Pre-mRNA Differential 5' Splicing: A Rescue of Functional Protein Properties from Pathogenic Gene Variants and a Lifeline for Fanconi Anemia D1 Patients.

Fanconi anemia (FA) is a DNA repair deficiency disorder associated with genomic and chromosomal instability and a high cancer risk. In a small percentage of cases, FA is caused by biallelic pathogenic variants (PVs) in the gene, defining the FA-D1 subtype. Experimental and epidemiologic data indicate that the complete absence of BRCA2 is incompatible with viability. Therefore, cells from individuals affected with FA caused by biallelic PVs must have a residual BRCA2 function. This activity may be maintained through hypomorphic missense mutations, translation termination-reinitiation associated with a translational stop mutation, or other non-canonical or uncommon translation initiation and elongation events. In some cases, however, residual BRCA2 function is provided by alternatively or aberrantly spliced transcripts. Here, we review and debate aspects of the contribution of splicing in the 5' segment to BRCA2 functions in the context of PVs affecting this largely intrinsically disordered protein region, with a focus on recent findings in individuals with FA-D1. In this Perspective, we also discuss some of the broader biological implications and open questions that arise from considering 5'-terminal splicing in light of old and new findings from FA-D1 patients and beyond.