Department of Internal Medicine V Hematology Oncology Rheumatology, University Hospital Heidelberg, Heidelberg, Germany.
Department of Internal Medicine, Croix Rousse, University Hospital, Lyon, France.
Rheumatology (Oxford). 2024 May 3;63(6):1512-1517. doi: 10.1093/rheumatology/kead349.
To analyse genetic mechanisms triggering familial sarcoidosis, whole exome screening of a family of six persons with four cases of sarcoidosis and two healthy controls was performed integrating progressive and spontaneous remission cases and evaluating involved genetic alterations that could potentially determine the individual course of the disease.
Clinical diagnostic criteria in patients of the selected sarcoidosis family were according to American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders guidelines. Exome screening of four patients and the two intrafamilial healthy relatives was performed by paired-end (2 × 100 bp) sequencing. We then selected the gene variants considered pathogenic on the basis of a series of prediction software applications and presence only in members of the family affected by sarcoidosis, after subtracting the common variations observed in healthy subjects.
Four persons out of six family members were affected by sarcoidosis. Fifty genes with uncommon in silico pathogenic variants could be identified that differentiated affected and healthy family members. One patient with sarcoidosis showed spontaneous remission whereas the remaining three patients required immunosuppressive treatment. Subtraction analysis revealed 18 genes that distinguished the three progressive cases from the patient with spontaneous remission.
The genetic analysis of these cases with familial sarcoidosis identified several involved genes and functional pathways that could help in understanding the basic mechanisms that determine the development of the disease and that discriminate spontaneously regressive and progressive forms.
分析引发家族性结节病的遗传机制。对一个六口之家（四名结节病患者和两名健康对照者）进行了外显子组全筛查，整合了进展性和自发性缓解病例，并评估了可能潜在决定个体疾病进程的相关遗传改变。
根据美国胸科学会/欧洲呼吸学会/世界结节病和其他肉芽肿性疾病协会指南，对所选结节病家族中的患者进行临床诊断标准。对四名患者和两名家族内健康亲属进行了配对末端（2×100bp）测序的外显子组筛查。然后，我们根据一系列预测软件应用程序选择了被认为具有致病性的基因变异，并在减去健康受试者中观察到的常见变异后，仅在受结节病影响的家族成员中存在这些变异。
六名家庭成员中有四人患有结节病。可以识别出 50 个具有罕见计算机预测致病性变异的基因，这些变异可以区分患病和健康的家庭成员。一名结节病患者出现自发性缓解，而其余三名患者需要免疫抑制治疗。减法分析显示，有 18 个基因可以区分这三个进展性病例和自发性缓解的患者。
对这些家族性结节病病例的遗传分析确定了几个涉及的基因和功能途径，这有助于理解决定疾病发展的基本机制，并区分自发消退和进展形式。
