Most humans are exposed to Tropheryma whipplei (Tw). Whipple’s disease (WD) strikes only a small minority of individuals infected with Tw (<0.01%), whereas asymptomatic chronic carriage is more common (<25%). We studied a multiplex kindred, containing four WD patients and five healthy Tw chronic carriers. We hypothesized that WD displays autosomal dominant (AD) inheritance, with age-dependent incomplete penetrance. We identified a single very rare non-synonymous mutation in the four patients: the private R98W variant of IRF4, a transcription factor involved in immunity. The five Tw carriers were younger, and also heterozygous for R98W. We found that R98W was loss-of-function, modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. We also found that only six of the other 153 known non-synonymous IRF4 variants were loss-of-function. Finally, we found that IRF4 had evolved under purifying selection. AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance.

中文翻译：

---

Whipple 病家族中 IRF4 单倍体不足

大多数人都接触过 Tropheryma Whipplei (Tw)。Whipple 病 (WD) 仅影响少数 Tw 感染者 (<0.01%)，而无症状慢性携带者则更为常见 (<25%)。我们研究了一个多重亲属，其中包括四名 WD 患者和五名健康的 Tw 慢性携带者。我们假设 WD 表现出常染色体显性 (AD) 遗传，具有年龄依赖性不完全外显率。我们在四名患者中发现了一个非常罕见的非同义突变：IRF4 的私有 R98W 变体，这是一种参与免疫的转录因子。五个 Tw 携带者更年轻，而且也是 R98W 杂合子。我们发现R98W功能丧失，在Tw刺激后改变了杂合白细胞的转录组，并且不是显性失活。我们还发现其他 153 个已知的非同义 IRF4 变体中只有 6 个出现功能丧失。最后，我们发现IRF4是在纯化选择下进化的。AD IRF4 缺陷可能因单倍体不足而成为 WD 的基础，且具有年龄依赖性的不完全外显率。