We describe a lethal combined nervous and reproductive systems disease in three affected siblings of a consanguineous family. The phenotype was characterized by visceroautonomic dysfunction (neonatal bradycardia/apnea, feeding problems, hyperactive startle reflex), severe postnatal progressive neurological abnormalities (including abnormal neonatal cry, hypotonia, epilepsy, polyneuropathy, cerebral gray matter atrophy), visual impairment, testicular dysgenesis in males and sudden death at infant age by brainstem-mediated cardiorespiratory arrest. Whole-exome sequencing revealed a novel homozygous frameshift variant p.Val242GlufsTer52 in the TSPY-like 1 gene (TSPYL1). The truncated TSPYL1 protein that lacks the nucleosome assembly protein domain was retained in the Golgi of fibroblasts from the three patients, whereas control fibroblasts express full-length TSPYL1 in the nucleus. Proteomic analysis of nuclear extracts from fibroblasts identified 24 upregulated and 20 downregulated proteins in the patients compared with 5 controls with ‘regulation of cell cycle’ as the highest scored biological pathway affected. TSPYL1-deficient cells had prolonged S and G2 phases with reduced cellular proliferation rates. Tspyl1 depletion in zebrafish mimicked the patients’ phenotype with early lethality, defects in neurogenesis and cardiac dilation. In conclusion, this study reports the third pedigree with recessive TSPYL1 variants, confirming that TSPYL1 deficiency leads to a combined nervous and reproductive systems disease, and provides for the first time insights into the disease mechanism.

中文翻译：

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解开 TSPYL1 缺乏症的疾病机制

我们在一个近亲家庭的三个受影响的兄弟姐妹中描述了一种致命的神经和生殖系统疾病。该表型的特征是内脏自主神经功能障碍（新生儿心动过缓/呼吸暂停、喂养问题、惊跳反射亢进）、严重的出生后进行性神经系统异常（包括新生儿异常哭闹、张力减退、癫痫、多发性神经病、脑灰质萎缩）、视力障碍、睾丸发育不良男性和婴儿时期因脑干介导的心肺骤停而猝死。全外显子组测序揭示了 TSPY 样 1 基因（TSPYL1）。缺乏核小体组装蛋白结构域的截短 TSPYL1 蛋白保留在三名患者的成纤维细胞的高尔基体中，而对照成纤维细胞在细胞核中表达全长 TSPYL1。对来自成纤维细胞的核提取物的蛋白质组学分析确定了患者中有 24 个上调和 20 个下调的蛋白质，与 5 个对照相比，“细胞周期调节”作为受影响的最高评分生物途径。TSPYL1 缺陷细胞的 S 和 G2 期延长，细胞增殖率降低。斑马鱼中的 Tspyl1 耗竭模拟了患者的表型，具有早期致死率、神经发生缺陷和心脏扩张。总之，本研究报告了隐性TSPYL1的第三个谱系 变异，证实 TSPYL1 缺乏导致神经和生殖系统疾病，并首次提供对疾病机制的见解。