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Children with neurofibromatosis type 1 (NF\u20101) carry a defective <jats:italic>NF1<\/jats:italic> allele in the germline and are predisposed to JMML, which presumably requires somatic inactivation of the <jats:italic>NF1<\/jats:italic> wild\u2010type allele. Here we examined the two\u2010hit concept in leukaemic cells of 25 patients with JMML and NF\u20101. Ten patients with JMML\/NF\u20101 exhibited a <jats:italic>NF1<\/jats:italic> loss\u2010of\u2010function variant in combination with uniparental disomy of the 17q arm. Five had <jats:italic>NF1<\/jats:italic> microdeletions combined with a pathogenic <jats:italic>NF1<\/jats:italic> variant and nine carried two compound\u2010heterozygous <jats:italic>NF1<\/jats:italic> variants. We also examined 16 patients without clinical signs of NF\u20101 and no variation in the JMML\u2010associated driver genes <jats:italic>PTPN11<\/jats:italic>, <jats:italic>KRAS<\/jats:italic>, <jats:italic>NRAS<\/jats:italic> or <jats:italic>CBL<\/jats:italic> (JMML\u20105neg) and identified eight patients with NF1 variants. Three patients had microdeletions combined with hemizygous <jats:italic>NF1<\/jats:italic> variants, three had compound\u2010heterozygous <jats:italic>NF1<\/jats:italic> variants and two had heterozygous <jats:italic>NF1<\/jats:italic> variants. In addition, we found a high incidence of secondary <jats:italic>ASXL1<\/jats:italic> and\/or <jats:italic>SETBP1<\/jats:italic> variants in both groups. We conclude that the clinical diagnosis of JMML\/NF\u20101 reliably indicates a <jats:italic>NF1<\/jats:italic>\u2010driven JMML subtype, and that careful <jats:italic>NF1<\/jats:italic> analysis should be included in the genetic workup of JMML even in the absence of clinical evidence of NF\u20101.<\/jats:p>","DOI":"10.1111\/bjh.19190","type":"journal-article","created":{"date-parts":[[2023,11,10]],"date-time":"2023-11-10T02:14:58Z","timestamp":1699582498000},"page":"595-605","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Biallelic inactivation of the <scp><i>NF1<\/i><\/scp> tumour suppressor gene in juvenile myelomonocytic leukaemia: Genetic evidence of driver function and implications for diagnostic workup"],"prefix":"10.1111","volume":"204","author":[{"given":"Senthilkumar","family":"Ramamoorthy","sequence":"first","affiliation":[{"name":"Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine University of Freiburg  Freiburg Germany"},{"name":"Institute of Medical Bioinformatics and Systems Medicine, Medical Center, Faculty of Medicine University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Lebrecht","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denny","family":"Schanze","sequence":"additional","affiliation":[{"name":"Human Genetics University of Magdeburg  Magdeburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ina","family":"Schanze","sequence":"additional","affiliation":[{"name":"Human Genetics University of Magdeburg  Magdeburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilse","family":"Wieland","sequence":"additional","affiliation":[{"name":"Human Genetics University of Magdeburg  Magdeburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffroy","family":"Andrieux","sequence":"additional","affiliation":[{"name":"Institute of Medical Bioinformatics and Systems Medicine, Medical Center, Faculty of Medicine University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Metzger","sequence":"additional","affiliation":[{"name":"Institute of Medical Bioinformatics and Systems Medicine, Medical Center, Faculty of Medicine University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Hess","sequence":"additional","affiliation":[{"name":"Institute of Medical Bioinformatics and Systems Medicine, Medical Center, Faculty of Medicine University of Freiburg  Freiburg Germany"},{"name":"Faculty of Biology University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael H.","family":"Albert","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology, Dr. v. Hauner Children's Hospital University Hospital, LMU  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arndt","family":"Borkhardt","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology, Hematology and Immunology University of Dusseldorf  Dusseldorf Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorine","family":"Bresters","sequence":"additional","affiliation":[{"name":"Princess Maxima Center for Pediatric Oncology  Utrecht Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Buechner","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Oncology Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Catala","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Hospital Sant Joan de D\u00e9u  Barcelona 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