Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR-1163, Paris, France.
Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France.
PLoS Negl Trop Dis. 2018 Apr 30;12(4):e0006429. doi: 10.1371/journal.pntd.0006429. eCollection 2018 Apr.
Buruli ulcer (BU), the third most frequent mycobacteriosis worldwide, is a neglected tropical disease caused by Mycobacterium ulcerans. We report the clinical description and extensive genetic analysis of a consanguineous family from Benin comprising two cases of unusually severe non-ulcerative BU. The index case was the most severe of over 2,000 BU cases treated at the Centre de Dépistage et de Traitement de la Lèpre et de l'Ulcère de Buruli, Pobe, Benin, since its opening in 2003. The infection spread to all limbs with PCR-confirmed skin, bone and joint infections. Genome-wide linkage analysis of seven family members was performed and whole-exome sequencing of both patients was obtained. A 37 kilobases homozygous deletion confirmed by targeted resequencing and located within a linkage region on chromosome 8 was identified in both patients but was absent from unaffected siblings. We further assessed the presence of this deletion on genotyping data from 803 independent local individuals (402 BU cases and 401 BU-free controls). Two BU cases were predicted to be homozygous carriers while none was identified in the control group. The deleted region is located close to a cluster of beta-defensin coding genes and contains a long non-coding (linc) RNA gene previously shown to display highest expression values in the skin. This first report of a microdeletion co-segregating with severe BU in a large family supports the view of a key role of human genetics in the natural history of the disease.
布鲁里溃疡（BU）是世界上第三常见的分枝杆菌病，是由溃疡分枝杆菌引起的被忽视的热带病。我们报告了来自贝宁的一个近亲家庭的临床描述和广泛的遗传分析，该家庭包括两例异常严重的非溃疡性 BU。索引病例是自 2003 年贝宁波贝麻风溃疡检测和治疗中心开业以来治疗的 2000 多例 BU 病例中最严重的一例。感染扩散到所有四肢，皮肤、骨骼和关节感染均经 PCR 证实。对 7 名家庭成员进行了全基因组连锁分析，并对两名患者进行了全外显子组测序。在两名患者中均发现了通过靶向重测序证实的 37 千碱基的纯合缺失，该缺失位于 8 号染色体的连锁区域内，但在未受影响的兄弟姐妹中不存在。我们进一步评估了该缺失在 803 名独立当地个体（402 例 BU 病例和 401 例 BU 对照）的基因分型数据中的存在情况。有两个 BU 病例被预测为纯合携带者，而对照组中没有发现。缺失区域靠近一个β防御素编码基因簇，包含一个先前在皮肤中显示最高表达值的长非编码（linc）RNA 基因。这是首例与严重 BU 共分离的微缺失在一个大家庭中的报告，支持了人类遗传学在疾病自然史中起关键作用的观点。
