6 JAG1, NOTCH2 gene mutations ID’d as likely cause of Alagille
6 of 14 children in Chinese study each found to have 1 of these mutations
Researchers in China have identified six new mutations in the JAG1 and NOTCH2 genes as likely causes of Alagille syndrome.
In their study, six of 14 children with Alagille were each found to carry one of these mutations, with each child identified as having a different one. The other eight children were found to have previously identified mutations.
Consistent with previous studies, all of the Alagille children had cholestasis, which is when the flow of the digestive fluid bile from the liver to the intestines is impaired. Other common disease manifestations included characteristic facial features, skeletal abnormalities, and heart defects.
“JAG1 and NOTCH2 gene mutant spectra are abundant and there are many novel mutations in Chinese children with ALGS [Alagille syndrome],” the researchers wrote. “This study enriches the spectrum of genetic variation in Chinese children with ALGS.”
The team noted that “genetic testing is helpful for early diagnosis.”
The study, “Clinical and genetic characteristics of patients with Alagille syndrome in China: identification of six novel JAG1 and NOTCH2 mutations,” was published in the journal Translational Pediatrics by researchers at the Zhejiang University School of Medicine.
Chinese team sought better ways to diagnose Alagille in patients
A genetic disease, Alagille is caused primarily by mutations in the JAG1 gene and, less frequently, in the NOTCH2 gene. These genes provide instructions for making proteins of the Notch signaling pathway, which is involved in the development of body structures before birth, in the developing embryo.
Mutations in these genes are thought to cause abnormalities and errors during early development, ultimately leading to Alagille symptoms.
The most common feature of Alagille is cholestasis due to fewer than normal bile ducts — the tubes that transport bile from the liver to the intestines. Without enough ducts, bile builds up inside the liver, promoting tissue scarring that disrupts liver function.
Beyond liver damage, the condition is marked by characteristic facial features and abnormalities in the heart, bones, blood vessels, kidneys, and pancreas.
“The clinical manifestations of ALGS are diverse, and early diagnosis of atypical children is difficult and prone to misdiagnosis,” the researchers wrote. The team specifically cited a common misdiagnosis of biliary atresia, another infantile condition marked by cholestasis in which the bile ducts are blocked or absent.
This study aimed to provide a basis for the early diagnosis of [Alagille syndrome] patients whose clinical identification is difficult and to enrich the spectrum of genetic variants implicated in Chinese children with [the condition].
Seeking ways to better diagnose young children with the condition, the team of researchers, from Hangzhou, retrospectively reviewed the medical records of 14 Alagille syndrome patients. All were diagnosed between 2016 and 2022.
“This study aimed to provide a basis for the early diagnosis of ALGS patients whose clinical identification is difficult and to enrich the spectrum of genetic variants implicated in Chinese children with” the condition, the team wrote.
Of the 14 children whose records were analyzed, 11 were boys and three were girls. The mean age when the first symptom of liver disease among these children appeared was 0.4 months, or at nearly 2 weeks of life. The mean age at diagnosis was 5.6 months, ranging from 2.4 months to about 4 years.
All of the children developed cholestasis, and 78.6% had Alagille’s hallmark facial features. Among all patients, 57.1% had heart problems. Almost half (42.9%) showed abnormalities in the vertebrae, the bones that make up the spine, such as butterfly vertebra, in which vertebra take on the shape of a butterfly.
Of the eight children who underwent an eye exam, two had posterior embryotoxon, an eye abnormality marked by a white ring lining the thin, transparent membrane that covers the eyeballs. Kidney abnormalities were detected in one child.
Blood tests revealed high levels of several markers of liver damage in 71.4% to 100% of patients. Such markers were found regarding bile acids, which are the main component of bile, liver enzymes, and bilirubin, a yellow-reddish waste product typically added to bile in the liver to be excreted through the intestines.
In study, JAG1 mutations found in 12 children, NOTCH2 in 2
Genetic testing revealed JAG1 gene mutations in 12 children (85.7%). NOTCH2 gene mutations were found in two (14.3%). All of the mutations differed, and in more than half of the children (57.1%), these were de novo mutations, meaning they were not inherited from parents and instead occurred spontaneously when the DNA was copied during cell division.
In three children (21.4%), the mutation was inherited from the father, while in other three (21.4%), the mutation was inherited from the mother.
Six of the 14 mutations identified (46.2%) were previously unknown: four JAG1 mutations and both NOTCH2 mutations.
Two of the JAG1 mutations — c.35_45delGCCCCCTAAGC and c.1860delC — were classified as frameshift, referring to the insertion or deletion of a part of the gene that dramatically changes the protein sequence. The other two, namely c.2849_2850del and c.1293_1294insTAGTAGACA, were classified as nonsense mutations, or alterations that result in a shorter, likely nonworking, version of the resulting protein.
Both nonsense mutations and the c.1860delC frameshift mutation were classified as disease-causing, while the c.35_45delGCCCCCTAAGC frameshift mutation was classified as likely disease-causing.
The NOTCH2 mutations included one frameshift mutation (c.6040_6041del), and one splice mutation (c.1915+1G>T), which can change the length and sequence of the resulting protein. Both were classified as likely disease-causing.
The most common treatment was ursodeoxycholic acid, a medication that helps bile move through the bile ducts, as well as vitamin supplements, given to 85.7% of children.
During a mean follow-up of 48.5 months, or very slightly longer than four years, four children (28.6%) showed delayed growth. More than half (57.1%) had persistent itching, and two children developed xanthomas, or fatty growths underneath the skin. One child’s liver function returned to normal after 8 months of age, while elevated blood levels of liver enzymes persisted in the remaining patients (92.9%).
“This study presents new gene mutations and enriches the present data concerning ALGS patients in China,” the researchers concluded. “In subsequent studies, the study population size should be expanded, and multicenter research is further needed.”
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