First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM.

The genomic region surrounding the Tenascin‐XB gene (TNXB) is a complex and duplicated region, with several pseudogenes that predispose to high rates of homologous recombination. Classical‐like Ehlers–Danlos syndrome (clEDS) is the result of tenascin‐X deficiency due to biallelic loss of function variants in the TNXB gene. Here we present a patient with clEDS and spontaneous pneumothorax, a feature not previously reported to be associated with this condition. Two inherited pathogenic/likely pathogenic variants were identified; a previously reported deletion resulting in a TNXA/TNXB chimeric gene and a novel frameshift variant. The Tenascin‐XB gene is well described in the literature to be associated with collagen metabolism, stabilization of the fibrillar‐collagen matrix and is expressed abundantly in the extracellular matrix. We propose that tenascin‐X deficiency is directly related to pneumothorax predisposition. This case expands the phenotypic spectrum of clEDS and highlights the challenges with molecular analysis and diagnosis

The role of RNF43 as a cause of an inherited predisposition to colorectal cancer (CRC) is yet to be fully explored. This report presents our findings of two individuals with CRC from a single family carrying a likely-pathogenic inherited germline variant in RNF43. The proband (III:1) and the proband's mother (II:2) were diagnosed with mismatch repair proficient CRCs at the age of 50 years and 65 years, respectively.Both patients had BRAF V600E mutated colon tumours, indicating that the CRCs arose in sessile serrated lesions. The germline variant RNF43:c.375+1G>A was identified in both patients. RNA studies showed that this variant resulted in an aberrantly spliced transcript, which was predicted to encode RNF43:p.Ala126Ilefs*50 resulting in premature termination of protein synthesis and was classified as a likely-pathogenic variant. Our report adds further evidence to the hereditary role of RNF43 as a tumour suppressor gene in colorectal tumorigenesis and supports the inclusion of RNF43 as a gene of interest in the investigation of CRC predispositions outside the setting of serrated polyposis.

Background: This year, germline predisposition to haematological malignancy (HM) debuts in the World Health Organization classification of myeloid neoplasms and acute leukemia (Blood, 2016;127:2391). It has been 17 years since germline mutations in RUNX1 were found to lead to familial platelet disorder (FPD) with predisposition to myelodysplastic syndrome and acute myeloid leukaemia (MDS/AML) (Nat Genet. 1999;23:166). Now, nearly 80 families have been reported with damaging germline mutations or deletions affecting RUNX1 function, associated with FPD, making it an increasingly significant clinical presence. Although thrombocytopenia and platelet dysfunction are present in almost all RUNX1 mutant carriers, we and others have observed that the predisposition to HM varies between family members, with respect to age at diagnosis and the type of malignancy, and in some cases RUNX1 mutation carriers have no apparent HM development over their lifespan. The reasons for this heterogeneity are currently unknown. Aims: We are conducting an international collaborative study examining RUNX1 mutated families. The aim of the research project is to classify the range of phenotypes correlated with RUNX1 mutations comprehensively (including non-malignant phenotypes such as skin disorders) and to determine if the type of RUNX1 mutation and the presence of other germline and acquired mutations in relevant HM genes correlate with the likelihood of HM development, or the type of HM that develops. Across all of our data we aim to analyse clinically relevant information that will be used to inform prognosis and clinical management in germline RUNX1 mutation carriers. Results:From a review of the literature for previously characterised RUNX1 mutant families most mutations are predicted to be loss-of-function, with the combination of frameshift, stopgain, splicing and deletion accounting for the majority of alterations (57, 70%) compared to missense mutations (22, Figure 1). The most common sites of mutation are R201 and R204, affected by both missense and stopgain (10 total), which lie within the nuclear localisation signal at the end of the RUNT domain (Figure 1). We also surveyed in detail 12 RUNX1 pedigrees with both novel and previously described missense, frameshift, stopgain and deletion mutations and found that, while all families developed myeloid malignancies, 6 families also had individuals who developed lymphoid malignancy (most often Acute lymphoblastic leukemia (ALL)) which was heritable in sub-families, and subject to anticipation (e.g see IV-5 and V-5 in Figure 2). Consistent with population genome wide association studies identifying RUNX1 as a susceptibility locus for psoriasis (J Autoimmun. 2015;64:66), we find that skin conditions (psoriasis, eczema) are common, and present in germline RUNX1 carriers in 50% of our families; most commonly observed in families with stopgain and frameshift mutations. Genomic analysis of selected samples confirms that mutation of the other RUNX1 allele is the most commonly acquired mutation in germline RUNX1 mutation carriers developing HM. Alterations of chromosomes 21 and 7 are also common. DNMT3A and PHF6 acquired mutations were the next most frequently observed in tumors and mutations in U2AF1 and ASXL1 in the blood of RUNX1 carriers without HM were observed, suggestive of pre-HM clonal expansion. Finally, in a family with a novel R169I RUNX1 mutation, a rare germline ASXL1 variant (E1102D, 1.0% in ExAC) was found in two RUNX1 carriers who developed early onset AML. This variant is also significantly enriched in an MDS cohort unselected for family history compared to the general population (HR 1.3, p=0.02), as well as ASXL1 N986S (0.1% in ExAC, HR 3.3, p=0.0002) suggesting they operate as germline HM risk modifiers. Interestingly RUNX1 and ASXL1 acquired mutations often co-occur in sporadic MDS/AML and our data suggests this collaboration may also occur at the germline level. Conclusions:Annotation of skin phenotypes co-existent with a family history of haematological malignancy may assist in identifying RUNX1 mutant families. Both acquired and germline mutations in known HM genes may modify germline RUNX1 driven HM penetrance and phenotype. Our data suggest that screening of RUNX1 germline mutation carriers for germline and acquired variants in other HM genes could provide an important tool for defining risk and requires further investigation. Disclosures Owen: Pharmacyclics: Research Funding; Janssen: Honoraria; Roche: Honoraria, Research Funding; Novartis: Honoraria; Gilead: Honoraria, Research Funding; Lundbeck: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria. Godley:UpToDate: Honoraria; Onconova, Inc.: Research Funding.

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