Abstract：
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.
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.
摘要：
Cockayne综合征（CS）是一种罕见的常染色体隐性遗传疾病，由ERCC6/CSB或ERCC8/CSA突变引起，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，其原因还没有完全理解，这在诊断阶段是无法预料的。此外,受影响的兄弟姐妹的数据很少，这种疾病在北非基本上没有被诊断出来。
我们在此报告8名突尼斯CS患者的临床描述以及遗传和功能特征，包括兄弟姐妹.这些病人,属于六个不相关的家庭，接受了完整的临床检查和生化分析.对5个家族的复发突变进行了Sanger测序，对第六家族的一名患者进行了靶向基因测序。我们还进行了回收RNA合成(RRS)以确认患者来源的成纤维细胞中DNA修复的功能损害。
八名患者中有六名在ERCC8的外显子7中携带纯合indel突变（c.598_600delinsAA），并显示出可变的临床谱，包括兄弟姐妹之间共享相同的突变。另外两名患者是在ERCC8中携带纯合剪接位点变体的兄弟姐妹(c.843+1G>C)。最后一对呈现更严重的临床表现，很少与CSA突变相关，导致胃造口术和肝损伤。在6名受试患者中通过RRS证实TC-NER受损。
这项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描述。仅在该区域和中东描述了这些突变。我们还提供了多个无关患者的最大特征，以及兄弟姐妹，携带相同的突变,为剖析CS中难以捉摸的基因型-表型相关性提供了框架。
我们在此报告8名突尼斯CS患者的临床描述以及遗传和功能特征，包括兄弟姐妹.这些病人,属于六个不相关的家庭，接受了完整的临床检查和生化分析.对5个家族的复发突变进行了Sanger测序，对第六家族的一名患者进行了靶向基因测序。我们还进行了回收RNA合成(RRS)以确认患者来源的成纤维细胞中DNA修复的功能损害。
八名患者中有六名在ERCC8的外显子7中携带纯合indel突变（c.598_600delinsAA），并显示出可变的临床谱，包括兄弟姐妹之间共享相同的突变。另外两名患者是在ERCC8中携带纯合剪接位点变体的兄弟姐妹(c.843+1G>C)。最后一对呈现更严重的临床表现，很少与CSA突变相关，导致胃造口术和肝损伤。在6名受试患者中通过RRS证实TC-NER受损。
这项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描述。仅在该区域和中东描述了这些突变。我们还提供了多个无关患者的最大特征，以及兄弟姐妹，携带相同的突变,为剖析CS中难以捉摸的基因型-表型相关性提供了框架。
