Shwachman-Diamond syndrome (SDS; OMIM: #260400) is caused by variants in SBDS (Shwachman-Bodian-Diamond syndrome gene), which encodes a protein that plays an important role in ribosome assembly. Recent reports suggest that recessive variants in EFL1 are also responsible for SDS. However, the precise genetic mechanism that leads to EFL1-induced SDS remains incompletely understood. Here we present three unrelated Korean SDS patients that carry biallelic pathogenic variants in EFL1 with biased allele frequencies, resulting from a bone marrow-specific somatic uniparental disomy (UPD) in chromosome 15. The recombination events generated cells that were homozygous for the relatively milder variant, allowing for the evasion of catastrophic physiological consequences. Still, the milder EFL1 variant was solely able to impair 80S ribosome assembly and induce SDS features in cell line, zebrafish, and mouse models. The loss of EFL1 resulted in a pronounced inhibition of terminal oligo-pyrimidine element-containing ribosomal protein transcript 80S assembly. Therefore, we propose a more accurate pathogenesis mechanism of EFL1 dysfunction that eventually leads to aberrant translational control and ribosomopathy.

中文翻译：

---

体细胞单亲二体性减轻了Shwachman-Diamond综合征中最具破坏性的EFL1等位基因组合

Shwachman-Diamond综合征（SDS; OMIM：＃260400）是由SBDS（Shwachman-Bodian-Diamond综合征基因）的变异引起的，该基因编码一种蛋白质，在核糖体装配中起重要作用。最近的报告表明EFL1中的隐性变异体也与SDS有关。但是，导致EFL1诱导SDS的确切遗传机制仍不完全清楚。在这里，我们介绍了三名韩国SDS无关患者，这些患者在EFL1中携带双等位基因致病变体，其等位基因频率偏向，这是由15号染色体上的骨髓特异性体细胞单亲二体性（UPD）引起的。重组事件产生的细胞相对较轻的变体是纯合的，从而规避灾难性的生理后果。仍然，较温和的EFL1变体只能破坏细胞系，斑马鱼和小鼠模型中的80S核糖体装配并诱导SDS功能。EFL1的丧失导致末端寡聚嘧啶元件的核糖体蛋白转录本80S装配的明显抑制。因此，我们提出了一种更准确的EFL1功能障碍的发病机制，最终导致异常的翻译控制和核糖体病。