Dysosteosclerosis (DOS) is a distinct form of sclerosing bone disease characterized by platyspondyly and progressive osteosclerosis. DOS is genetically heterogeneous. Three causal genes, SLC29A3, CSF1R, and TNFRSF11A are reported. TNFRSF11A-associated DOS has been identified in two patients; however, TNFRSF11A is also a causal gene for osteopetrosis, autosomal recessive 7 (OP-AR7). Whole-exome sequencing in a patient with sclerosing bone disease identified novel compound heterozygous variants (c.414_427 + 7del, c.1664del) in TNFRSF11A. We examined the impact of the two variants on five splicing isoforms of TNFRSF11A by RT-PCR. We found that c.1664del resulted in elongated proteins (p.S555Cfs*121, etc.), while c.414_427 + 7del generated two aberrant splicing products (p.A139Wfs*19 and p.E132Dfs*19) that lead to nonsense mediated mRNA decay (NMD). In the previous two cases of TNFRSF11A-associated DOS, their mutations produced truncated TNFRSF11A protein isoforms. The mutations in all three cases thus contrast with TNFRSF11A mutations reported in OP-AR7, which does not generated truncated or elongated TNFRSF11A proteins. Thus, we identified the third case of TNFRSF11A-associated DOS and reinforced the genotype–phenotype correlation that aberrant protein-producing TNFRSF11A mutations cause DOS.

Dysosteosclerosis (DOS) 是一种不同形式的硬化性骨病，其特征是扁平脊柱和进行性骨硬化。DOS 在基因上是异质的。报告了三个因果基因，SLC29A3、CSF1R和TNFRSF11A。已在两名患者中鉴定出TNFRSF11A相关的 DOS；然而，TNFRSF11A也是骨硬化症的致病基因，常染色体隐性遗传 7 (OP-AR7)。全基因组测序中，在硬化性骨病鉴定的新型复合杂合的变体（c.414_427 + 7del，c.1664del）的患者TNFRSF11A。我们检查了两种变体对TNFRSF11A 的五种剪接同种型的影响通过 RT-PCR。我们发现 c.1664del 导致蛋白质延长（p.S555Cfs*121 等），而 c.414_427 + 7del 产生两种异常剪接产物（p.A139Wfs*19 和 p.E132Dfs*19），导致无意义介导mRNA 衰减 (NMD)。在前两个与TNFRSF11A相关的 DOS病例中，它们的突变产生了截短的 TNFRSF11A 蛋白同种型。因此，所有三个病例中的突变与 OP-AR7 中报道的TNFRSF11A突变形成对比，后者不产生截短或延长的 TNFRSF11A 蛋白。因此，我们确定了第三例与TNFRSF11A相关的 DOS，并加强了基因型-表型相关性，即产生异常蛋白质的TNFRSF11A突变导致 DOS。