Clinical, Cytogenetic and Molecular Findings in Nine Moroccan Patients with Fanconi Anemia

Overview

Journal Pan Afr Med J

Date 2021 Aug 23

PMID 34422195

Authors

Yassamine Doubaj

Abdelali Zrhidri

Siham Chafai Elalaoui

Jaber Lyahyai

Youssef El Kadiri

Nadia Elkassimi

Aziza Sbiti

Maria El Kababri

Laila Hessissen

Abdelaziz Sefiani

Affiliations

Soon will be listed here.

Abstract

Introduction: Fanconi anemia (FA) is a rare inherited hematological disease due to a defect in the DNA repair pathway resulting in congenital abnormalities and high susceptibility to develop cancers. The cytogenetic analysis using alkylating agents is still a reference test to establish the diagnosis. Despite the genetic heterogeneity, the identification of the causal mutation is actually performed especially after the development of next generation sequencing (NGS).

Methods: we report here nine Moroccan patients referred to the department of Medical Genetics for suspicion of FA. We realized a genetic consultation to establish a clinical record with biological data before carrying out the genetic analysis. Karyotyping with mitomycin was performed for all the probands before elaborating molecular study. We used massively parallel sequencing to analyse the three most frequent mutated genes FANCA, FANCC, and FANCG, representing 84% of all genes involved in FA.

Results: all the patients showed hematological signs associated with at least one extra-hematological congenital anomaly. The chromosomal breaks were significantly higher for the nine patients, compared to the controls. The molecular diagnosis was confirmed in 8 of the 9 families tested (88.8%) with 4 novel mutations. The next generation based sequencing identified 9 variations: 6 in the FANCA gene (66.6%), 3 in the FANCG gene (33.3%) and no FANCC variation was found. Of those, 7 were homozygous and 2 were compounds heterozygous.

Conclusion: to the best of our knowledge, this is the first molecular report of Moroccan patients with FA suggesting the predominance of two genes without any recurrent mutation. The molecular analysis of FANCA and FANCG genes should be offered first for all patients in Morocco.

References

Esmer C, Sanchez S, Ramos S, Molina B, Frias S, Carnevale A . DEB test for Fanconi anemia detection in patients with atypical phenotypes. Am J Med Genet A. 2003; 124A(1):35-9. DOI: 10.1002/ajmg.a.20327. View

Wegman-Ostrosky T, Savage S . The genomics of inherited bone marrow failure: from mechanism to the clinic. Br J Haematol. 2017; 177(4):526-542. DOI: 10.1111/bjh.14535. View

Park J, Chung N, Chae H, Kim M, Lee S, Kim Y . FANCA and FANCG are the major Fanconi anemia genes in the Korean population. Clin Genet. 2012; 84(3):271-5. DOI: 10.1111/cge.12042. View

Amouri A, Talmoudi F, Messaoud O, dEnghien C, Rekaya M, Allegui I . High frequency of exon 15 deletion in the FANCA gene in Tunisian patients affected with Fanconi anemia disease: implication for diagnosis. Mol Genet Genomic Med. 2014; 2(2):160-5. PMC: 3960058. DOI: 10.1002/mgg3.55. View

Kee Y, DAndrea A . Molecular pathogenesis and clinical management of Fanconi anemia. J Clin Invest. 2012; 122(11):3799-806. PMC: 3484428. DOI: 10.1172/JCI58321. View

Molina B, Marchetti F, Gomez L, Ramos S, Torres L, Ortiz R . Hydroxyurea induces chromosomal damage in G2 and enhances the clastogenic effect of mitomycin C in Fanconi anemia cells. Environ Mol Mutagen. 2015; 56(5):457-67. DOI: 10.1002/em.21938. View

Ameziane N, Sie D, Dentro S, Ariyurek Y, Kerkhoven L, Joenje H . Diagnosis of fanconi anemia: mutation analysis by next-generation sequencing. Anemia. 2012; 2012:132856. PMC: 3374947. DOI: 10.1155/2012/132856. View

Auerbach A . Fanconi anemia and its diagnosis. Mutat Res. 2009; 668(1-2):4-10. PMC: 2742943. DOI: 10.1016/j.mrfmmm.2009.01.013. View

Kopanos C, Tsiolkas V, Kouris A, Chapple C, Albarca Aguilera M, Meyer R . VarSome: the human genomic variant search engine. Bioinformatics. 2018; 35(11):1978-1980. PMC: 6546127. DOI: 10.1093/bioinformatics/bty897. View

10.

Castella M, Pujol R, Callen E, Trujillo J, Casado J, Gille H . Origin, functional role, and clinical impact of Fanconi anemia FANCA mutations. Blood. 2011; 117(14):3759-69. PMC: 3083295. DOI: 10.1182/blood-2010-08-299917. View

11.

Rosenberg P, Tamary H, Alter B . How high are carrier frequencies of rare recessive syndromes? Contemporary estimates for Fanconi Anemia in the United States and Israel. Am J Med Genet A. 2011; 155A(8):1877-83. PMC: 3140593. DOI: 10.1002/ajmg.a.34087. View

12.

Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn M, Timmers C, Hejna J . Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Mol Cell. 2001; 7(2):249-62. DOI: 10.1016/s1097-2765(01)00173-3. View

13.

Levran O, Diotti R, Pujara K, Batish S, Hanenberg H, Auerbach A . Spectrum of sequence variations in the FANCA gene: an International Fanconi Anemia Registry (IFAR) study. Hum Mutat. 2005; 25(2):142-9. DOI: 10.1002/humu.20125. View

14.

Esmail Nia G, Fadaee M, Royer R, Najmabadi H, Akbari M . Profiling Fanconi Anemia Gene Mutations among Iranian Patients. Arch Iran Med. 2016; 19(4):236-40. DOI: 0161904/AIM.003. View

15.

Ameziane N, Errami A, Leveille F, Fontaine C, de Vries Y, van Spaendonk R . Genetic subtyping of Fanconi anemia by comprehensive mutation screening. Hum Mutat. 2007; 29(1):159-66. DOI: 10.1002/humu.20625. View