Goldenberg-Cohen Nitza, Banin Eyal, Zalzstein Yael, Cohen Ben, Rotenstreich Ygal, Rizel Leah, Basel-Vanagaite Lina, Ben-Yosef Tamar
The Krieger Eye Research Laboratory, Felsenstein Medical Research Center, Schneider Children's Medical Center, Beilinson Campus, Petah Tikva, Israel.
Mol Vis. 2013 Jul 20;19:1565-71. Print 2013.
Retinitis pigmentosa (RP), the most genetically heterogeneous disorder in humans, actually represents a group of pigmentary retinopathies characterized by night blindness followed by visual-field loss. RP can appear as either syndromic or nonsyndromic. One of the most common forms of syndromic RP is Usher syndrome, characterized by the combination of RP, hearing loss, and vestibular dysfunction.
The underlying cause of the appearance of syndromic and nonsyndromic RP in three siblings from a consanguineous Israeli Muslim Arab family was studied with whole-genome homozygosity mapping followed by whole exome sequencing.
THE FAMILY WAS FOUND TO SEGREGATE NOVEL MUTATIONS OF TWO DIFFERENT GENES: myosin VIIA (MYO7A), which causes type 1 Usher syndrome, and phosphodiesterase 6B, cyclic guanosine monophosphate-specific, rod, beta (PDE6B), which causes nonsyndromic RP. One affected child was homozygous for both mutations. Since the retinal phenotype seen in this patient results from overlapping pathologies, one might expect to find severe retinal degeneration. Indeed, he was diagnosed with RP based on an abnormal electroretinogram (ERG) at a young age (9 months). However, this early diagnosis may be biased, as two of his older siblings had already been diagnosed, leading to increased awareness. At the age of 32 months, he had relatively good vision with normal visual fields. Further testing of visual function and structure at different ages in the three siblings is needed to determine whether the two RP-causing genes mutated in this youngest sibling confer increased disease severity.
This report further supports the genetic heterogeneity of RP, and demonstrates how consanguinity could increase intrafamilial clustering of multiple hereditary diseases. Moreover, this report provides a unique opportunity to study the clinical implications of the coexistence of pathogenic mutations in two RP-causative genes in a human patient.
视网膜色素变性（RP）是人类中基因异质性最高的疾病，实际上代表了一组以夜盲症继以视野丧失为特征的色素性视网膜病变。RP可表现为综合征型或非综合征型。综合征型RP最常见的形式之一是Usher综合征，其特征为RP、听力丧失和前庭功能障碍同时存在。
通过全基因组纯合性图谱分析，随后进行全外显子组测序，研究了一个来自以色列近亲穆斯林阿拉伯家庭的三名同胞中综合征型和非综合征型RP出现的潜在原因。
发现该家族存在两个不同基因的新突变：肌球蛋白VIIA（MYO7A），其导致1型Usher综合征；以及磷酸二酯酶6B，环鸟苷单磷酸特异性，视杆细胞，β（PDE6B），其导致非综合征型RP。一名患病儿童对这两种突变均为纯合子。由于该患者所见的视网膜表型是由重叠的病理改变引起的，人们可能会预期发现严重的视网膜变性。事实上，他在幼年（9个月）时基于异常的视网膜电图（ERG）被诊断为RP。然而，这种早期诊断可能存在偏差，因为他的两个哥哥姐姐已经被诊断出来，导致了更高的警觉性。在32个月大时，他的视力相对较好，视野正常。需要对这三名同胞在不同年龄进行进一步的视觉功能和结构测试，以确定在这个最年幼的同胞中发生突变的两个导致RP的基因是否会使疾病严重程度增加。
本报告进一步支持了RP的基因异质性，并证明了近亲结婚如何可能增加多种遗传性疾病在家族内的聚集性。此外，本报告提供了一个独特的机会来研究人类患者中两个导致RP的基因中致病突变共存的临床意义。
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