Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening

Doron M. Behar*, Ori Inbar, Michal Shteinberg, Michal Gur, Huda Mussaffi, David Shoseyov, Moshe Ashkenazi, Soliman Alkrinawi, Concetta Bormans, Fahed Hakim, Meir Mei-Zahav, Malena Cohen-Cymberknoh, Adi Dagan, Dario Prais, Ifat Sarouk, Patrick Stafler, Bat El Bar Aluma, Gidon Akler, Elie Picard, Micha AviramOri Efrati, Galit Livnat, Joseph Rivlin, Lea Bentur, Hannah Blau, Eitan Kerem, Amihood Singer

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Background: Preconception carrier screening for cystic fibrosis (CF) is usually performed using ethnically targeted panels of selected mutations. This has been recently challenged by the use of expanded, ethnically indifferent, pan-population panels. Israel is characterized by genetically heterogeneous populations carrying a wide range of CFTR mutations. To assess the potential of expanding the current Israeli preconception screening program, we sought the subset of molecularly unresolved CF patients listed in the Israeli CF data registry comprising ~650 patients. Methods: An Israeli nationwide genotyping of 152 CF cases, representing 176 patients lacking molecular diagnosis, was conducted. Molecular analysis included Sanger sequencing for all exons and splice sites, multiplex ligation probe amplification (MLPA), and next-generation sequencing of the poly-T/TG tracts. Results: We identified 54 different mutations, of which only 16 overlapped the 22 mutations included in the Israeli preconception screening program. A total of 29/54 (53.7%) mutations were already listed as CF causing by the CFTR2 database, and only 4/54 (7.4%) were novel. Molecular diagnosis was reached in 78/152 (51.3%) cases. Prenatal diagnosis of 24/78 (30.8%) cases could have been achieved by including all CFTR2-causing mutations in the Israeli panel. Conclusions: Our data reveal an overwhelming hidden abundance of CFTR gene mutations suggesting that expanded preconception carrier screening might achieve higher preconception detection rates.

Original languageEnglish
Pages (from-to)223-236
Number of pages14
JournalMolecular genetics & genomic medicine
Issue number3
StatePublished - May 2017


FundersFunder number
Carmel Medical Center
Cystic Fibrosis Center
Cystic Fibrosis Foundation of Israel
Genomic Research Center
Hebrew University Medical Center
Houston Texas 4The Cystic Fibrosis Foundation of Israel
Medison Pharma Corporation
Tel Aviv University
Technion-Israel Institute of Technology


    • Carrier screening
    • cystic fibrosis
    • detection rate
    • preconception


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