Snyder-Robinson syndrome (SRS) is an X-linked syndromic intellectual disability condition caused by variants in the spermine synthase gene (SMS). The syndrome is characterized by facial dysmorphism, thin body build, kyphoscoliosis, osteoporosis, hypotonia, developmental delay and associated neurological features (seizures, unsteady gait, abnormal speech). Until now, only missense variants with a functionally characterized partial loss of function (LoF) have been described. Here we describe the first complete LoF variant, Met303Lysfs*, in a male patient with a severe form of Snyder-Robinson syndrome. He presented with multiple malformations and severly delayed development, and died at 4 months of age. Functional in vitro assays showed a complete absence of functional SMS protein. Taken together, our findings and those of previously reported patients confirm that pathogenic variants of SMS are indeed LoF and that there might exist a genotype-phenotype correlation between the type of variant and the severity of the syndrome.

Snyder-Robinson综合征（SRS）是由精胺合酶基因（SMS）的变异引起的X连锁综合征智力障碍性疾病。该综合征的特征是面部畸形，瘦弱身材，后凸畸形，骨质疏松，肌张力低下，发育迟缓和相关的神经系统特征（癫痫发作，步态不稳，语言异常）。迄今为止，仅描述了具有功能上表征的部分功能丧失（LoF）的错义变体。在这里，我们描述了患有严重形式的Snyder-Robinson综合征的男性患者中的第一个完整的LoF变体Met303Lysfs *。他表现出多种畸形和严重延迟发育，并在4个月大时死亡。体外功能分析显示完全没有功能性SMS蛋白。综上所述，我们的发现和先前报道的患者的发现证实，SMS的致病变异确实是LoF，并且变异类型与综合症严重程度之间可能存在基因型与表型的相关性。