Identification of a Novel Non-V600E BRAF Mutation in Papillary Thyroid Cancer.

Papillary thyroid cancer (PTC) is a common endocrine malignancy, and its incidence is reported to be constantly increasing. BRAF mutation is detected in approximately 44% of PTCs, and the most common BRAF mutation is thymine (T) to adenine (A) missense mutation in nucleotide 1796 (T1796A, V600E). Although BRAFV600E represents 95% of all BRAF mutations, uncommon BRAF mutations have been reported in thyroid carcinomas and represent an alternative mechanism of BRAF activation with unclear clinical significance. We report a novel non-V600E mutation (c.1799_1812delinsAT, p.V600_W604delinsD), identified preoperatively with next-generation sequencing (NGS) on the material obtained with fine-needle aspiration cytology (FNAC) performed on a thyroid nodule cytologically suspicious for malignancy in a 35-year-old male patient. The presence of this new variant of BRAF mutation was subsequently confirmed in the postoperative phase by direct Sanger sequencing. In conclusion, we report a new non-V600E variant previously undetected in papillary thyroid cancer. In addition, this case report shows that the NGS technique on cytological tissue allows to detect the presence of rare mutations, thus increasing the diagnostic specificity of molecular analysis.

Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19.

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF-platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage.