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Craniosynostosis is caused by abnormalities of multiple signaling pathways, including excessive RAS signaling. Recently, a truncating variant in ETS2 repressor factor (ERF), a negative transcriptional regulator of the RAS pathway, was shown to be associated with craniosynostosis. Here, we report a 10‐year‐old male patient with a heterozygous nonsense mutation, p.Arg183*, in ERF who exhibited craniosynostosis with Noonan syndrome‐like phenotypes. In consideration that loss‐of‐function variants in ERF would result in excessive RAS signaling and RASopathy phenotypes, we propose that ERF may represent a causative gene for Noonan syndrome. Since preceding studies on ERF mutations dealt with patients who were ascertained because of craniosynostosis, further studies are needed to evaluate whether patients with variants in ERF can present with Noonan syndrome‐like features without craniosynostosis. [ABSTRACT FROM AUTHOR]

Chimeric transcripts are formed by chromosomal aberrations. Little is known about the role of chimeric transcripts in the pathogenesis of birth defects. We reanalyzed RNA‐seq data in alignment map files from the peripheral blood of 56 patients in whom the diagnoses could not be confirmed by standard exome analysis and transcriptome analysis to screen for chimeric transcripts using a dedicated software, ChimPipe. Chimeric analysis led to a diagnosis in two of the 56 patients: (a) the first patient had a chimeric transcript spanning the causative gene ZEB2 and the GTDC1 gene in its neighboring locus. RNA‐seq revealed reads spanning exon 5 of ZEB2 and exon 7 of GTDC1. Whole genome sequencing revealed a 436‐kb deletion spanning intron 4 of ZEB2 and intron 7 of GTDC1 and the diagnosis of Mowat‐Wilson syndrome was made. (b) The second patient had a chimeric transcript spanning the causative gene KCNK9 and the TRAPPC9 gene in its neighboring locus. RNA‐seq revealed reads spanning exon 21 of TRAPPC9 and exon 1 of KCNK9. Whole genome sequencing revealed a 186‐kb deletion spanning intron 20 of TRAPPC9 and intron 1 of KCNK9 in this patient. KCNK9 gene is a maternally expressed imprinted gene. The diagnosis of Birk‐Barel syndrome was made. Thus, both patients had chimeric transcripts that were directly involved in the pathogenesis of the birth defects. The approach reported herein, of detecting chimeric transcripts from RNA‐seq data, is unique in that the approach does not rely on any prior information on the presence of genomic deletion. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) and Legius syndrome (LS) are caused by pathogenic variants of the I NF1 i gene and the I SPRED1 i gene, respectively.[1] I Café-au-lait i macules (CALMs) are an essential clinical feature of both disorders and appear by 3 months of age. Familial café-au-lait macules associated with in-frame deletion of NF1 p.Met992del mimicking Legius syndrome The natural history of the two disorders is distinctive after puberty: cutaneous neurofibromas and nodular plexiform neurofibromas appear after adolescence in NF1 patients,[2] but never in LS patients. [Extracted from the article]