Minority Patients in the NIH RUNX1-FPDMM Natural History Study Present Mostly with Large Deletions Affecting RUNX1

Introduction

Germline RUNX1 pathogenic variants lead to familial platelet disorder with associated myeloid malignancy (FPDMM). The autosomal dominant syndrome is rare and even less is known about minority patients with FPDMM. Patients present with varying degrees of bleeding symptoms that may not be clinically severe. However, a high lifetime incidence (35-45%) of developing hematologic malignancies (HM) makes early genetic diagnosis essential for patients and their families. Genetic testing can be a hindrance to diagnosis for minority patients, yet key to understanding the natural history of the disease and the first step in assuring appropriate patient care and monitoring.

Objective

Using the largest, single-center cohort of patients with germline RUNX1 variants (#NCT03854318) we aim to evaluate the variant type, pathogenicity, malignancy, and mortality of minority patients with FPDMM.

Methods

From January 2019 to May 2024, we enrolled 430 participants including those suspected of having any type of germline RUNX1 variants, and unaffected family members. A total of 218 patients (97 families) were identified with RUNX1 germline variants of interest for analysis. The other 212 participants include 176 unaffected familial controls, 10 with benign/likely benign variants, 1 with a somatic variant, and 25 unconfirmed. RUNX1 germline variants were confirmed with Clinical Laboratory Improvement Amendments [CLIA]-certified Sanger sequencing and classified using the ACMG/ClinGen MM-VCEP RUNX1 classification criteria. Participants were asked to identify by ethnicity (Hispanic/Latino or Not) and/or race (White, Asian, Black/African American or More than one race).

Results

Of the 218 patients (97 families) with RUNX1 germline variant, 27 were minorities (16 families, 16%) and 191 (81 families, 84%) were White Non-Hispanic. Among the minority patients, fifteen patients (8 families, 50%) were Hispanic or Latino, seven patients (4 families, 25%) were Black or African American, and five patients (4 families, 25%) were Asian. The current median and average age of minority patients in our study are 18 (2-58) and 23 years of age (n = 25), respectively, compared with 32 (2-85) and 32 years of age respectively, for White Non-Hispanic (n = 184; median p=0.0586, mean p=0.0563).

Among the 16 minority families, fifteen unique RUNX1 variants were identified, including 7 (44%) large deletions, 4 (25%) missense, 3 (19%) frameshift, and 2 (12%) nonsense. The 7 large deletions included contiguous gene deletions resulting from 21q deletions. Fourteen variants (87.5%) were pathogenic (P), one (6.25%) likely pathogenic (LP), and one (6.25%) variant of uncertain significance (VUS). In contrast, among 81 White Non-Hispanic families, 19 (23%) of the variants were missense, 14 (17%) nonsense, 16 (20%) frameshift, 11 (14%) splice site, 10 (12%) partial deletions, 9 (11%) large deletions, and 2 (2%) duplications (p =0.0013). Forty-eight (59%) variants were classified as P, 18 (22%) LP, and 15 (19%) VUS (p =0.0517).

Five (19%) of the minority patients developed HM (2 AML, 2 MDS, and 1 ALL). In the White Non-Hispanic group, 27 patients (14%, p=0.56) developed HM (44% AML, 33% MDS, 11% CMML, 4% myeloma, and 8% other). Of the 27 minority patients, 2 (7.4%) are deceased compared to 7 (3.7%) of the 191 White Non-Hispanic group (p=0.3).

Conclusions

In the NIH RUNX1-FPDMM natural history Study, large deletions including contiguous gene deletions encompassing the RUNX1 locus, were more common in minority patient families at 44% compared to 11% in White Non-Hispanic. The minority patients were younger, had a higher percentage of pathogenic mutations, and increased deaths. Altogether minority patients had significant disease and mortality which likely contributed to their access to medical attention, identification of RUNX1 variant, and study enrollment. Access to genetic testing can be a barrier to identifying germline variants, particularly if no clinically severe phenotype exists. Less severe phenotypes may go unnoticed, decreasing early diagnosis amidst the nonetheless equally high risk of developing HM. Our data reinforces that although severe phenotypes in minority populations may alert genetic testing, more RUNX1 variant carriers with less severe phenotypes will likely go undiagnosed. Expanding our study population by increasing diversity will improve our understanding of inherited thrombocytopenia syndromes.