Several types of pediatric cancers reportedly contain high frequency missense mutations in histone H3, yet the underlying oncogenic mechanism remains poorly characterized. Here, we report that the H3 lysine 36 to methionine (H3K36M) mutation impairs the differentiation of mesenchymal progenitor cells and generates undifferentiated sarcoma in vivo. H3K36M mutant nucleosomes inhibit the enzymatic activities of several H3K36 methyltransferases. Depleting H3K36 methyltransferases, or expressing an H3K36I mutant that similarly inhibits H3K36 methylation, is sufficient to phenocopy the H3K36M mutation. Following the loss of H3K36 methylation, a genome-wide gain in H3K27 methylation leads to a redistribution of Polycomb Repressive Complex 1 and de-repression of its target genes known to block mesenchymal differentiation. Our findings are mirrored in human undifferentiated sarcomas where novel K36M/I mutations in H3.1 are identified.

An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole‐exome sequencing (WES), are identifying the genetic basis of disease for 25–40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation‐wide effort to identify mutations for childhood‐onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.

Deficiency in BRCA dependent DNA inter-strand crosslink (ICL) repair is intimately connected to breast cancer susceptibility and to the rare developmental syndrome, Fanconi Anemia (FA). Bona fide FA proteins, BRCA2 (FANCD1), PALB2 (FANCN), and BRIP1 (FANCJ) interact with BRCA1 during ICL repair. However, lack of detailed phenotypic and cellular characterization of a patient with biallelic BRCA1 mutations has precluded assignment of BRCA1 as a definitive FA susceptibility gene. Here we report the presence of biallelic BRCA1 mutations in a woman with multiple congenital anomalies consistent with a FA-like disorder and breast cancer at age 23. Patient cells exhibited deficiency in BRCA1 (FANCS) and Rad51 localization to DNA damage sites, combined with radial chromosome formation and hypersensitivity to ICL inducing agents. Restoration of these functions was achieved by ectopic introduction of a BRCA1 transgene. These observations provide evidence in support of BRCA1 as a new Fanconi anemia subtype (FA-S).