It also shows that the Gly551Asp mutation is almost three times more common among newborns in Ireland than in other parts of Europe and the U.S. Since these patients are potentially eligible for treatment with CFTR modulators, this finding should help inform care policies, the research team noted.
The study, “National Newborn Screening for cystic fibrosis in the Republic of Ireland: genetic data from the first 6.5 years,” was published in the European Journal of Human Genetics.
The Republic of Ireland has the highest incidence of CF globally. A 2007 study estimated that about 1 in every 1,353 people there have the disease, and 1 in 19 carry mutations in one copy of the CFTR gene that could pass the disease to their children.
Early diagnosis and treatment start is known to result in better outcomes and quality of life. For this reasons, newborns in the U.S., Canada, Australia, and most of Europe are tested for CF immediately after birth. In Ireland, screening for CF began in 2011, and is done three to five days after birth.
The test consists in collecting a few drops of blood that are placed on a card to measure how much of immunoreactive trypsinogen (IRT), a precursor of a pancreatic protein, is found in blood circulation. This enzyme is often elevated in CF patients due to blockages in the pancreatic ducts, and high IRT levels raise a suspicion of CF.
In Ireland, newborns with the 1% highest IRT levels are referred for CFTR genetic analysis and a sweat test, used to confirm a CF diagnosis. This cut-off has been established to maximize the detection of newborns with classical CF, while minimizing the detection of mutation carriers and of newborns with an inconclusive diagnosis.
Researchers reported findings from the first 6.5 years of the NBS program in Ireland, including all babies born between July 2011 and December 2017 who screened positive for CF on the IRT test and were referred for a genetic test examining the 38 most common disease-causing CFTR variants.
In total 5,053 babies, accounting for 1.16% of all newborns, underwent CF screening during that period. Of them, 170 were diagnosed with CF, 320 were deemed mutation carriers, and 32 had an inconclusive diagnosis — meaning they tested positive on NBS and genetic screening, but sweat tests were either normal or intermediate.
Researchers noted there were fewer babies with CF than expected based on prior estimates. Their model had expected about 53 new CF diagnoses each year, with a total of 344 new cases in the study period.
This was nearly double the actual incidence found — 170 cases — and could not be fully explained by the lower birth rate seen in that period. Researchers suggested that immigration and a greater number of babies from non-Irish parents may play a role.
Among the 170 children diagnosed with CF, 146 were diagnosed with the initial 38 CFTR variant panel, while 24 had one mutation that was not detected using the panel and required more extensive DNA sequencing.
The most common mutation identified was the F508del mutation, with 90.7% of patients carrying at least one CFTR copy with this mutation.
The second most common was the Gly551Asp mutation (15%), which causes gating defects in the CFTR channel. While this mutation is among the top 5 common variants in CF patients, its incidence in this study group was at least three times higher than that reported elsewhere in Europe and in the U.S. (which ranges from 1.4% to 5%).
People with the Gly551Asp mutation are potentially eligible for treatment with CFTR modulators, such as Kalydeco (ivacaftor) and Orkambi (ivacaftor/lumacaftor), both by Vertex. Along with patients carrying two copies of the F508del mutation, 120 patients (70%) in the group analyzed could potentially use these medications.
In carriers, mutations were similar to that of patients, with 78% having the F508del mutation, and 11% the Gly551Asp mutation.
To date, only one case of CF has been missed in this program, and this child had a rare CFTR variant that would not have been identified with the 38-variant genetic panel. This patient was not included in the analysis.
Overall, “the observed incidence of CF in the NBS programme is 1 in 2570 (170 cases in 436,940 births) yielding an estimated carrier frequency of 1 in 25.3,” the researchers wrote. This revised incidence is lower than previously estimated, but the team recommends that former numbers be used for more accurate counseling.
“We recommend that in case of counselling a couple of Irish origin carrier rate of 1 in 19 should still be used for more accurate counselling purposes,” they stated.
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