SPONASTRIME dysplasia is an ultrarare spondyloepimetaphyseal dysplasia featuring short stature and short limbs, platyspondyly, depressed nasal bridge with midface hypoplasia, and striated metaphyses. In 2019, an autosomal recessive inheritance was demonstrated by the identification of bi-allelic hypomorphic alleles in TONSL. The encoded protein has a critical role in maintaining genome integrity by promoting the homologous recombination required for repairing spontaneous replication-associated DNA lesions at collapsed replication forks. We report a 9-year-old girl with typical SPONASTRIME dysplasia and resulted carrier of the novel missense p.(Gln430Arg) and p.(Leu1090Arg) variants in TONSL at whole exome sequencing. To better explore the molecular mechanism that drive SPONASTRIME dysplasia, several functional studies on primary fibroblast patient cell cultures were employed for the first time. In silico analysis predicted that these variants induced thermodynamic changes with a pathogenic impact on protein function. To support the pathogenicity of the identified variants, cytogenetic analysis and microscopy assays showed that patient-derived fibroblasts exhibited spontaneous chromosomal breaks and flow cytometry demonstrated defects in cell proliferation and enhanced apoptosis. These findings contribute to our understanding of the molecular pathogenesis of SPONASTRIME dysplasia and might open the way to therapeutic approaches.

中文翻译：

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新型 TONSL 变体导致 SPONASTRIME 发育不良并与自发性染色体断裂、细胞增殖和凋亡缺陷相关。

SPONASTRIME发育不良是一种ultrarare spondyloepimetaphyseal发育不良特色身材矮小，四肢短，板状SPO ndyly，郁闷呐SAL与面中部发育不全桥，STRI ated我taphyses。2019 年，通过在TONSL 中鉴定出双等位基因亚型等位基因，证明了常染色体隐性遗传。编码的蛋白质通过促进修复折叠复制叉处自发复制相关 DNA 损伤所需的同源重组，在维持基因组完整性方面具有关键作用。我们报告了一名患有典型 SPONASTRIME 发育不良的 9 岁女孩，并导致了 TONSL 中新型错义 p.(Gln430Arg) 和 p.(Leu1090Arg) 变体的携带者在全外显子组测序。为了更好地探索驱动 SPONASTRIME 发育不良的分子机制，首次对原代成纤维细胞患者细胞培养物进行了几项功能研究。计算机分析预测，这些变异引起热力学变化，对蛋白质功能产生致病性影响。为了支持已鉴定变异的致病性，细胞遗传学分析和显微镜分析表明，患者来源的成纤维细胞表现出自发的染色体断裂，流式细胞术显示细胞增殖缺陷和细胞凋亡增强。这些发现有助于我们了解 SPONASTRIME 发育不良的分子发病机制，并可能为治疗方法开辟道路。