Insights into the role of JAK2-I724T variant in myeloproliferative neoplasms from a unique cohort of New Zealand patients.

Objectives: This study aimed to compile bioinformatic and experimental information for missense variants previously reported in myeloproliferative neoplasms (MPN) and determine if germline -I724T, recently found to be common in New Zealand Polynesians, associates with MPN.

Methods: For all variants found in the literature, gnomAD_exome allele frequencies were extracted and REVEL scores were calculated using the dbNSFP database. We investigated the prevalence of -I724T in a cohort of 111 New Zealand MPN patients using a TaqMan assay, examined its allelic co-occurrence with -V617F using Oxford Nanopore sequencing, and modelled the impact of I724T on JAK2 using I-Mutant and ChimeraX software.

Results: Several non-V617F variants previously reported in MPN had REVEL scores greater than 0.5, suggesting pathogenicity. -I724T (REVEL score 0.753) was more common in New Zealand Polynesian MPN patients (n = 2/27; 7.4%) than in other New Zealand patients (n = 0/84; 0%) but less common than expected for healthy Polynesians (n = 56/377; 14.9%). Patients carrying I724T (n = 2), one with polycythaemia vera and one with essential thrombocythaemia, had high-risk MPN. Both patients with -I724T were also positive for -V617F, found on the same allele as I724T, as well as separately. In silico modelling did not identify noticeable structural changes that would give -I724T a gain-of-function.

Conclusion: Several non-canonical variants with high REVEL scores have been reported in MPN, highlighting the need to further understand their relationship with disease. The -I724T variant does not drive MPN, but additional investigations are required to exclude any potential modulatory effect on the MPN phenotype.