DICER1 tumor predisposition syndrome is a pleiotropic disorder that gives rise to various mainly pediatric-onset lesions. We report an extraskeletal chondroma (EC) of the great toe occurring in a child who, unusually, carries a germline “hotspot” missense DICER1 variant rather than the more usual loss-of-function (LOF) variant. No heterozygous LOF allele was identified in the EC. We demonstrate this variant impairs 5p cleavage of precursor-miRNA (pre-miRNA) and competes with wild-type (WT) DICER1 protein for pre-miRNA processing. These results suggest a mechanism through which a germline RNase IIIb variant could impair pre-miRNA processing without complete LOF of the WT DICER1 allele.

DICER1 肿瘤易感综合征是一种多效性疾病，可引起各种主要是儿童发病的病变。我们报告了一名儿童发生的大脚趾骨外软骨瘤 (EC)，该儿童异常地携带种系“热点”错义DICER1变异，而不是更常见的功能丧失 (LOF) 变异。 EC 中未发现杂合 LOF 等位基因。我们证明该变异会损害前体 miRNA (pre-miRNA) 的 5p 裂解，并与野生型 (WT) DICER1 蛋白竞争 pre-miRNA 加工。这些结果表明，在 WT DICER1等位基因没有完全 LOF 的情况下，种系 RNase IIIb 变体可能会损害 pre-miRNA 加工。