Institute for Ophthalmic Research, Molecular Genetics Laboratory, Tuebingen, Germany.
Praxis fuer Humangenetik Tuebingen, Tuebingen, Germany.
Eur J Hum Genet. 2020 Jun;28(6):742-753. doi: 10.1038/s41431-019-0566-3. Epub 2020 Jan 2.
Visual impairment due to inherited ophthalmic disorders is amongst the most common disabilities observed in populations practicing consanguineous marriages. Here we investigated the molecular genetic basis of an unselected broad range of ophthalmic disorders in 20 consanguineous families from Arab villages of Israel and the Palestinian Authority. Most patients had little or very poor prior clinical workup and were recruited in a field study. Homozygosity mapping followed by candidate gene sequencing applying conventional Sanger sequencing or targeted next generation sequencing was performed in six families. In the remaining 14 families, one affected subject per family was chosen for whole exome sequencing. We discovered likely disease-causing variants, all homozygous, in 19 of 20 independent families (95%) including a previously reported novel disease gene for congenital nystagmus associated with foveal hypoplasia. Moreover, we found a family in which disease-causing variants for two collagenopathies - Stickler and Knobloch syndrome - segregate within a large sibship. Nine of the 19 distinct variants observed in this study were novel. Our study demonstrated a very high molecular diagnostic yield for a highly diverse spectrum of rare ophthalmic disorders in Arab patients from Israel and the Palestinian Authority, even with very limited prior clinical investigation. We conclude that 'genetic testing first' may be an economic way to direct clinical care and to support proper genetic counseling and risk assessment in these families.
遗传性眼病导致的视力障碍是在进行近亲结婚的人群中观察到的最常见的残疾之一。在这里，我们研究了来自以色列和巴勒斯坦权力机构阿拉伯村庄的 20 个近亲结婚家庭中未选择的广泛眼科疾病的分子遗传基础。大多数患者的临床前期检查很少或非常差，并在现场研究中招募。在六个家庭中，我们进行了纯合子作图，然后对候选基因进行测序，应用常规的桑格测序或靶向下一代测序。在其余的 14 个家庭中，每个家庭选择一个受影响的个体进行全外显子组测序。我们在 20 个独立家庭中的 19 个（95%）发现了可能导致疾病的纯合变体，包括以前报道的与黄斑发育不良相关的先天性眼球震颤的新疾病基因。此外，我们发现了一个家系，其中两种胶原病（Stickler 和 Knobloch 综合征）的致病变体在一个大的同胞群体中分离。本研究中观察到的 19 个不同变体中有 9 个是新的。我们的研究表明，即使是在非常有限的前期临床研究中，对于来自以色列和巴勒斯坦权力机构的阿拉伯患者中多样化的罕见眼科疾病，遗传检测具有很高的分子诊断率。我们得出结论，“先进行基因检测”可能是一种经济有效的方法，可以指导临床护理，并为这些家庭提供适当的遗传咨询和风险评估。
