Phenotype reversion as "natural gene therapy" in Fanconi anemia by a gene conversion event

Ilaria Persico; Ilaria Fiscarelli; Alessandra Pelle; Michela Faleschini; Barbara Pasini; Anna Savoia; Roberta Bottega

doi:10.3389/fgene.2023.1240758

Phenotype reversion as "natural gene therapy" in Fanconi anemia by a gene conversion event

Front Genet. 2023 Sep 18:14:1240758. doi: 10.3389/fgene.2023.1240758. eCollection 2023.

Authors

Ilaria Persico^#¹, Ilaria Fiscarelli^#^{2

3}, Alessandra Pelle³, Michela Faleschini⁴, Barbara Pasini^{2

3}, Anna Savoia⁵, Roberta Bottega⁴

Affiliations

¹ Genomic Instability DNA Repair Syndromes Group, Joint Research Unit in Genomic Medicine UAB-IR Sant Pau, Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain.
² Dipartimento di Scienze Mediche, Università degli Studi di Torino, Torino, Italy.
³ SC Genetica Medica U, AOU Città della Salute e della Scienza di Torino, Torino, Italy.
⁴ Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste, Italy.
⁵ Department of Engineering for Innovation Medicine, University of Verona, Verona, Italy.

^# Contributed equally.

Abstract

Somatic mosaicism appears as a recurrent phenomenon among patients suffering from Fanconi anemia (FA), but its direct prognostic significance mostly remains an open question. The clinical picture of FA mosaic subjects could indeed vary from just mild features to severe hematologic failure. Here, we illustrate the case of a proband whose FA familiarity, modest signs (absence of hematological anomalies and fertility issues), and chromosome fragility test transition to negative overtime were suggestive of somatic mosaicism. In line with this hypothesis, genetic testing on patient's peripheral blood and buccal swab reported the presence of the only FANCA paternal variant (FANCA:c.2638C>T, p. Arg880*) and of both parental alleles (the additional FANCA:c.3164G>A, p. Arg1055Gln), respectively. Moreover, the SNP analysis performed on the same biological specimens allowed us to attribute the proband's mosaicism status to a possible gene conversion mechanism. Our case clearly depicts the positive association between somatic mosaicism and the proband's favorable clinical course due to the occurrence of the reversion event at the hematopoietic stem cell level. Since this condition concerns only a limited subgroup of FA individuals, the accurate evaluation of the origin and extent of clonality would be key to steer clinicians toward the most appropriate therapeutic decision for their FA mosaic patients.

Keywords: Fanconi anemia; gene conversion; mosaicism; natural gene therapy; phenotype reversion.

Grants and funding

This work was supported by the Ministry of Health, Rome, Italy, in collaboration with the Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy (grant number RC 03/21), and AIRFA (Italian Association for Fanconi Anemia Research).