Delayed fatherhood results in a higher risk to inherit a new germline mutation that might result in a congenital disorder in the offspring. In particular, some FGFR3 mutations increase in frequency with age, but there are still a large number of uncharacterized FGFR3 mutations that could be expanding in the male germline with potentially early or late-onset effects in the offspring. Here, we investigated the mutation frequency in the DNA of human testis and sperm and the activation state of the expressed mutant protein of eight different FGFR3 variants categorized by ClinVar as deleterious, benign, or not reported. Overall, the ligand-independent activation of the mutant protein resulted in a increased number of mutant sperm; although, strong activating mutations did not necessarily result in the highest frequencies. Moreover, only two mutants c.952G>A and c.1620C>A showed an increase with the donor's age; the latter also forming larger clonal expansions in the testis. We also showed that the prediction of deleteriousness of a mutation is not always accurate, and similar in silico scores can reflect either a gain-of-function or loss-of-function. Our approach led to the discovery of two novel variants c.1261G>A and c.952G>A to have promiscuous FGFR3 activation and increased mutation frequencies in the male germline. The large fraction of donors with mutations suggests a high de novo rate potentially explained by a selective advantage before the maturation of the male germline. This sequence-function study provides important data for the evaluation and interpretation of variants with relevant clinical implications

Understanding elemental corrosion currents and visualizing corroding topographies provides a detailed insight into corrosion mechanisms at the nanoscale. Here, we develop a strategy to understand the elemental composition, corrosion resistivity, and local stability of passive materials. Specifically, we utilize a pulse voltammetry approach in a novel electrochemical atomic force microscopy (AFM) cell and complement this data by real-time dissolution currents based on spectroelectrochemical online analysis in an inductively coupled plasma mass spectroscopy (ICP-MS) flow cell. We study the oxide properties and their protective behavior when formed under different applied potentials using Alloy 600 as a model sample. Both AFM and ICP-MS data show that passive films formed on Alloy 600 at around +0.3 to +0.4 V in neutral 1 mM NaCl solution are most stable during anodic corrosion at +1.0 V, while AFM further demonstrates that local dissolution occurs, indicating locally varying defect levels in the passive film. In combination with both techniques, our approach provides real-time elementally resolved and localized information of passive film quality under corrosive conditions, and it may prove useful for other corroding materials.

Understanding elemental corrosion currents and visualizing corroding topographies provide a detailed insight into corrosion mechanisms at the nano-scale. Here, we develop a strategy to understand the elemental composition, corrosion resistivity and local stability of passive materials. Specifically, we utilize a pulse voltammetry approach in a novel electrochemical AFM cell and complement this data by real-time dissolution currents based on spectro-electrochemical online analysis in an ICP-MS flow cell. We study the oxide properties and their protective behaviour, when formed under different applied potentials using alloy 600 as model sample. Both AFM and ICP-MS data show that passive films formed on alloy 600 at around +0.3 to +0.4 V in neutral 1 mM NaCl solution are most stable during anodic corrosion at +1.0 V, while AFM further demonstrates that local dissolution occurs, indicating locally varying defect levels in the passive film. In combination of both techniques, our approach provide real-time elementally resolved and localized information of passive film quality under corrosive conditions, and it may prove useful for other corroding materials.