Clinical phenotype of germline RUNX1 haploinsufficiency: from point mutations to large genomic deletions

Abstract

Germline RUNX1 mutations result in a rare autosomal dominant condition characterized by qualitative and quantitative platelet defects and predisposition to the development of myeloid malignancies (familial platelet disorder with propensity to acute myeloid leukaemia, FPD/AML). Only 13 pedigrees have previously been described so far. We report on two novel germline RUNX1 mutations: (1) an out-of-frame 8 bp heterozygous deletion (c.442_449del) in an FPD/AML pedigree and (2) a de novo 3.5 Mb deletion in the 21q22.11.21q22.12 region encompassing the RUNX1 gene in a mentally retarded female patient with short stature and thrombocytopenia. Interestingly, a similar de novo submicroscopic deletion has been recently reported in the literature in a mentally retarded patient. Mental retardation is one of the most common disorders and primary causes of thrombocytopenia are rare. When occurring together, these features should prompt to test for 21q22 deletion for comprehensive genetic counselling and clinical management.

Familial myelodysplastic syndromes: a review of the literature

“…[28][29][30][31][32][33][34][35][36] All but one case 32 reported thrombocytopenia, with qualitative platelet defects described in 2 cases. 30,36 MDS/AML developed in 3 cases, with a median age of onset of six years (range 5-8 years). This median age is much lower than that of traditional FPD/AML and suggests that other genes within the 21q22 locus may also be important in leukemogenesis.…”

Myeloid Neoplasm With Germline Predisposition: A 2016 Update for Pathologists

“…Rare cases reporting intragenic deletion of RUNX1 gene or duplication of the chromosome 21 carrying the RUNX1-deleted or mutated allele may have similar phenotype. [29][30][31] A recent study indicated that familial platelet disorder should be suspected in AML cases with a RUNX1 biallelic mutation or with a single RUNX1 mutation with a variant allele frequency more than 50%, which could indicate trisomy 21 with a duplication of the mutated chromosome or loss of heterozygosity.…”

Elucidation of a novel pathogenomic mechanism using genome-wide long mate-pair sequencing of a congenital t(16;21) in a series of three RUNX1-mutated FPD/AML pedigrees

“…6 These data suggest that the 5q-syndrome represents a disorder of aberrant ribosome biogenesis. 3,6 Erythroid progenitor cells have a very high rate of proliferation and a requirement for massive globin synthesis, thus necessitating a very high level of ribosome biogenesis and ribosomal activity. This may explain the particular sensitivity of the erythroid lineage to reduced expression levels of ribosomal proteins.…”

“…Constitutional deletions spanning RUNX1 have been reported in isolated congenital or syndromic thrombocytopenia, stipulating copy number analysis (CNA) of RUNX1 next to sequencing. [5][6][7][8] Given clinical heterogeneity, vigilance in diagnosing FPD/AML is required, reducing the risk of stem cell transplantation (SCT) with carrier siblings. 2,3 Furthermore, the identification of a RUNX1 abnormality and the elucidation of the underlying pathogenomic mechanism may have implications for genetic counseling for recurrence risk of FPD/AML.…”