Differential rates of germline heterozygote and mosaic variants in <i>NF2</i> may show varying propensity for meiotic or mitotic mutation.

Abstract

NF2-related schwannomatosis is an autosomal dominant tumour predisposition condition that causes multiple benign tumours of the nervous system, especially schwannomas. This results from germline pathogenic variants in the <i>NF2</i> gene, which are most commonly de novo NF2 nonsense variants. Over half of these de novo variants occur at just six CpG dinucleotides. In this study, we show that the six <i>NF2</i> CpG nonsense variants make up 54% (136/252) of de novo nonsense variants, despite constituting <10% of nonsense positions in the germline (total=62), and that this pattern is different from the <i>APC</i> gene, which is also known to have a high rate of mosaicism. In addition, the <i>NF2</i> c.586C>T; p.(Arg196Ter) has a higher de novo heterozygote to mosaicism ratio than the five other CpG variants (73.1% vs 53.7%, p=0.03) and the neighbouring CpG variant (<i>NF2</i> c.592C>T; p.(Arg198Ter) 38.5%, p=0.02). This may be due to differences in rates of mutation at meiosis versus mitosis.