Abstract：
Inherited photosensitivity syndromes are a heterogeneous group of genetic skin disorders with tremendous phenotypic variability, characterized by photosensitivity and defective DNA repair, especially nucleotide excision repair. A cohort of 17 Iranian families with heritable photosensitivity syndromes was evaluated to identify their genetic defect. The patients\' DNA was analyzed with either whole-exome sequencing or RNA sequencing (RNA-Seq). The interpretations of the genomic results were guided by genome-wide homozygosity mapping. Haplotype analysis was performed for cases with recurrent mutations. RNA-Seq, in addition to mutation detection, was also utilized to confirm the pathogenicity. Thirteen sequence variants, including six previously unreported pathogenic variants, were disclosed in 17 Iranian families, with XPC as the most common mutated gene in 10 families (59%). In one patient, RNA-Seq, as a first-tier diagnostic approach, revealed a non-canonical homozygous germline variant: XPC:c.413-9 T > A. The Sashimi plot showed skipping of exon 4 with dramatic XPC down-expression. Haplotype analysis of XPC:c.2251-1 G>C and XPC:1243 C>T in four families showed common haplotypes of 1.7 Mb and 2.6 Mb, respectively, denoting a founder effect. Lastly, two extremely rare cases were presented in this report: a homozygous UVSSA:c .1990 C>T was disclosed, and ERCC2-related cerebro-oculo-facio-skeletal (COFS) syndrome with an early childhood death. A direct comparison of our data with the results of previously reported cohorts demonstrates the international mutation landscape of DNA repair-related photosensitivity disorders, although population-specific differences were observed.
摘要：
遗传性光敏综合征是一组异质性的遗传性皮肤病，具有巨大的表型变异性，以光敏性和DNA修复缺陷为特征，尤其是核苷酸切除修复。对17个具有遗传性光敏性综合征的伊朗家庭进行了评估，以确定其遗传缺陷。用全外显子组测序或RNA测序(RNA-Seq)分析患者的DNA。基因组结果的解释由全基因组纯合性图谱指导。对具有复发突变的病例进行单倍型分析。RNA-Seq,除了突变检测，还用于确认致病性。13个序列变体,包括六种以前未报告的致病变种，在17个伊朗家庭中被披露，XPC是10个家族中最常见的突变基因(59%)。在一个病人中,RNA-Seq,作为第一层诊断方法，揭示了一种非规范的纯合种系变体：XPC：c.413-9T>A。Sashimi图显示外显子4的跳过，XPC明显下降表达。四个家族的XPC：c.2251-1G>C和XPC：1243C>T的单倍型分析显示出1.7Mb和2.6Mb的常见单倍型，分别,表示创始人效应。最后,本报告提出了两个极其罕见的病例：一个纯合的UVSSA：c。1990C>T被披露，和ERCC2相关的脑-眼-面-骨骼（COFS）综合征伴儿童早期死亡。我们的数据与先前报道的队列的结果的直接比较表明DNA修复相关的光敏性疾病的国际突变景观，尽管观察到群体特异性差异。
