Bailey.Glen: Created page with " ==Primary Author(s)*== Malini Sathanoori, PhD, FACMG Pathgroup Labs, Nashville, TN TOC ==Cancer Category/Type== Myeloid Neoplasms with Germline Predisposition..."

2023-11-03T17:31:47Z

Created page with " ==Primary Author(s)*== Malini Sathanoori, PhD, FACMG Pathgroup Labs, Nashville, TN __TOC__ ==Cancer Category/Type== Myeloid Neoplasms with Germline Predisposition..."

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==Primary Author(s)*==

Malini Sathanoori, PhD, FACMG

Pathgroup Labs, Nashville, TN

__TOC__

==Cancer Category/Type==
[[Myeloid Neoplasms with Germline Predisposition]]

==Cancer Sub-Classification / Subtype==

Myeloid Neoplasms with Germline RUNX1 Mutation

==Definition / Description of Disease==

This is a distinct entity in the World Health Organization (WHO) classification system within the section of [[Myeloid Neoplasms with Germline Predisposition]]<ref>Peterson LC, et al., (2017). Myeloid neoplasms with germline predisposition, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p125.</ref>.

Familial platelet disorder with propensity to myeloid malignancies (FPDMM aka FPD) is an autosomal dominant disorder characterized by quantitative and/or qualitative platelet defects with a tendency to develop a variety of hematological malignancies including MDS/AML. Heterozygous germline mutations in the RUNX1 gene are responsible genetic events for FPD/AML<ref name=":0">{{Cite journal|last=Hayashi|first=Yoshihiro|last2=Harada|first2=Yuka|last3=Huang|first3=Gang|last4=Harada|first4=Hironori|date=2017|title=Myeloid neoplasms with germ line RUNX1 mutation|url=http://link.springer.com/10.1007/s12185-017-2258-5|journal=International Journal of Hematology|language=en|volume=106|issue=2|pages=183–188|doi=10.1007/s12185-017-2258-5|issn=0925-5710}}</ref><ref name=":1">{{Cite journal|last=Owen|first=Carolyn|last2=Barnett|first2=Michael|last3=Fitzgibbon|first3=Jude|date=2007|title=Familial myelodysplasia and acute myeloid leukaemia - a review: Review|url=http://doi.wiley.com/10.1111/j.1365-2141.2007.06909.x|journal=British Journal of Haematology|language=en|volume=140|issue=2|pages=123–132|doi=10.1111/j.1365-2141.2007.06909.x}}</ref>.

RUNX1 germline mutations cause impaired megakaryopoiesis that gives rise to inherited thrombocytopenia and subsequent acute myeloid leukemia (AML)<ref>{{Cite journal|last=Matsui|first=Hirotaka|date=2017|title=Familial predisposition of myeloid malignancies: biological and clinical significance of recurrent germ line mutations|url=http://link.springer.com/10.1007/s12185-017-2284-3|journal=International Journal of Hematology|language=en|volume=106|issue=2|pages=160–162|doi=10.1007/s12185-017-2284-3|issn=0925-5710}}</ref>.

==Synonyms / Terminology==

Familial Platelet Disorder with associated Myeloid Malignancy; [https://www.omim.org/entry/601399 FPDMM]

Familial platelet disorder with predisposition to acute myelogenous leukemia; FPD/AML

Familial platelet disorder with predisposition to myeloid malignancy

Familial platelet disorder with propensity to acute myeloid leukemia

[https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=71290 Familial thrombocytopenia with propensity to acute myelogenous leukemia]

==Epidemiology / Prevalence==

FPD/AML typically manifests in individuals at around 30-40 yrs. of age<ref name=":0" />. The lifetime risk of developing MDS/AML in FPD/AML patients is about 40% as reported in various studies with an average age of onset being 33 years<ref>{{Cite journal|last=Liew|first=E.|last2=Owen|first2=C.|date=2011|title=Familial myelodysplastic syndromes: a review of the literature|url=http://www.haematologica.org/cgi/doi/10.3324/haematol.2011.043422|journal=Haematologica|language=en|volume=96|issue=10|pages=1536–1542|doi=10.3324/haematol.2011.043422|issn=0390-6078|pmc=PMC3186316|pmid=21606161}}</ref>. Although the majority of these patients develop MDS/AML, other types of leukemia such as T-acute lymphoblastic leukemia (T‐ALL)<ref>{{Cite journal|last=Nishimoto|first=Nahoko|last2=Imai|first2=Yoichi|last3=Ueda|first3=Koki|last4=Nakagawa|first4=Masahiro|last5=Shinohara|first5=Akihito|last6=Ichikawa|first6=Motoshi|last7=Nannya|first7=Yasuhito|last8=Kurokawa|first8=Mineo|date=2010|title=T cell acute lymphoblastic leukemia arising from familial platelet disorder|url=http://link.springer.com/10.1007/s12185-010-0612-y|journal=International Journal of Hematology|language=en|volume=92|issue=1|pages=194–197|doi=10.1007/s12185-010-0612-y|issn=0925-5710}}</ref>, hairy cell leukemia (HCL)<ref>{{Cite journal|last=Toya|first=Takashi|last2=Yoshimi|first2=Akihide|last3=Morioka|first3=Takehiko|last4=Arai|first4=Shunya|last5=Ichikawa|first5=Motoshi|last6=Usuki|first6=Kensuke|last7=Kurokawa|first7=Mineo|date=2014|title=Development of hairy cell leukemia in familial platelet disorder with predisposition to acute myeloid leukemia|url=http://www.tandfonline.com/doi/full/10.3109/09537104.2013.818636|journal=Platelets|language=en|volume=25|issue=4|pages=300–302|doi=10.3109/09537104.2013.818636|issn=0953-7104}}</ref>, and chronic myelomonocytic leukemia (CMML)<ref>{{Cite journal|last=Shiba|first=Norio|last2=Hasegawa|first2=Daisuke|last3=Park|first3=Myoung-ja|last4=Murata|first4=Chisato|last5=Sato-Otsubo|first5=Aiko|last6=Ogawa|first6=Chitose|last7=Manabe|first7=Atsushi|last8=Arakawa|first8=Hirokazu|last9=Ogawa|first9=Seishi|date=2012|title=CBL mutation in chronic myelomonocytic leukemia secondary to familial platelet disorder with propensity to develop acute myeloid leukemia (FPD/AML)|url=https://ashpublications.org/blood/article/119/11/2612/29593/CBL-mutation-in-chronic-myelomonocytic-leukemia|journal=Blood|language=en|volume=119|issue=11|pages=2612–2614|doi=10.1182/blood-2011-02-333435|issn=0006-4971}}</ref> have been described.

==Clinical Features==

The clinical presentation of FPDMM is highly variable, even within the same family with heterogeneity in age, presentation and significant risk of MDS/AML transformation estimated at 20–60%<ref>{{Cite journal|last=Babushok|first=Daria V.|last2=Bessler|first2=Monica|last3=Olson|first3=Timothy S.|date=2016|title=Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults|url=https://www.tandfonline.com/doi/full/10.3109/10428194.2015.1115041|journal=Leukemia & Lymphoma|language=en|volume=57|issue=3|pages=520–536|doi=10.3109/10428194.2015.1115041|issn=1042-8194|pmc=PMC4798888|pmid=26693794}}</ref><ref name=":2">{{Cite journal|last=Rio-Machin|first=Ana|last2=Vulliamy|first2=Tom|last3=Hug|first3=Nele|last4=Walne|first4=Amanda|last5=Tawana|first5=Kiran|last6=Cardoso|first6=Shirleny|last7=Ellison|first7=Alicia|last8=Pontikos|first8=Nikolas|last9=Wang|first9=Jun|date=2020|title=The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants|url=http://www.nature.com/articles/s41467-020-14829-5|journal=Nature Communications|language=en|volume=11|issue=1|doi=10.1038/s41467-020-14829-5|issn=2041-1723|pmc=PMC7042299|pmid=32098966}}</ref><ref name=":3">{{Cite journal|last=Brown|first=Anna L.|last2=Arts|first2=Peer|last3=Carmichael|first3=Catherine L.|last4=Babic|first4=Milena|last5=Dobbins|first5=Julia|last6=Chong|first6=Chan-Eng|last7=Schreiber|first7=Andreas W.|last8=Feng|first8=Jinghua|last9=Phillips|first9=Kerry|date=2020|title=RUNX1-mutated families show phenotype heterogeneity and a somatic mutation profile unique to germline predisposed AML|url=https://ashpublications.org/bloodadvances/article/4/6/1131/452758/RUNX1mutated-families-show-phenotype-heterogeneity|journal=Blood Advances|language=en|volume=4|issue=6|pages=1131–1144|doi=10.1182/bloodadvances.2019000901|issn=2473-9529|pmc=PMC7094007|pmid=32208489}}</ref>. Patients often present with either personal or family history of mild‐to‐moderate bleeding tendency typically present from childhood. The bleeding tendencies are secondary to thrombocytopenia and/or platelet dysfunction. However, some family members harboring the germline RUNX1 mutation have normal platelet counts, thus escaping the diagnosis of inherited thrombocytopenia (IT)<ref name=":4">{{Cite journal|last=Galera|first=Pallavi|last2=Dulau‐Florea|first2=Alina|last3=Calvo|first3=Katherine R.|date=2019|title=Inherited thrombocytopenia and platelet disorders with germline predisposition to myeloid neoplasia|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/ijlh.12999|journal=International Journal of Laboratory Hematology|language=en|volume=41|issue=S1|pages=131–141|doi=10.1111/ijlh.12999|issn=1751-5521}}</ref>.

==Sites of Involvement==

Blood and bone marrow

==Morphologic Features==

Bone marrow features in patients with FPDMM may overlap with idiopathic thrombocytopenic purpura (ITP) or sporadic MDS leading to misdiagnosis<ref name=":4" />. Patients with FPDMM often have atypical megakaryocytes with small hypolobated and eccentric nuclei even in the absence of clonal cytogenetic abnormalities; these findings are related to the underlying RUNX1 germline mutation and not diagnostic of MDS. Patients may present with isolated thrombocytopenia and megakaryocytic dysmorphia or atypia on baseline bone marrow evaluation, without constituting myelodysplasia (MDS). Isolated megakaryocytic dysplasia in patients with unexplained thrombocytopenia should raise the possibility of an underlying germline RUNX1 mutation<ref>{{Cite journal|last=Chisholm|first=Karen M|last2=Denton|first2=Christopher|last3=Keel|first3=Sioban|last4=Geddis|first4=Amy E|last5=Xu|first5=Min|last6=Appel|first6=Burton E|last7=Cantor|first7=Alan B|last8=Fleming|first8=Mark D|last9=Shimamura|first9=Akiko|date=2019|title=Bone Marrow Morphology Associated With Germline RUNX1 Mutations in Patients With Familial Platelet Disorder With Associated Myeloid Malignancy|url=http://journals.sagepub.com/doi/10.1177/1093526618822108|journal=Pediatric and Developmental Pathology|language=en|volume=22|issue=4|pages=315–328|doi=10.1177/1093526618822108|issn=1093-5266}}</ref>.

==Immunophenotype==

Documented reports on flow cytometry findings in FPDMM are limited in the literature. However, two studies<ref>{{Cite journal|last=Cy|first=Ok|last2=V|first2=Leventaki|last3=Sa|first3=Wang|last4=C|first4=Dinardo|last5=Lj|first5=Medeiros|last6=S|first6=Konoplev|date=2016|title=Detection of an Abnormal Myeloid Clone by Flow Cytometry in Familial Platelet Disorder With Propensity to Myeloid Malignancy|url=https://pubmed.ncbi.nlm.nih.gov/26800764/|language=en|doi=10.1093/ajcp/aqv080|pmc=PMC4934016|pmid=26800764}}</ref><ref>{{Cite journal|last=R|first=Kanagal-Shamanna|last2=S|first2=Loghavi|last3=Cd|first3=DiNardo|last4=Lj|first4=Medeiros|last5=G|first5=Garcia-Manero|last6=E|first6=Jabbour|last7=Mj|first7=Routbort|last8=R|first8=Luthra|last9=Ce|first9=Bueso-Ramos|date=2017|title=Bone Marrow Pathologic Abnormalities in Familial Platelet Disorder With Propensity for Myeloid Malignancy and Germline RUNX1 Mutation|url=https://pubmed.ncbi.nlm.nih.gov/28659335/|language=en|doi=10.3324/haematol.2017.167726|pmc=PMC5622850|pmid=28659335}}</ref> reported findings on a panel of markers listed in the below table. In general, the histopathological findings in FPDMM is very similar to sporadic AML/MDS at the onset of myeloid malignancy.

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||CD34, CD33
|-
|Increased Expression||CD13, CD117, CD123
|-
|Decreased Expression||CD38
|}

==Chromosomal Rearrangements (Gene Fusions)==

While there are no characteristic chromosome rearrangements associated with FPDMM per se, a few case reports on constitutional rearrangements involving chromosome 21q22 at the RUNX1 gene location have been described in the literature<ref name=":5">{{Cite journal|last=E|first=Vormittag-Nocito|last2=H|first2=Ni|last3=Ml|first3=Schmidt|last4=V|first4=Lindgren|date=2019|title=Thrombocytopenia and Predisposition to Acute Myeloid Leukemia Due to Mosaic Ring 21 With Loss of RUNX1: Cytogenetic and Molecular Characterization|url=https://pubmed.ncbi.nlm.nih.gov/30800047/|language=en|doi=10.1159/000494645|pmc=PMC6381886|pmid=30800047}}</ref><ref name=":6">{{Cite journal|last=A|first=Buijs|last2=M|first2=Poot|last3=S|first3=van der Crabben|last4=B|first4=van der Zwaag|last5=E|first5=van Binsbergen|last6=Mj|first6=van Roosmalen|last7=M|first7=Tavakoli-Yaraki|last8=O|first8=de Weerdt|last9=Hk|first9=Nieuwenhuis|date=2012|title=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|url=https://pubmed.ncbi.nlm.nih.gov/22430633/|language=en|pmid=22430633}}</ref>

{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|-
|r(21)(p13q22)||Unknown||Haploinsufficiency due to loss of RUNX1 gene||Case report<ref name=":5" />
|-
|t(16;21)(p13;q22)||?/5' RUNX1||Likely haploinsufficiency due to disruption of RUNX1 gene||Case report<ref name=":6" />
|}

==Characteristic Chromosomal Aberrations / Patterns==

Both sporadic and germline RUNX1-mutated AMLs demonstrated a similar frequency of monosomy 7, whereas sporadic RUNX1-mutated AML had an increased frequency of trisomy 8<ref name=":3" />.

==Genomic Gain/Loss/LOH==

Although most of the FPDMM families harbor germline RUNX1 variants, inherited large intragenic duplications/deletions have been also described in these families<ref name=":2" />. In addition, de novo microdeletion 21q22.11~12 as a cause of syndromic thromobocytopenia and predisposition to MDS/AML have been reported in the literature <ref>{{Cite journal|last=M|first=Shinawi|last2=A|first2=Erez|last3=Dl|first3=Shardy|last4=B|first4=Lee|last5=R|first5=Naeem|last6=G|first6=Weissenberger|last7=Ac|first7=Chinault|last8=Sw|first8=Cheung|last9=Se|first9=Plon|date=2008|title=Syndromic Thrombocytopenia and Predisposition to Acute Myelogenous Leukemia Caused by Constitutional Microdeletions on Chromosome 21q|url=https://pubmed.ncbi.nlm.nih.gov/18487507/|language=en|doi=10.1182/blood-2008-01-135970|pmc=PMC2515126|pmid=18487507}}</ref><ref>{{Cite journal|last=E|first=Katzaki|last2=G|first2=Morin|last3=M|first3=Pollazzon|last4=Ft|first4=Papa|last5=S|first5=Buoni|last6=J|first6=Hayek|last7=J|first7=Andrieux|last8=L|first8=Lecerf|last9=C|first9=Popovici|date=2010|title=Syndromic Mental Retardation With Thrombocytopenia Due to 21q22.11q22.12 Deletion: Report of Three Patients|url=https://pubmed.ncbi.nlm.nih.gov/20578134/|language=en|pmid=20578134}}</ref><ref>{{Cite journal|last=Rd|first=Christensen|last2=Se|first2=Wiedmeier|last3=Hm|first3=Yaish|date=2013|title=A Neonate With Congenital Amegakaryocytic Thrombocytopenia Associated With a Chromosomal Microdeletion at 21q22.11 Including the Gene RUNX1|url=https://pubmed.ncbi.nlm.nih.gov/23443295/|language=en|pmid=23443295}}</ref>.
==Gene Mutations (SNV/INDEL)==

Most patients with FPD carry RUNX1 gene point mutations and small indels, that result in missense, nonsense or frame shift changes in the protein. Rarely, larger intragenic deletions and duplications have also been reported. Most often, RUNX1 germline mutations cluster in the runt-homology domain (RHD) and transactivation domain (TAD) <ref name=":7">{{Cite journal|last=Sood|first=Raman|last2=Kamikubo|first2=Yasuhiko|last3=Liu|first3=Paul|date=2017-04-13|title=Role of RUNX1 in hematological malignancies|url=https://pubmed.ncbi.nlm.nih.gov/28179279|journal=Blood|volume=129|issue=15|pages=2070–2082|doi=10.1182/blood-2016-10-687830|issn=1528-0020|pmc=5391618|pmid=28179279}}</ref>. Family studies reported in literature have observed most RUNX1 germline mutations in residues within RHD (AA 105-204) <ref name=":7" /><ref>{{Cite journal|last=Luo|first=Xi|last2=Feurstein|first2=Simone|last3=Mohan|first3=Shruthi|last4=Porter|first4=Christopher C.|last5=Jackson|first5=Sarah A.|last6=Keel|first6=Sioban|last7=Chicka|first7=Michael|last8=Brown|first8=Anna L.|last9=Kesserwan|first9=Chimene|date=2019-10-22|title=ClinGen Myeloid Malignancy Variant Curation Expert Panel recommendations for germline RUNX1 variants|url=https://pubmed.ncbi.nlm.nih.gov/31648317|journal=Blood Advances|volume=3|issue=20|pages=2962–2979|doi=10.1182/bloodadvances.2019000644|issn=2473-9537|pmc=6849945|pmid=31648317}}</ref>. A complete list of known and reported germline mutations can be found in external public databases such as [https://search.clinicalgenome.org/kb/genes/HGNC:10471 ClinGen] <ref>{{Cite journal|last=Wu|first=David|last2=Luo|first2=Xi|last3=Feurstein|first3=Simone|last4=Kesserwan|first4=Chimene|last5=Mohan|first5=Shruthi|last6=Pineda-Alvarez|first6=Daniel E.|last7=Godley|first7=Lucy A.|last8=collaborative group of the American Society of Hematology - Clinical Genome Resource Myeloid Malignancy Variant Curation Expert Panel|date=2020-04|title=How I curate: applying American Society of Hematology-Clinical Genome Resource Myeloid Malignancy Variant Curation Expert Panel rules for RUNX1 variant curation for germline predisposition to myeloid malignancies|url=https://pubmed.ncbi.nlm.nih.gov/32165484|journal=Haematologica|volume=105|issue=4|pages=870–887|doi=10.3324/haematol.2018.214221|issn=1592-8721|pmc=7109758|pmid=32165484}}</ref> and [https://www.ncbi.nlm.nih.gov/clinvar/?term=Runx1%5Bgene%5D ClinVar].<br />
===Other Mutations===
Acquisition of second genetic event involving RUNX1 or secondary mutations in other myeloid-related genes is associated with progression to MDS/AML<ref name=":3" />. Studies reported in literature are a small cohort of family studies, and have observed a high frequency of RUNX1 alterations on the other allele as the second hit.
{| class="wikitable sortable"
|-
!Type!!Gene/Region/Other
|-
|Secondary Mutations||RUNX1 (second hit), GATA2, ASXL1, CEBPA, JAK2 <ref name=":3" />
|}
==Epigenomics (Methylation)==

None at this time

==Genes and Main Pathways Involved==

RUNX1 is a tumor suppressor gene. It encodes a subunit of the core binding factor (CBF) transcription factor, which regulates expression of several hematopoietic genes. The RUNX1 protein contains a DNA‐binding domain (termed runt homology domain – RHD) and a domain that enables it to dimerize with its partner, CBFB. A variety of mutations in RUNX1 have been described in individual families with FPD/AML, most in the RHD<ref>{{Cite journal|last=Song|first=Woo-Joo|last2=Sullivan|first2=Melanie G.|last3=Legare|first3=Robert D.|last4=Hutchings|first4=Sarah|last5=Tan|first5=Xiaolian|last6=Kufrin|first6=Dubravka|last7=Ratajczak|first7=Janina|last8=Resende|first8=Isabel C.|last9=Haworth|first9=Catherine|date=1999|title=Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia|url=http://www.nature.com/articles/ng1099_166|journal=Nature Genetics|language=en|volume=23|issue=2|pages=166–175|doi=10.1038/13793|issn=1061-4036}}</ref>. Individual mutations are thought to result in different degrees of functional loss of the RUNX1 protein and variable phenotypes of the FPD/AML disease between families<ref name=":1" />.
==Diagnostic Testing Methods==

RUNX1 mutations are unique for each FPDMM family with very few recurrent mutations described in literature, making diagnostic molecular testing challenging. Genomic Sequencing of all RUNX1 coding exons is recommended and copy number analysis by whole genome arrays for large deletions and duplications will be useful in such instances when there is a high index of suspicion for a germline mutation and standard testing is negative<ref name=":4" />.

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==

RUNX1 germline mutation is known to be associated with a long-standing thrombocytopenia. RUNX1 germline mutation by itself is not sufficient to cause hematological neoplasm. Most individuals that carry a germline RUNX1 mutation need additional secondary genetic alteration in either RUNX1 or other myeloid genes to develop hematological neoplasms. Progression to MDS/AML may be associated with bi‐ or pancytopenia, multilineage dysplasia, acquisition of cytogenetic abnormalities, or somatic mutations indicating clonal progression, and/or bi‐allelic mutations in RUNX1, ANKRD26, or ETV6<ref name=":4" />.

Currently there is no specific targeted therapy for RUNX1 germline mutation. However, the curative therapy of choice for many of the myeloid neoplasms with germline predisposition is an allogeneic HSCT<ref>{{Cite journal|last=Godley|first=Lucy A.|last2=Shimamura|first2=Akiko|date=2017-07-27|title=Genetic predisposition to hematologic malignancies: management and surveillance|url=https://pubmed.ncbi.nlm.nih.gov/28600339|journal=Blood|volume=130|issue=4|pages=424–432|doi=10.1182/blood-2017-02-735290|issn=1528-0020|pmc=5533201|pmid=28600339}}</ref>. There is mounting evidence that preemptive allogeneic hematopoietic stem-cell transplantation (pHSCT) can improve overall outcomes <ref>{{Cite journal|last=Hamilton|first=Kayla V.|last2=Maese|first2=Luke|last3=Marron|first3=Jonathan M.|last4=Pulsipher|first4=Michael A.|last5=Porter|first5=Christopher C.|last6=Nichols|first6=Kim E.|date=2019-08-20|title=Stopping Leukemia in Its Tracks: Should Preemptive Hematopoietic Stem-Cell Transplantation be Offered to Patients at Increased Genetic Risk for Acute Myeloid Leukemia?|url=https://pubmed.ncbi.nlm.nih.gov/31170028|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=37|issue=24|pages=2098–2104|doi=10.1200/JCO.19.00181|issn=1527-7755|pmid=31170028}}</ref>.
==Familial Forms==

Familial platelet disorder with predisposition to acute myelogenous leukemia; [https://www.omim.org/entry/601399 FPD/AML]

==Other Information==

Genetic counseling is an important consequence of the identification of RUNX1 germline mutation. Equally important is choosing appropriate treatment regimens and genetic screening of potential‐related donors for HSCT to avoid using a mutation positive‐related donor and subsequent donor‐derived MDS/AML or other hematologic malignancy<ref name=":2" /><ref name=":4" /><ref>{{Cite journal|last=Schlegelberger|first=Brigitte|last2=Heller|first2=Paula G.|date=2017|title=RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM)|url=https://linkinghub.elsevier.com/retrieve/pii/S0037196317300471|journal=Seminars in Hematology|language=en|volume=54|issue=2|pages=75–80|doi=10.1053/j.seminhematol.2017.04.006}}</ref>.

Individuals carrying homozygous RUNX1 mutations, bi-allelic RUNX1 mutations ''in trans'' (compound heterozygous RUNX1 mutations)'','' RUNX1 mutations at heterozygous allele frequency of 50%, and trisomy 21 may indicate that those individuals are likely to carry germline RUNX1 variants causing FPDMM <ref>{{Cite journal|last=B|first=Schlegelberger|last2=Pg|first2=Heller|date=2017|title=RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM)|url=https://pubmed.ncbi.nlm.nih.gov/28637620/|language=en|pmid=28637620}}</ref>.

==Links==

[[RUNX1]]

[https://omim.org/entry/601399 Platelet Disorder, Familial, With Associated Myeloid Malignancy; FPDMM]

[https://search.clinicalgenome.org/kb/genes/HGNC:10471 ClinGen]

[https://www.ncbi.nlm.nih.gov/clinvar/?term=RUNX1%5Bgene%5D ClinVar]

[https://rarediseases.info.nih.gov/diseases/10352/index GARD]

==References==
<references />

==Notes==
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HAEM4Backup:Myeloid Neoplasms with Germline RUNX1 Mutation - Revision history

Bailey.Glen: Created page with " ==Primary Author(s)*== Malini Sathanoori, PhD, FACMG Pathgroup Labs, Nashville, TN __TOC__ ==Cancer Category/Type== Myeloid Neoplasms with Germline Predisposition..."

Bailey.Glen: Created page with " ==Primary Author(s)*== Malini Sathanoori, PhD, FACMG Pathgroup Labs, Nashville, TN TOC ==Cancer Category/Type== Myeloid Neoplasms with Germline Predisposition..."