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

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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 and Genomic Medicine
Volume5
Issue number3
DOIs
StatePublished - May 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

Funding

1Clalit National Personalized Medicine Program, Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel 2Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel 3Gene by Gene, Genomic Research Center, Houston Texas 4The Cystic Fibrosis Foundation of Israel, Ramat Gan, Israel 5Pulmonology Institute and CF Center, Carmel Medical Center, Haifa, Israel 6Pediatric Pulmonary Institute and CF Center, Rappaport Children’s Hospital, Rambam Health Care Campus, Haifa, Israel 7Kathy and Lee Graub Cystic Fibrosis Center, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel 8Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel 9Cystic Fibrosis Center, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 10Cystic Fibrosis Center, Sheba Medical Center, Ramat Gan, Israel 11Cystic Fibrosis Center, Soroka Medical Center, Beersheva, Israel 12Cystic Fibrosis Center, Shaare Zedek Medical Center, Hebrew University Medical Center, Jerusalem, Israel 13Medical Genetics, Barzilai Medical Center, Ashkelon, Israel The authors thank the patients and their families for their participation in the study. We are grateful to Danyel Biotech, Ltd., for their excellent logistic help. This study was partially sponsored by Medison Pharma Corporation, which did not collaborate with investigators on any aspect of the study. This study was also partially sponsored by The Cystic Fibrosis Foundation of Israel, a charitable organization which collaborated with the investigators on the study design, interpretation of results, preparation of the manuscript, and decision to submit the manuscript for publication.

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
University
Tel Aviv University
Technion-Israel Institute of Technology

    Keywords

    • Carrier screening
    • cystic fibrosis
    • detection rate
    • preconception

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