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The study sought to identify genetic aberrations driving oral squamous cell carcinoma (OSCC) development among users of shammah, an Arabian preparation of smokeless tobacco. Twenty archival OSCC samples, 15 of which with a history of shammah exposure, were whole-exome sequenced at an average depth of 127×. Somatic mutations were identified using a novel, matched controls-independent filtration algorithm. CODEX and Exomedepth coupled with a novel, Database of Genomic Variant-based filter were employed to call somatic gene-copy number variations. Significantly mutated genes were identified with Oncodrive FM and the Youn and Simon's method. Candidate driver genes were nominated based on Gene Set Enrichment Analysis. The observed mutational spectrum was similar to that reported by the TCGA project. In addition to confirming known genes of OSCC (TP53, CDKNA2, CASP8, PIK3CA, HRAS, FAT1, TP63, CCND1 and FADD) the analysis identified several candidate novel driver events including mutations of NOTCH3, CSMD3, CRB1, CLTCL1, OSMR and TRPM2, amplification of the proto-oncogenes FOSL1, RELA, TRAF6, MDM2, FRS2 and BAG1, and deletion of the recently described tumor suppressor SMARCC1. Analysis also revealed significantly altered pathways not previously implicated in OSCC including Oncostatin-M signalling pathway, AP-1 and C-MYB transcription networks and endocytosis. There was a trend for higher number of mutations, amplifications and driver events in samples with history of shammah exposure particularly those that tested EBV positive, suggesting an interaction between tobacco exposure and EBV. The work provides further evidence for the genetic heterogeneity of oral cancer and suggests shammah-associated OSCC is characterized by extensive amplification of oncogenes.

Smith-Magenis syndrome (SMS) is a mental retardation syndrome with distinctive behavioral characteristics, dysmorphic features, and congenital anomalies usually associated with an interstitial deletion of chromosome 17p11.2. While high quality G-banding will identify most SMS patients, fluorescent in situ hybridization (FISH) is the recommended test for confirmation of an SMS diagnosis. Recently, haploinsufficiency of the RAI1 gene due to deletion or mutation was determined to be the likely cause of SMS. All diagnostic FISH probes available commercially contain the FLII gene and are approximately 580 kb centromeric to RAI1. We present two patients with SMS who have interstitial deletions at 17p11.2 but are not deleted for currently available commercial FISH probes that include FLII; both patients have deletions that are demonstrated with probes containing the RAI1 gene. We recommend that for diagnostic accuracy, all future FISH tests for SMS be performed with probes containing the RAI1 gene, as some atypical deletions in the region critical to the SMS phenotype will otherwise be missed.

Greig cephalopolysyndactyly syndrome (GCPS) is caused by haploinsufficiency of GLI3 on 7p13. Features of GCPS include polydactyly, macrocephaly, and hypertelorism, and may be associated with cognitive deficits and abnormalities of the corpus callosum. GLI3 mutations in GCPS patients include point, frameshift, translocation, and gross deletion mutations. FISH and STRP analyses were applied to 34 patients with characteristics of GCPS. Deletions were identified in 11 patients and the extent of their deletion was determined. Nine patients with deletions had mental retardation (MR) or developmental delay (DD) and were classified as severe GCPS. These severe GCPS patients have manifestations that overlap with the acrocallosal syndrome (ACLS). The deletion breakpoints were analyzed in six patients whose deletions ranged in size from 151 kb to 10.6 Mb. Junction fragments were found to be distinct with no common sequences flanking the breakpoints. We conclude that patients with GCPS caused by large deletions that include GLI3 are likely to have cognitive deficits, and we hypothesize that this severe GCPS phenotype is caused by deletion of contiguous genes.

We describe a 38-year-old adult who has a supernumerary marker chromosome in 40% of metaphase cells which was identified by reverse in situ hybridization with a DNA probe made by microdissection to be derived from chromosome 17. The breakpoints are estimated by G-banding and fluorescence in situ hybridization (FISH) to consist of the region from 17p11.1 to proximal 17q21. The propositus displayed severe growth retardation, kyphoscoliosis, bilateral cataracts, severe calcaneovalgus deformity of the feet, dysmorphic facies, profound mental retardation, and multiple medical problems requiring ongoing medical management. These problems included a mitral valve prolapse with regurgitation, recurrent upper and lower respiratory tract infections, and severe respiratory insufficiency. The relatively long survival of this patient enabled us to describe the natural history of this rare chromosomal mutation.