Purpose

Germline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown.

Methods

We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives.

Results

We identified 12 heterozygous GATA2 mutations, two of which had not been reported. Eight of these mutations were loss-of-function, and four were hypomorphic. None was dominant-negative in vitro, and the GATA2 locus was found to be subject to purifying selection, strongly suggesting a mechanism of haploinsufficiency. Three relatives of index cases had mycobacterial disease and were also heterozygous, resulting in 18 patients in total. Mycobacterial infection was the first clinical manifestation in 11 patients, at a mean age of 22.5 years (range: 12 to 42 years). Most patients also suffered from other infections, monocytopenia, or myelodysplasia. Strikingly, the clinical penetrance was incomplete (32.9% by age 40 years), as 16 heterozygous relatives aged between 6 and 78 years, including 4 older than 60 years, were completely asymptomatic.

Conclusion

Clinical penetrance for mycobacterial disease was found to be similar to other GATA2 deficiency-related manifestations. These observations suggest that other mechanisms contribute to the phenotypic expression of GATA2 deficiency. A diagnosis of autosomal dominant GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life. Moreover, all direct relatives should be genotyped at the GATA2 locus.

中文翻译：

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遗传性 GATA2 缺乏以单倍体不足为主，并显示不完全的临床外显率

目的

GATA2的种系杂合突变是多种血液学和临床表型的基础。在家族背景下，GATA2 缺陷型分枝杆菌疾病患者的遗传、免疫学和临床特征在很大程度上仍然未知。

方法

我们招募了 15 例因分枝杆菌病转诊的 GATA2 指数病例。我们描述了他们的遗传和临床特征，包括他们的亲属。

结果

我们鉴定了 12 个杂合GATA2突变，其中两个尚未报道。这些突变中有八个是功能丧失，四个是异形。在体外没有一个是显性阴性的，而GATA2发现基因座受到纯化选择，强烈表明单倍体不足的机制。指示病例的3名亲属患有分枝杆菌病，也是杂合子，总共有18名患者。分枝杆菌感染是 11 名患者的第一个临床表现，平均年龄为 22.5 岁（范围：12 至 42 岁）。大多数患者还患有其他感染、单核细胞减少症或骨髓发育不良。引人注目的是，临床外显率不完整（40 岁时为 32.9%），因为 16 名 6 至 78 岁的杂合子亲属（包括 4 名 60 岁以上）完全无症状。

结论

发现分枝杆菌疾病的临床外显率与其他 GATA2 缺乏相关表现相似。这些观察结果表明，其他机制有助于 GATA2 缺陷的表型表达。任何年龄的分枝杆菌感染和/或其他 GATA2 缺乏相关表型的患者都应考虑诊断为常染色体显性遗传 GATA2 缺乏。此外，所有直系亲属都应在GATA2基因座上进行基因分型。