背景:先天性中性粒细胞减少症的特征是严重感染和髓样转化的高风险;致病基因因种族而异。以色列人口的特点是种族多样化,血缘关系率高。
目的:评估以色列先天性中性粒细胞减少症的临床和遗传谱。
方法:我们纳入了以色列遗传性骨髓衰竭登记处列出的先天性中性粒细胞减少症患者。对ELANE或G6PC3进行Sanger测序,并将具有野生型ELANE/G6PC3的患者转诊进行下一代测序。
结果:纳入65例中性粒细胞减少症患者。在51例严重的先天性中性粒细胞减少症患者中,34人是基因诊断的,最常见的是ELANE变异(15例患者)。9名患者在G6PC3中具有双等位基因变体,均为近亲穆斯林阿拉伯血统。其他涉及的基因是SRP54,JAGN1,TAZ,SLC37A4七个病人有周期性中性粒细胞减少症,都有伊兰的致病变异,七个患有由双等位基因SBDS变体引起的Shwachman-Diamond综合征。8例患者(12%)发生髓样转化,其中包括6名遗传原因不明的患者.19例(29%)患者接受了造血干细胞移植,主要是由于对粒细胞集落刺激因子治疗的反应不足或髓样转化。
结论:以色列先天性中性粒细胞减少症的遗传谱特征是G6PC3变异的高患病率和HAX1突变的缺失。类似于其他登记册,26%的病人,未实现分子诊断.然而,髓样转化在该组中很常见,强调需要密切跟进。
BACKGROUND: Congenital neutropenias are characterized by severe infections and a high risk of myeloid transformation; the causative genes vary across ethnicities. The Israeli population is characterized by an ethnically diverse population with a high rate of consanguinity.
OBJECTIVE: To evaluate the clinical and genetic spectrum of congenital neutropenias in Israel.
METHODS: We included individuals with congenital neutropenias listed in the Israeli Inherited Bone Marrow Failure Registry. Sanger sequencing was performed for ELANE or G6PC3, and patients with wild-type ELANE/G6PC3 were referred for next-generation sequencing.
RESULTS: Sixty-five patients with neutropenia were included. Of 51 patients with severe congenital neutropenia, 34 were genetically diagnosed, most commonly with variants in ELANE (15 patients). Nine patients had biallelic variants in G6PC3, all of consanguineous Muslim Arab origin. Other genes involved were SRP54, JAGN1, TAZ, and SLC37A4. Seven patients had cyclic neutropenia, all with pathogenic variants in ELANE, and seven had Shwachman-Diamond syndrome caused by biallelic SBDS variants. Eight patients (12%) developed myeloid transformation, including six patients with an unknown underlying genetic cause. Nineteen (29%) patients underwent hematopoietic stem cell transplantation, mostly due to insufficient response to treatment with granulocyte-colony stimulating factor or due to myeloid transformation.
CONCLUSIONS: The genetic spectrum of congenital neutropenias in Israel is characterized by a high prevalence of G6PC3 variants and an absence of HAX1 mutations. Similar to other registries, for 26% of the patients, a molecular diagnosis was not achieved. However, myeloid transformation was common in this group, emphasizing the need for close follow-up.