Whole-exome sequencing identifies novel mutations in genes responsible for retinitis pigmentosa in 2 nonconsanguineous Chinese families
Whole-exome sequencing identifies novel mutations in genes responsible for retinitis pigmentosa in 2 nonconsanguineous Chinese families
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DOI：
10.18240/ijo.2019.06.06
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发表时间：
2019-06-18
影响因子：
1.4
通讯作者：
Li, Tuo
中科院分区：
文献类型：
--
作者：
Hu, Yan-Shan;Song, Hui;Li, Tuo
目的：目的检测2个非血缘关系的中国人非综合征型常染色体隐性遗传性视网膜色素变性（RP）家系的致病基因突变。临床资料包括详细的病史、最佳矫正视力（BCVA）、裂隙灯生物显微镜检查、眼底照相、光学相干断层扫描、静态视野检查和全视野视网膜电图，从初步诊断为RP的2个非血缘中国家庭成员中收集。从先证者和其他可用的家族成员中提取基因组DNA;使用先证者提供的DNA样本进行全外显子组测序，并使用先证者和其他可用的家族成员中的桑格测序验证通过全外显子组测序检测到的所有突变。结果：2个家系的患者均表现为RP的典型症状，包括夜盲和进行性视野缩小，眼底检查显示视网膜小动脉变细，周围骨针色素沉着，视盘蜡样变。全外显子组测序显示FAM 161 A（c.943A>T，p.Lys315*）存在一种新的无义突变，RP 1 L1（c.56C>A，p.Pro19His; c.5470C>T，p.Gln1824*）存在复合杂合突变。无义c.5470C>T，p.Gln1824* 突变是新的。通过桑格测序验证所有突变。FAM 161 A的p.Lys315* 突变与表型共分离，所有的无义突变在种族匹配的健康对照和所有可用的database.CONCLUSION：我们发现了2个新的常染色体隐性遗传RP基因突变，FAM 161 A的突变在中国人群中是首次报道。我们的结果不仅丰富了非综合征型RP相关基因突变频率和谱的知识，而且为未来的基因治疗提供了新的靶点。
AIM: To detect the pathogenetic mutations responsible for nonsyndromic autosomal recessive retinitis pigmentosa (RP) in 2 nonconsanguineous Chinese families.METHODS: The clinical data, including detailed medical history, best corrected visual acuity (BCVA), slit-lamp biomicroscope examination, fundus photography, optical coherence tomography, static perimetry, and full field electroretinogram, were collected from the members of 2 nonconsanguineous Chinese families preliminarily diagnosed with RP. Genomic DNA was extracted from the probands and other available family members; whole-exome sequencing was conducted with the DNA samples provided by the probands, and all mutations detected by whole-exome sequencing were verified using Sanger sequencing in the probands and the other available family members. The verified novel mutations were further sequenced in 192 ethnicity matched healthy controls.RESULTS: The patients from the 2 families exhibited the typical symptoms of RP, including night blindness and progressive constriction of the visual field, and the fundus examinations showed attenuated retinal arterioles, peripheral bone spicule pigment deposits, and waxy optic discs. Whole-exome sequencing revealed a novel nonsense mutation in FAM161A (c.943A>T, p.Lys315*) and compound heterozygous mutations in RP1L1 (c.56C>A, p.Pro19His; c.5470C>T, p.Gln1824*). The nonsense c.5470C>T, p.Gln1824* mutation was novel. All mutations were verified by Sanger sequencing. The mutation p.Lys315* in FAM161A co-segregated with the phenotype, and all the nonsense mutations were absent from the ethnicity matched healthy controls and all available databases.CONCLUSION: We identify 2 novel mutations in genes responsible for autosomal recessive RP, and the mutation in FAM161A is reported for the first time in a Chinese population. Our result not only enriches the knowledge of the mutation frequency and spectrum in the genes responsible for nonsyndromic RP but also provides a new target for future gene therapy.