Csilla Krausz1,2, Antoni Riera-Escamilla3, Chiara Chianese3, Daniel Moreno-Mendoza3, Elisabet Ars3, Osvaldo Rajmil3, Roser Pujol4, Massimo Bogliolo4, Ignacio Blanco5, Ines Rodríguez5, Isabel Badell6, Eduard Ruiz-Castañé3, Jordi Surrallés7. 1. Department of Experimental and Clinical Biomedical Sciences "Mario Serio", Centre of Excellence DeNothe, University of Florence, Florence, Italy. csilla.krausz@unifi.it. 2. Andrology Department, Fundació Puigvert, Universitat Autònoma de Barcelona, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Barcelona, Catalonia, Spain. csilla.krausz@unifi.it. 3. Andrology Department, Fundació Puigvert, Universitat Autònoma de Barcelona, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Barcelona, Catalonia, Spain. 4. Genetics Department and Biomedical Research Institute, Hospital de Sant Pau, Center for Biomedical Research on Rare Diseases (CIBERER), and Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain. 5. Hospital Germans Trias i Pujol, Badalona, Catalonia, Spain. 6. Pediatrics Department, Hospital de Sant Pau, Barcelona, Catalonia, Spain. 7. Genetics Department and Biomedical Research Institute, Hospital de Sant Pau, Center for Biomedical Research on Rare Diseases (CIBERER), and Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain. jsurralles@santpau.cat.
Abstract
PURPOSE: In about 10% of patients affected by Fanconi anemia (FA) the diagnosis is delayed until adulthood, and the presenting symptom in these "occult" FA cases is often a solid cancer and cancer treatment-related toxicity. Highly predictive clinical parameter(s) for diagnosing such an adult-onset cases are missing. METHODS: (1) Exome sequencing (ES), (2) Sanger sequencing of FANCA, (3) diepoxybutane (DEB)-induced chromosome breakage test. RESULTS: ES identified a pathogenic homozygous FANCA variant in a patient affected by Sertoli cell-only syndrome (SCOS) and in his azoospermic brother. Although they had no overt anemia, chromosomal breakage test revealed a reverse somatic mosaicism in the former and a typical FA picture in the latter. In 27 selected SCOS cases, 1 additional patient showing compound heterozygous pathogenic FANCA variants was identified with positive chromosomal breakage test. CONCLUSION: We report an extraordinarily high frequency of FA in a specific subgroup of azoospermic patients (7.1%). The screening for FANCA pathogenic variants in such patients has the potential to identify undiagnosed FA before the appearance of other severe clinical manifestations of the disease. The definition of this high-risk group for "occult" FA, based on specific testis phenotype with mild/borderline hematological alterations, is of unforeseen clinical relevance.
PURPOSE: In about 10% of patients affected by Fanconi anemia (FA) the diagnosis is delayed until adulthood, and the presenting symptom in these "occult" FA cases is often a solid cancer and cancer treatment-related toxicity. Highly predictive clinical parameter(s) for diagnosing such an adult-onset cases are missing. METHODS: (1) Exome sequencing (ES), (2) Sanger sequencing of FANCA, (3) diepoxybutane (DEB)-induced chromosome breakage test. RESULTS: ES identified a pathogenic homozygous FANCA variant in a patient affected by Sertoli cell-only syndrome (SCOS) and in his azoospermic brother. Although they had no overt anemia, chromosomal breakage test revealed a reverse somatic mosaicism in the former and a typical FA picture in the latter. In 27 selected SCOS cases, 1 additional patient showing compound heterozygous pathogenic FANCA variants was identified with positive chromosomal breakage test. CONCLUSION: We report an extraordinarily high frequency of FA in a specific subgroup of azoospermic patients (7.1%). The screening for FANCA pathogenic variants in such patients has the potential to identify undiagnosed FA before the appearance of other severe clinical manifestations of the disease. The definition of this high-risk group for "occult" FA, based on specific testis phenotype with mild/borderline hematological alterations, is of unforeseen clinical relevance.
Entities:
Keywords:
Azoospermia; Exome sequencing; Fanconi anemia; Genetics; Male infertility
Authors: Antoni Riera-Escamilla; Matthias Vockel; Liina Nagirnaja; Miguel J Xavier; Albert Carbonell; Daniel Moreno-Mendoza; Marc Pybus; Ginevra Farnetani; Viktoria Rosta; Francesca Cioppi; Corinna Friedrich; Manon S Oud; Godfried W van der Heijden; Armin Soave; Thorsten Diemer; Elisabet Ars; Josvany Sánchez-Curbelo; Sabine Kliesch; Moira K O'Bryan; Eduard Ruiz-Castañe; Fernando Azorín; Joris A Veltman; Kenneth I Aston; Donald F Conrad; Frank Tüttelmann; Csilla Krausz Journal: Am J Hum Genet Date: 2022-07-08 Impact factor: 11.043