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Mol Genet Genomic Med. 2017 Feb 19;5(3):223-236. doi: 10.1002/mgg3.278. eCollection 2017 May.

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

Author information

1
Clalit National Personalized Medicine ProgramDepartment of Community Medicine and EpidemiologyCarmel Medical CenterHaifaIsrael.
2
Bruce Rappaport Faculty of MedicineTechnion-Israel Institute of TechnologyHaifaIsrael.
3
Gene by GeneGenomic Research CenterHoustonTexas.
4
The Cystic Fibrosis Foundation of IsraelRamat GanIsrael.
5
Pulmonology Institute and CF CenterCarmel Medical CenterHaifaIsrael.
6
Pediatric Pulmonary Institute and CF CenterRappaport Children's HospitalRambam Health Care CampusHaifaIsrael.
7
Kathy and Lee Graub Cystic Fibrosis CenterSchneider Children's Medical Center of IsraelPetach TikvaIsrael.
8
Sackler Faculty of MedicineTel Aviv UniversityRamat AvivIsrael.
9
Cystic Fibrosis CenterHadassah-Hebrew University Medical CenterJerusalemIsrael.
10
Cystic Fibrosis CenterSheba Medical CenterRamat GanIsrael.
11
Cystic Fibrosis CenterSoroka Medical CenterBeershevaIsrael.
12
Cystic Fibrosis CenterShaare Zedek Medical CenterHebrew University Medical CenterJerusalemIsrael.
13
Medical GeneticsBarzilai Medical CenterAshkelonIsrael.

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.

KEYWORDS:

Carrier screening; cystic fibrosis; detection rate; preconception

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