnoses,” the team noted, stressing the importance of such genetic testing.

The clinical pictures of the two boys were described in the new study, titled “Novel JAG1 variants leading to Alagille syndrome in two Chinese cases” and published in Scientific Reports.

JAG1 gene provides instruction for protein needed in embryo development

Alagille syndrome is most often caused by mutations in the JAG1 gene, which provides instruction to produce a protein, Jagged-1, that is needed for normal embryonic development. When Jagged-1 is faulty, errors may occur during early development, ultimately resulting in Alagille syndrome features.

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 cholestasis, or the slowing or stalling of bile flow, which results in toxic bile buildup in the liver and bile leakage into the bloodstream.

Besides bile duct paucity, the disease spans “a wide spectrum of clinical manifestations affecting multiple organ systems, including the … heart, bones, eyes, face, and kidneys,” the researchers wrote.

Because symptoms of Alagille syndrome vary so widely, misdiagnoses or delayed diagnoses can occur, which “can lead to inappropriate therapeutic interventions,” the researchers wrote. Thus, to be able to confirm a diagnosis with genetic testing, it is important to broaden the spectrum of known disease-causing mutations.

Now, a team of researchers in China described the clinical profiles of two boys who were found to carry JAG1 mutations that likely were the cause of their Alagille syndrome.

The first boy was born small, via cesarean section. Due to his low birth weight, he stayed in the hospital for one week. About three weeks later, he was hospitalized again due to jaundice — a yellowing of the skin and the whites of the eyes often occurring with liver problems — and signs of hypothyroidism, or reduced thyroid function.

A common Alagille symptom, jaundice is caused by too much bilirubin, a yellow-orange bile pigment, in the blood. The thyroid, a gland located in the neck, is responsible for the production of hormones involved in the body’s metabolic rate, growth, and development.

Imaging scans revealed no abnormalities in the thyroid gland, bones, kidneys, or liver, though the infant’s liver was found to be enlarged.

One patient inherited mutation from his father

At the age of 2 months, a liver biopsy revealed inflammation and tissue scarring, as well as the absence of bile ducts inside the liver. This prompted genetic testing, which revealed a previously unknown JAG1 mutation called c.974delC (p.Pro325Leufs*87).

The mutation was inherited from his father, who had a history of jaundice and a heart defect. The c.974delC mutation was predicted to cause an early stop in protein production, resulting in a shorter, nonworking Jagged-1 protein.

“This discovery implies the potential existence of additional locations or types of genetic abnormalities in the JAG1 gene that may be linked to [congenital hypothyroidism], emphasizing the importance of diligent monitoring of thyroid function in individuals diagnosed with [Alagille syndrome],” the team wrote.

At 5 months, a chest X-ray revealed butterfly vertebrae, a bone abnormality seen in Alagille syndrome in which the bones that make up the spine take on the shape of a butterfly. A heart ultrasound showed patent foramen ovale, or a hole between the left and right upper chambers of the heart. The boy also showed considerable failure to thrive.

Five months later, the boy continued to have jaundice and his liver enzymes remained elevated, a sign of liver damage. His face had characteristics of Alagille syndrome, with a prominent forehead, deeply set eyes, and a pointed chin, “giving the face an inverted triangle appearance,” the researchers wrote.

Study emphasized ‘critical need’ for novel ways to diagnose Alagille

The second boy was born prematurely, at 34 weeks of gestation. He was hospitalized due to higher than normal levels of bilirubin, occurring as a result of cholestasis and an infection in the small intestine.

At 1 month of age, imaging scans revealed a small right kidney, patent foramen ovale, and butterfly vertebrae. Despite receiving treatment to drain bile from the bile ducts at the age of 3 months, the baby’s liver enzymes remained high.

Over time, the boy started showing facial features consistent with Alagille syndrome. He showed slightly delayed motor development, as well as language delay. He starting speaking in two-word sentences at 2, and by 3 years was speaking only short phrases. The child developed seizures at age 2, and showed failure to thrive.

[This study] emphasizes the critical need for individualized and innovative approaches to diagnosis and medical interventions, uniquely intended to address the complexity of this syndrome.

Genetic testing revealed a large deletion in chromosome 20 that affected multiple genes, including JAG1 and SNAP25. Mutations in that gene have been linked to epilepsy and speech difficulties. A missing SNAP2 gene may be a possible explanation for the boy’s seizures and language delays, the researchers noted.

Neither of the child’s parents showed signs of disease.

Overall, according to the researchers, this study “emphasizes the critical need for individualized and innovative approaches to diagnosis and medical interventions, uniquely intended to address the complexity of this syndrome.”

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