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Rare and private spliceosomal gene mutations drive partial, complete, and dual phenocopies of hotspot alterations.

ABSTRACT: Genes encoding the RNA splicing factors SF3B1, SRSF2, and U2AF1 are subject to frequent missense mutations in clonal hematopoiesis and diverse neoplastic diseases. Most "spliceosomal" mutations affect specific hotspot residues, resulting in splicing changes that promote disease pathophysiology. However, a subset of patients carries spliceosomal mutations that affect non-hotspot residues, whose potential functional contributions to disease are unstudied. Here, we undertook a systematic characterization of diverse rare and private spliceosomal mutations to infer their likely disease relevance. We used isogenic cell lines and primary patient materials to discover that 11 of 14 studied rare and private mutations in SRSF2 and U2AF1 induced distinct splicing alterations, including partially or completely phenocopying the alterations in exon and splice site recognition induced by hotspot mutations or driving "dual" phenocopies that mimicked 2 co-occurring hotspot mutations. Our data suggest that many rare and private spliceosomal mutations contribute to disease pathogenesis and illustrate the utility of molecular assays to inform precision medicine by inferring the potential disease relevance of newly discovered mutations.

SUBMITTER: Pangallo J

PROVIDER: S-EPMC7099330 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe extent to which different US private insurers require their enrollees to meet the same coverage criteria before gaining access to treatment is unclear. Our objective was to scrutinize the patient access criteria imposed by US private insurers for a set of rare neuromuscular disease (NMD) disease-modifying therapies (DMTs).MethodsWe examined coverage policies issued by 17 large US private insurers for the following NMD treatments: nusinersen and onasemnogene abeparvovec for spinal muscular atrophy, edaravone for amyotrophic lateral sclerosis, and eteplirsen for Duchenne muscular dystrophy. We reviewed the plans' coverage policies and identified the patient access criteria, including clinical prerequisites, step therapy protocols, and prescriber requirements. We compared the plans' patient access criteria with the therapies' US Food and Drug Administration (FDA)-labeled indications.ResultsThe included insurers issued 65 coverage policies for the included therapies. Plans imposed coverage restrictions beyond the FDA-approved indications in 60 coverage policies; plans did not cover eteplirsen in five policies. No therapy was covered the same way by all insurers. Plans applied clinical criteria beyond the FDA label indication in 56 policies and step therapy protocols in three policies. Plans required that a neurologist prescribe the therapy in 37 policies, 22 of which required the neurologist to have expertise in the particular disease. Plans often required patients to suffer from symptoms of particular severity; e.g. for eteplirsen, plans differed in their 6-min walk test requirements; for edaravone, some plans required that patients had normal respiratory function, while others required only that patients did not require ventilation; for nusinersen and onasemnogene abeparvovec, plans differed in the number of SMN2 gene copies they required patients to have (SMN2 copy number is correlated with disease severity).ConclusionsThe evaluated large US private insurers tended to impose coverage restrictions beyond the FDA label indication for the included set of rare NMD DMTs. Plans rarely applied the same patient access criteria in their coverage policies for the same products. Inconsistent coverage criteria mean that patients with different insurers have variable access to the same therapies across insurers.

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Rare and private spliceosomal gene mutations drive partial, complete, and dual phenocopies of hotspot alterations.

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