Laboratory of Biomedical Genomics and Oncogenetics (LR20IPT05), Institut Pasteur de Tunis, Université Tunis El Manar, El Manar I, BP 74, 13 Place Pasteur, 1002, Tunis-Belvedere, Tunisia.
LR18SP04 and Department of Child and Adolescent Neurology, National Institute Mongi Ben Hmida of Neurology, 1007, Tunis, Tunisia.
Orphanet J Rare Dis. 2022 Mar 5;17(1):121. doi: 10.1186/s13023-022-02257-1.
Cockayne syndrome (CS) is a rare autosomal recessive disorder caused by mutations in ERCC6/CSB or ERCC8/CSA that participate in the transcription-coupled nucleotide excision repair (TC-NER) of UV-induced DNA damage. CS patients display a large heterogeneity of clinical symptoms and severities, the reason of which is not fully understood, and that cannot be anticipated in the diagnostic phase. In addition, little data is available for affected siblings, and this disease is largely undiagnosed in North Africa.
We report here the clinical description as well as genetic and functional characterization of eight Tunisian CS patients, including siblings. These patients, who belonged to six unrelated families, underwent complete clinical examination and biochemical analyses. Sanger sequencing was performed for the recurrent mutation in five families, and targeted gene sequencing was done for one patient of the sixth family. We also performed Recovery RNA Synthesis (RRS) to confirm the functional impairment of DNA repair in patient-derived fibroblasts.
Six out of eight patients carried a homozygous indel mutation (c.598_600delinsAA) in exon 7 of ERCC8, and displayed a variable clinical spectrum including between siblings sharing the same mutation. The other two patients were siblings who carried a homozygous splice-site variant in ERCC8 (c.843+1G>C). This last pair presented more severe clinical manifestations, which are rarely associated with CSA mutations, leading to gastrostomy and hepatic damage. Impaired TC-NER was confirmed by RRS in six tested patients.
This study provides the first deep characterization of case series of CS patients carrying CSA mutations in North Africa. These mutations have been described only in this region and in the Middle-East. We also provide the largest characterization of multiple unrelated patients, as well as siblings, carrying the same mutation, providing a framework for dissecting elusive genotype-phenotype correlations in CS.
Cockayne 综合征（CS）是一种罕见的常染色体隐性遗传病，由 ERCC6/CSB 或 ERCC8/CSA 基因突变引起，这些基因参与紫外线诱导的 DNA 损伤的转录偶联核苷酸切除修复（TC-NER）。CS 患者表现出很大的临床症状和严重程度的异质性，其原因尚未完全阐明，在诊断阶段也无法预测。此外，受影响的兄弟姐妹的数据很少，这种疾病在北非也没有得到广泛诊断。
我们在此报告了 8 名突尼斯 CS 患者（包括兄弟姐妹）的临床描述、遗传和功能特征。这些患者来自 6 个无关家庭，接受了全面的临床检查和生化分析。对 5 个家庭的常见突变进行了 Sanger 测序，对第 6 个家庭的 1 名患者进行了靶向基因测序。我们还进行了 Recovery RNA Synthesis（RRS）以确认患者源性成纤维细胞中 DNA 修复功能的损伤。
8 名患者中有 6 名携带 ERCC8 外显子 7 中的纯合缺失突变（c.598_600delinsAA），表现出不同的临床谱，包括携带相同突变的兄弟姐妹之间的谱。另外两名患者是携带 ERCC8 剪接位点变异（c.843+1G>C）的同胞。这对最后一对表现出更严重的临床表现，这很少与 CSA 突变相关，导致胃造口术和肝损伤。在 6 名受测患者中，通过 RRS 证实 TC-NER 受损。
本研究首次对北非携带 CSA 突变的 CS 患者病例系列进行了深入的特征描述。这些突变仅在该地区和中东地区有描述。我们还对携带相同突变的多个无关患者及其兄弟姐妹进行了最大特征描述，为剖析 CS 中难以捉摸的基因型-表型相关性提供了框架。
