A self-repair history: compensatory effect of a de novo variant on the FANCA c.2778+83C>G splicing mutation

Introduction: Fanconi anemia (FA) is a genome instability condition that drives somatic mosaicism in up to 25% of all patients, phenomenon now acknowledged as good prognostic factor. Herein, we describe the case P1, FA proband carrying splicing variant, molecularly compensated by de novo insertion. Methods and Results: Targeted next-generation sequencing on P1’s peripheral blood DNA detected known FANCA c.2778 + 83C > G intronic mutation suggested presence large deletion other allele, which was then assessed MLPA RT-PCR. To determine effect, performed RT-PCR lymphoblastoid cell line (LCL) LCL another patient (P2) same variant. Although confirmed expected alternative spliced form with partial retention P2, no aberrant products sample. Sequencing allowed identification 86insT predicted compensate 2778 impact. Albeit not found bone marrow (BM) DNA, second established afterward, suggesting its occurrence at low level vivo . Minigene assay recapitulated effect compensatory role re-establishing physiological mechanism. Accordingly, under mitomycin C selection preserved pathway activity terms FANCD2 monoubiquitination survival. Discussion: Our findings prove second-site variant capable rescuing pathogenicity vitro , might contribute slow hematopoietic deterioration mild hematologic evolution.