A novel RUNX1 exon 3 - 7 deletion causing a familial platelet disorder

Area of Science:

• Hematology
• Genetics
• Oncology

Background:

• Familial Platelet Disorder with associated Myeloid Malignancy (FPDMM) is a rare inherited disorder.
• It is characterized by pathogenic germline RUNX1 variants and is often underdiagnosed.
• RUNX1 mutations are also implicated in approximately 10% of adult acute myeloid leukemia (AML) and other hematologic malignancies.

Observation:

• A kindred with multiple affected individuals presented with thrombocytopenia and a history of bleeding.
• Targeted next-generation sequencing (NGS) and MLPA analysis were employed.
• A novel heterozygous large deletion (exon 3-7) in the RUNX1 gene was detected in all affected family members.

Findings:

• The identified RUNX1 deletion is predicted to eliminate the Runt-homology DNA-binding domain and part of the Activation domain.
• The combination of targeted NGS and MLPA effectively detects copy number variants (CNVs) missed by conventional sequencing.
• This study precisely diagnosed a novel germline RUNX1 deletion in FPDMM.

Implications:

• Accurate diagnosis of FPDMM enables precise genetic counseling for affected families.
• Early identification facilitates proactive clinical management to monitor for potential myeloid malignancies.
• This diagnostic approach highlights the importance of investigating CNVs in inherited hematologic disorders.