From exome analysis in idiopathic azoospermia to the identification of a high-risk subgroup for occult Fanconi anemia

Csilla Krausz, Antoni Riera-Escamilla, Chiara Chianese, Daniel Moreno-Mendoza, Elisabet Ars, Osvaldo Rajmil, Roser Pujol, Massimo Bogliolo, Ignacio Blanco, Ines Rodríguez, Isabel Badell, Eduard Ruiz-Castañé (+1 others)
2018 Genetics in Medicine  
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 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 : i) Whole-Exome Sequencing (WES) ii) Sanger sequencing of the FANCA gene; iii) DEB-induced chromosome breakage test. Results: WES identified a pathogenic homozygous FANCA variant
more » ... ygous 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 one additional patient showing compound heterozygous pathogenic FANCA variants was identified with positive chromosomal breakage test. Conclusion: We report an extraordinary high frequency of FA in a specific subgroup of azoospermic patients (7.1%). The screening for FANCA mutations 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.
doi:10.1038/s41436-018-0037-1 pmid:29904161 fatcat:jthwixduwjddpjkhtjfkbdcygy