Identification of Mutations Causing Inherited Retinal Degenerations in the Israeli and Palestinian Populations Using Homozygosity Mapping
Identification of Mutations Causing Inherited Retinal Degenerations in the Israeli and Palestinian Populations Using Homozygosity Mapping
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DOI：
10.1167/iovs.13-13625
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发表时间：
2014-02-01
影响因子：
4.4
通讯作者：
Sharon，Dror
中科院分区：
文献类型：
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作者：
Beryozkin，Avigail;Zelinger，Lina;Sharon，Dror
目的：以色列人和巴勒斯坦人的近亲结婚率较高，导致常染色体隐性遗传病的发病率较高。我们的目的是使用纯合性作图方法，旨在对基因组进行优先排序，并确定以色列和巴勒斯坦人群中AR视网膜变性的分子遗传原因。临床分析包括家族史、眼部检查、全视野视网膜电图（ERG）和眼底镜检查。分子生物学分析包括候选基因的纯合性定位和突变分析。我们为研究招募了患有AR非综合征性视网膜变性的家庭，主要包括视网膜色素变性（RP）、视锥杆变性（CRD）和莱伯先天性黑蒙（LCA）。为了确定这些家系中的致病基因，我们使用全基因组单核苷酸多态性（SNP）阵列对125个家系进行了纯合性定位。分析显示，在16个家族中鉴定出14个突变，其中5个是新的。在以下8个基因中鉴定了突变：RDH 12、PROM1、MFRP、TULP1、LCA 5、CEP 290、NR2E3和EYS。虽然大多数患者患有与致病基因相容的视网膜疾病，但在某些情况下，新的临床特征是明显的。纯合性定位是一个强有力的工具，以确定遗传缺陷的异质性AR疾病，如RP和LCA，在近亲和非近亲患者。不包括任何已知的视网膜疾病基因的显著和大的纯合区域的鉴定，可能是使用下一代测序鉴定新的致病基因的有用工具。
Purpose.: The Israeli and Palestinian populations are known to have a relatively high level of consanguineous marriages, leading to a relatively high frequency of autosomal recessive (AR) diseases. Our purpose was to use the homozygosity mapping approach, aiming to prioritize the set of genes and identify the molecular genetic causes underlying AR retinal degenerations in the Israeli and Palestinian populations.Methods.: Clinical analysis included family history, ocular examination, full-field electroretinography (ERG), and funduscopy. Molecular analysis included homozygosity mapping and mutation analysis of candidate genes.Results.: We recruited for the study families with AR nonsyndromic retinal degenerations, including mainly retinitis pigmentosa (RP), cone-rod degeneration (CRD), and Leber congenital amaurosis (LCA). With the aim to identify the causative genes in these families, we performed homozygosity mapping using whole genome single nucleotide polymorphism (SNP) arrays in 125 families. The analysis revealed the identification of 14 mutations, 5 of which are novel, in 16 of the families. The mutations were identified in the following eight genes: RDH12, PROM1, MFRP, TULP1, LCA5, CEP290, NR2E3, and EYS. While most patients had a retinal disease that is compatible with the causing gene, in some cases new clinical features are evident.Conclusions.: Homozygosity mapping is a powerful tool to identify genetic defects underlying heterogeneous AR disorders, such as RP and LCA, in consanguineous and nonconsanguineous patients. The identification of significant and large homozygous regions, which do not include any known retinal disease genes, may be a useful tool to identify novel disease-causing genes, using next generation sequencing.