New NOTCH2 gene mutations identified as likely Alagille cause
Effort could increase knowledge about variants, their related clinical profile
Researchers in Italy have identified 10 new mutations in the NOTCH2 gene, which has been linked to Alagille syndrome, in nine children and one adult with signs of liver problems that may explain their conditions, including Alagille.
Six children with symptoms of Alagille carried seven of these mutations and had no changes in genes known to be related to other liver diseases, likely helping to confirm their diagnosis.
By “describing the variants, alongside the clinical signs of patients in which they were identified, our results will increase the knowledge about NOTCH2 variants and the related [clinical profile], being useful to refine the [functional] evaluation of NOTCH2 variants,” the researchers wrote.
The study, “Association of Very Rare NOTCH2 Variants with Clinical Features of Alagille Syndrome,” was published in Genes.
Alagille syndrome is a genetic disease mainly caused by mutations in the JAG1 gene and less frequently in the NOTCH2 gene that result in organ abnormalities during early development. The most common symptoms include liver problems, mainly due to a reduced number of bile ducts, which are tubes in the liver that carry the digestive fluid bile to the intestines, which slows bile flow. This condition is called cholestasis and can cause bile to accumulate to toxic levels in the liver, causing damage and affecting its function.
Alagille can also lead to abnormalities in the heart, bone, blood vessels, eyes, and kidneys, along with characteristic facial features. Because Alagille symptoms can vary widely from patient to patient and overlap with other conditions, it can be challenging to achieve a diagnosis, which is commonly based on the presence of three of seven typical disease symptoms and can be confirmed by genetic testing to identify a disease-causing mutation.
NOTCH2 mutations and role in Alagille syndrome
Here, researchers in Italy sought to identify rare NOTCH2 mutations and evaluate their potential implications in signs of Alagille among 230 people with liver problems who were followed at three liver clinics.
All had genetic testing comprising a panel of 59 genes previously associated with liver diseases, including JAG1 and NOTCH2 for Alagille. Ten patients (nine children, one adult) were found to carry 11 rare NOTCH2 mutations, 10 that hadn’t been reported before. Of these, seven children had a clinical suspicion of Alagille, showing at least three clinical signs of the disease, including cholestasis in all of them. These corresponded to all the patients with clinical onset before 3 months of age, along with a 4-year-old child.
A 1-month-old boy carried a previously known NOTCH2 mutation called c.6007C>T that is deemed disease-causing. His symptoms included an underdeveloped gallbladder, the organ where bile is stored, facial features, and mild heart and kidney issues. The remaining six children carried seven new mutations.
New NOTCH2 mutations ID’d
A 1-month-old girl had a new frameshift mutation in the NOTCH2 gene, called c.1583_1590delTTTGCCAG, that was classified as disease-causing and a rare missense mutation in the JAG1 gene (c.94T>C) that was likely disease-causing. The frameshift mutation resulted in a deletion of a part of the gene that dramatically changes the protein sequence. Missense mutations are a variant type that results in only one amino acid (protein’s building blocks) being swapped for another in the resulting protein.
The girl’s symptoms included fewer bile ducts, cholestasis, severe itching (a sign of liver problems), typical facial features, and lung problems. She underwent a liver transplant at 19 months. Although the NOTCH2 mutation was considered the disease’s cause, its possible the JAG1 mutation contributed to worse symptoms, the researchers noted.
A girl who was 4 years old at her disease onset carried a new missense NOTCH2 mutation called c.665A>G that was considered as likely disease-causing. A child carrying two new missense mutations, called c.4868T>G and c.6011A>T, was a 2-month-old girl. Both mutations were classified as likely disease-causing.
Two 1-month-old boys, one with clear signs of Alagille and the other with only mild manifestations, carried one missense mutation each (c.6424T>C and c.6802T>C). The mutations’ impact on the resulting protein was unclear.
The last patient with clear Alagille signs, a 2-month-old boy, had a synonymous mutation, called c.5103A>G. This type of mutation doesn’t change the protein sequence, but may alter its structure or function. He also had mutations in the COG5 and ALG1 genes, which together could have contributed to his symptoms.
Each of the three patients without a clear suspicion of Alagille — two young girls and a 61-year-old man with a metabolic syndrome — carried a newly identified missense mutation (c.3142C>T, c.4462G>A, and c.2762A>G). The mutations were considered to have a low probability of causing disease.
This study “highlights that a wide genetic screening could be helpful both in excluding the other genetic [cholestatic diseases] and at evaluating … genes that are usually not investigated,” the researchers wrote.
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