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Characterization and Genotype-Phenotype Correlation of Patients with Fanconi Anemia in Ferrata Storti Foundation a Multi-Ethnic Population

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Characterization and Genotype-Phenotype Correlation of Patients with Fanconi Anemia in Ferrata Storti Foundation a Multi-Ethnic Population Bone Marrow Failure ARTICLE Characterization and genotype-phenotype correlation of patients with Fanconi anemia in Ferrata Storti Foundation a multi-ethnic population Orna Steinberg-Shemer,1,2,3* Tracie A. Goldberg,1* Joanne Yacobovich,1,2 Carina Levin,4,5 Ariel Koren,4,5 Shoshana Revel-Vilk,6 Tal Ben-Ami,7 Amir A. Kuperman,8,9 Vered Shkalim Zemer,1,2 Amos Toren,2,10 Joseph Kapelushnik,11 Ayelet Ben-Barak,12 Hagit Miskin,6 Tanya Krasnov,3 Sharon Noy-Lotan,3 Orly Dgany3 and Hannah Tamary1,2,3 1 Haematologica 2020 Department of Hematology-Oncology, Schneider Children's Medical Center of Israel, Volume 105(7):1825-1834 Petach Tikva; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv; 3Pediatric Hematology Laboratory, Felsenstein Medical Research Center, Petach Tikva; 4Pediatric Hematology Unit, Emek Medical Center, Afula; 5The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa; 6Pediatric Hematology/Oncology Unit, Shaare Zedek Medical Center, Jerusalem, affiliated with Hadassah- Hebrew University Medical School, Jerusalem; 7Pediatric Hematology Unit, Kaplan Medical Center, Rehovot; 8Blood Coagulation Service and Pediatric Hematology Clinic, Galilee Medical Center, Nahariya; 9Azrieli Faculty of Medicine, Bar-Ilan University, Safed; 10Department of Pediatric Hemato-Oncology, Children's Hospital (Edmond and Lily), Sheba Medical Center, Tel-Hashomer; 11Pediatric Hematology, Soroka University Medical Center, Ben-Gurion University, Beer Sheva and 12Pediatric Hematology-Oncology Department, Rambam Medical Center, Haifa, Israel *OS-S and TAG contributed equally as co-first authors. ABSTRACT ANCONI ANEMIA (FA), AN INHERITED BONE MARROW FAILURE (BMF) SYNDROME, CAUSED BY MUTATIONS IN DNA REPAIR GENES, IS CHARACTERIZED BY CONGENI- Correspondence: FTAL ANOMALIES, APLASTIC ANEMIA, HIGH RISK OF MALIGNANCIES AND EXTREME HANNAH TAMARY SENSITIVITY TO ALKYLATING AGENTS. WE AIMED TO STUDY THE CLINICAL PRESENTATION, [email protected] MOLECULAR DIAGNOSIS AND GENOTYPE-PHENOTYPE CORRELATION AMONG PATIENTS WITH FA FROM THE ISRAELI INHERITED BMF REGISTRY. OVERALL, 111 PATIENTS OF ARAB ORNA STEINBERG-SHEMER (57%) AND JEWISH (43%) DESCENT WERE FOLLOWED FOR A MEDIAN OF 15 YEARS [email protected] (RANGE: 0.1-49); 63% WERE OFFSPRING OF CONSANGUINEOUS PARENTS. ONE-HUN- Received: March 27, 2019. DRED PATIENTS (90%) HAD AT LEAST ONE CONGENITAL ANOMALY; OVER 80% OF THE Accepted: September 25, 2019. PATIENTS DEVELOPED BONE MARROW FAILURE; 53% UNDERWENT HEMATOPOIETIC STEM-CELL TRANSPLANTATION; 33% OF THE PATIENTS DEVELOPED CANCER; NO SIGNIFI- Pre-published: September 26, 2019. CANT ASSOCIATION WAS FOUND BETWEEN HEMATOPOIETIC STEM-CELL TRANSPLANT AND SOLID TUMOR DEVELOPMENT. NEARLY 95% OF THE PATIENTS TESTED HAD CONFIRMED doi:10.3324/haematol.2019.222877 MUTATIONS IN THE FANCONI GENES FANCA (67%), FANCC (13%), FANCG (14%), FANCJ (3%) AND FANCD1 (2%), INCLUDING TWENTY NOVEL MUTATIONS. Check the online version for the most updated PATIENTS WITH FANCA MUTATIONS DEVELOPED CANCER AT A SIGNIFICANTLY OLDER AGE information on this article, online supplements, COMPARED TO PATIENTS WITH MUTATIONS IN OTHER FANCONI GENES (MEAN 18.5 AND and information on authorship & disclosures: 5.2 YEARS, RESPECTIVELY, P=0.001); HOWEVER, THE OVERALL SURVIVAL DID NOT www.haematologica.org/content/105/7/1825 DEPEND ON THE CAUSATIVE GENE. WE HEREBY DESCRIBE A LARGE NATIONAL COHORT OF PATIENTS WITH FA, THE VAST MAJORITY GENETICALLY DIAGNOSED. OUR RESULTS SUGGEST ©2020 Ferrata Storti Foundation AN OLDER AGE FOR CANCER DEVELOPMENT IN PATIENTS WITH FANCA MUTATIONS AND Material published in Haematologica is covered by copyright. NO INCREASED INCIDENCE OF SOLID TUMORS FOLLOWING HEMATOPOIETIC STEM-CELL All rights are reserved to the Ferrata Storti Foundation. Use of TRANSPLANT. FURTHER STUDIES ARE NEEDED TO GUIDE INDIVIDUAL TREATMENT AND FOL- published material is allowed under the following terms and LOW-UP PROGRAMS. conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: Introduction https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- FANCONI ANEMIA (FA), AN INHERITED BONE MARROW FAILURE (BMF) SYNDROME, RESULTS mercial purposes is not allowed without permission in writing FROM DEFECTS IN THE DNA REPAIR PATHWAY, LEADING TO CHROMOSOMAL INSTABILITY. THE from the publisher. DISEASE iS rARE wITH aN eSTIMATED pREVALENCE oF 1:130,0001 BUT tENDS tO bE hIGHER iN CERTAIN COMMUNITIES DUE TO FOUNDER MUTATIONS, ESPECIALLY THOSE WITH A HIGH RATE OF haematologica | 2020; 105(7) 1825 O.Steinberg-Shemer et al. 1-5 CONSANGUINITY. THE CLINICAL PHENOTYPE INCLUDES CONGENI- Table 1. Characteristics of Fanconi anemia patients in Israel. TAL ANOMALIES, APLASTIC ANEMIA, A HIGH RISK OF MALIGNANCIES, N= 108 patients Ethnicities AND EXTREME SENSITIVITY TO CROSS-LINKING AGENTS. PATIENTS WITH FA CLASSICALLY PRESENT WITH MULTIPLE CONGENITAL 26 Sephardic ANOMALIES AND CYTOPENIAS, ALTHOUGH SEVERAL PATIENTS HAVE 46 10 Ashkenazi Jewish NO PHYSICAL DEFECTS AND NORMAL BLOOD COUNTS, COMPLICAT- 9 Mixed ING THE DIAGNOSIS, WHICH IS BASED ON THE CHROMOSOMAL 1 Ethiopian BREAKAGE TEST. GENOTYPING CONFIRMS THE DIAGNOSIS AND 54 Muslim ALLOWS FOR PROPER GENETIC COUNSELING. SOME PATIENTS EXHIB- 62 6 Druze Arab IT MOSAICISM, REQUIRING TESTING BY CHROMOSOMAL BREAKAGE AND GENETIC ANALYSIS IN NON-HEMATOPOIETIC TISSUE.6 2 Christian FA IS USUALLY INHERITED IN AN AUTOSOMAL RECESSIVE FASH- ION, WITH THE EXCEPTION OF THE X-LINKED FANCB AND THE DOMINANTLY INHERITED FANCR. TO DATE, MUTATIONS IN MORE THAN 20 GENES HAVE BEEN DETECTED. DETECTING GENOTYPE- FOR EACH PATIENT BY ADDING UP THE TOTAL NUMBER OF PHENOTYPIC PHENOTYPE CORRELATIONS IS IMPORTANT FOR PROGNOSTIC PREDIC- ABNORMALITIES IN A SET CONSISTING OF DEVELOPMENTAL DELAY, HEART OR TIONS, TREATMENT DECISIONS AND ESTABLISHMENT OF DIRECTED LUNG ABNORMALITIES, RENAL ANOMALIES, HEARING LOSS AND HEAD ABNOR- FOLLOW-UP PROGRAMS. HOWEVER, TO DATE, A CLEAR CORRELATION MALITIES.10 WHENEVER POSSIBLE, GENETIC ANALYSIS WAS PERFORMED AS BETWEEN THE AFFECTED GENE AND THE PATIENT'S PHENOTYPE PART OF THE ROUTINE WORK-UP. PATIENTS WERE INCLUDED IN THIS STUDY HAS NOT BEEN FOUND. ONE EXCEPTION IS THE MORE PRO- IF THEY WERE CLINICALLY SUSPECTED AS HAVING FA AND HAD EITHER A CON- NOUNCED CANCER PREDISPOSITION IN PATIENTS WITH FIRMED GENETIC DIAGNOSIS OF FA OR AN ABNORMAL CHROMOSOMAL FANCD1/BRCA2 AND FANCN/PALB2 MUTATIONS, IN WHICH BREAKAGE TEST, OR BOTH. EARLY ONSET OF MALIGNANCY IS ALMOST INVARIABLY PRESENT. GENETIC ANALYSIS WAS PERFORMED BY SANGER SEQUENCING, AS PRE- SOME EVIDENCE SUGGESTS THAT THE TYPE OF MUTATION CORRE- VIOUSLY DESCRIBED.11 SEQUENCING WAS PERFORMED ON AN ABIPRISM LATES BETTER WITH THE PHENOTYPE THAN THE SPECIFIC GENE. FOR 3130XL GENETIC ANALYZER (APPLIED BIOSYSTEMS, FOSTER CITY, CA, EXAMPLE, ONE REPORT FOUND THAT PATIENTS WITH NULL MUTA- USA). CHROMATOGRAMS WERE VISUALIZED WITH CHROMAS (V.2.6.4; TIONS IN FANCA PRESENT WITH A MORE SEVERE PHENOTYPE WWW.THECHNELYSIUM.COM.AU). VARIANT PATHOGENICITY WAS DETER- THAN THOSE WITH MUTATIONS LEADING TO ALTERED FANCA PRO- MINED BASED ON THE AMERICAN COLLEGE OF MEDICAL GENETICS AND TEIN PRODUCTION.7 CONVERSELY, IN A SEPARATE REPORT, NO FUNC- GENOMICS (ACMG) CRITERIA. MULTIPLEX LIGATION DEPENDENT PROBE TIONAL OR CLINICAL DIFFERENCE WAS FOUND BETWEEN PATIENTS AMPLIFICATION (MLPA) WAS PERFORMED USING THE COMMERCIALLY WITH ABSENT FANCA PROTEIN OR THOSE WITH ALTERED FANCA AVAILABLE KIT SALSA MLPA PROBEMIX P031-B2/P032-B2 FANCA PROTEIN.8 IT IS POSSIBLE THAT SPECIFIC MUTATIONS, AS OPPOSED (MRC-HOLLAND) FOLLOWING THE MANUFACTURER’S INSTRUCTION. TO AFFECTED GENE OR TYPE OF MUTATION, BEST CORRELATE WITH DATA ORGANIZATION WAS PERFORMED WITH MICROSOFT EXCEL THE PHENOTYPE.9 HOWEVER, EVEN FOR A SPECIFIC MUTATION, (WINDOWS, VERSION 16.11.1). THE DATA WERE ANALYZED USING BMDP THERE IS A VARIABLE PHENOTYPIC SEVERITY AMONG DIFFERENT SOFTWARE (1993, UNIVERSITY OF CALIFORNIA PRESS, USA). PEARSON'S ETHNICITIES AND AMONG SIBLINGS, EVEN TWINS, SUGGESTING A CHI-SQUARE TEST OR FISHER’S EXACT TEST (TWO-TAILED) WAS USED FOR ROLE FOR GENETIC OR EPIGENETIC MODIFIERS AND/OR ENVIRON- ANALYSIS OF BETWEEN-GROUP DIFFERENCES IN DISCRETE VARIABLES, AND MENTAL FACTORS. ANALYSIS OF VARIANCE (ANOVA) WAS USED FOR CONTINUOUS VARIABLES. HERE, WE PRESENT DATA REGARDING 111 PATIENTS WITH FA IN THOSE VARIABLES WHICH DID NOT HAVE GAUSSIAN DISTRIBUTIONS OR ISRAEL. THIS LARGE COHORT IS UNIQUE DUE TO ISRAEL'S ETHNIC WHEN THE SAMPLE SIZE WAS VERY SMALL WERE COMPARED USING THE DIVERSITY, A HIGH DEGREE OF CONSANGUINITY AND A VERY HIGH NON-PARAMETRIC MANN-WHITNEY TEST. THE KAPLAN-MEIER ESTIMATE PERCENTAGE OF GENETICALLY DIAGNOSED PATIENTS. WAS USED TO SHOW SURVIVAL FOR THE COHORT AND VARIOUS SUB-GROUPS. CALCULATIONS AND GRAPHIC REPRESENTATION OF SURVIVAL CURVES WERE PERFORMED ON PRISM 7 (GRAPH PAD SOFTWARE) AND ON MEDCALC SOFT- Methods WARE (BELGIUM). A P-VALUE OF ≤0.05 WAS CONSIDERED SIGNIFICANT. FA WAS DEFINED BY AN ABNORMAL CHROMOSOMAL BREAKAGE TEST AND/OR A GENETIC DIAGNOSIS OF BIALLELIC MUTATIONS IN ONE OF THE Results KNOWN FA GENES. PATIENTS WITH FA WERE REGISTERED BY THEIR TREAT- ING HEMATOLOGIST AS PART OF THE ISRAELI INHERITED BONE MARROW FAIL- Patient demographics URE REGISTRY (I-IBMFR). THE I-IBMFR IS APPROVED BY EACH LOCAL ONE HUNDRED AND ELEVEN PATIENTS (53% MALE) WITH FA INSTITUTIONAL REVIEW
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