Hozhabrpour Amir, Mojbafan Marzieh, Palizban Fahimeh, Vahidnezhad Fatemeh, Talebi Saeed, Amani Maliheh, Garshasbi Masoud, Naghavi Anoosh, Khalesi Raziyeh, Mansouri Parvin, Sotoudeh Soheila, Mahmoudi Hamidreza, Varghaei Aida, Daneshpazhooh Maryam, Karimi Fatemeh, Zeinali Sirous, Kalamati Elnaz, Uitto Jouni, Youssefian Leila, Vahidnezhad Hassan
Department of Medical Genetics, School of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran.
Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran.
DNA Repair (Amst). 2024 Apr;136:103633. doi: 10.1016/j.dnarep.2024.103633. Epub 2024 Feb 29.
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.
遗传性光敏综合征是一组具有巨大表型变异性的遗传性皮肤病，其特征为光敏性和DNA修复缺陷，尤其是核苷酸切除修复缺陷。对17个患有遗传性光敏综合征的伊朗家庭进行了队列研究，以确定其遗传缺陷。采用全外显子组测序或RNA测序（RNA-Seq）对患者的DNA进行分析。基因组结果的解读以全基因组纯合性定位为指导。对复发性突变的病例进行单倍型分析。RNA-Seq除了用于检测突变外，还用于确认致病性。在17个伊朗家庭中发现了13个序列变异，包括6个以前未报道的致病变异，其中XPC是10个家庭（59%）中最常见的突变基因。在一名患者中，RNA-Seq作为一线诊断方法，发现了一种非典型的纯合子种系变异：XPC:c.413-9 T>A。剪接比对图显示外显子4跳跃，XPC表达显著下调。对四个家庭中XPC:c.2251-1 G>C和XPC:1243 C>T的单倍型分析分别显示了1.7 Mb和2.6 Mb的常见单倍型，表明存在奠基者效应。最后，本报告介绍了两个极其罕见的病例：发现了一个纯合子UVSSA:c.1990 C>T，以及一例与ERCC2相关的儿童早期死亡的脑眼面骨骼（COFS）综合征。尽管观察到了人群特异性差异，但将我们的数据与先前报道队列的结果进行直接比较，展示了DNA修复相关光敏性疾病的国际突变格局。
