Inherited bone marrow failure syndromes (IBMFSs) are a group of disorders typified by impaired production of 1 or several blood cell types. The telomere biology disorders dyskeratosis congenita (DC) and its severe variant, Høyeraal-Hreidarsson (HH) syndrome, are rare IBMFSs characterized by bone marrow failure, developmental defects, and various premature aging complications associated with critically short telomeres. We identified biallelic variants in the gene encoding the 5'-to-3' DNA exonuclease Apollo/SNM1B in 3 unrelated patients presenting with a DC/HH phenotype consisting of early-onset hypocellular bone marrow failure, B and NK lymphopenia, developmental anomalies, microcephaly, and/or intrauterine growth retardation. All 3 patients carry a homozygous or compound heterozygous (in combination with a null allele) missense variant affecting the same residue L142 (L142F or L142S) located in the catalytic domain of Apollo. Apollo-deficient cells from patients exhibited spontaneous chromosome instability and impaired DNA repair that was complemented by CRISPR/Cas9-mediated gene correction. Furthermore, patients' cells showed signs of telomere fragility that were not associated with global reduction of telomere length. Unlike patients' cells, human Apollo KO HT1080 cell lines showed strong telomere dysfunction accompanied by excessive telomere shortening, suggesting that the L142S and L142F Apollo variants are hypomorphic. Collectively, these findings define human Apollo as a genome caretaker and identify biallelic Apollo variants as a genetic cause of a hitherto unrecognized severe IBMFS that combines clinical hallmarks of DC/HH with normal telomere length.

中文翻译：

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遗传的人类阿波罗缺陷会导致严重的骨髓衰竭和发育缺陷。

遗传性骨髓衰竭综合征 (IBMFS) 是一组以一种或几种血细胞类型的产生受损为代表的疾病。端粒生物学疾病先天性角化不良 (DC) 及其严重变异型 Høyeraal-Hreidarsson (HH) 综合征是罕见的 IBMFS，其特征是骨髓衰竭、发育缺陷和与极短端粒相关的各种过早衰老并发症。我们在 3 名不相关的患者中发现了编码 5' 到 3' DNA 外切核酸酶 Apollo/SNM1B 的基因中的双等位基因变异，这些患者表现为 DC/HH 表型，包括早发性低细胞骨髓衰竭、B 和 NK 淋巴细胞减少、发育异常、小头畸形和/或宫内发育迟缓。所有 3 名患者都携带纯合或复合杂合（与无效等位基因组合）错义变体，影响位于 Apollo 催化结构域的相同残基 L142（L142F 或 L142S）。来自患者的 Apollo 缺陷细胞表现出自发的染色体不稳定性和受损的 DNA 修复，这与 CRISPR/Cas9 介导的基因校正相辅相成。此外，患者的细胞显示出端粒脆弱的迹象，这与端粒长度的整体减少无关。与患者的细胞不同，人类 Apollo KO HT1080 细胞系表现出强烈的端粒功能障碍，并伴有端粒过度缩短，这表明 L142S 和 L142F Apollo 变体是亚型的。集体，