Hwang Eileen S, Morgan Denise J, Pennington Katie L, Owen Leah A, Fingert John H, Bernstein Paul S, DeAngelis Margaret M
Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah School of Medicine, 65 Mario Capecchi Drive, Salt Lake City, UT, 84132, USA.
Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
BMC Med Genet. 2019 Apr 27;20(1):63. doi: 10.1186/s12881-019-0800-4.
We performed clinical and genetic characterization of a family with cavitary optic disc anomaly (CODA), an autosomal dominant condition that causes vision loss due to adult-onset maculopathy in the majority of cases. CODA is characterized by a variably excavated optic nerve appearance such as morning glory, optic pit, atypical coloboma, and severe optic nerve cupping.
Four affected and fourteen unaffected family members of a multi-generation pedigree were phenotyped by visual acuity, intraocular pressure, dilated fundus examination, fundus photography, and optical coherence tomography. Genetic analysis was performed by breakpoint polymerase chain reaction (PCR), long range PCR, and direct Sanger sequencing. The functional relevance of the copy number alteration region was assessed by in silico analysis.
We found progressive optic nerve cupping in three affected members of a family with CODA. In one individual, an optic pit developed over time from a normal optic nerve. By two independent methods, we detected a previously described intergenic triplication that segregated with disease in all adults of the family. The copy number alteration was also detected in five children with normal optic nerves. eQTL analysis demonstrated that this CNA region regulates expression of up to 4 genes in cis.
Morning glory, optic pit and atypical coloboma are currently considered congenital anomalies of the optic nerve, but our data indicate that in CODA, the excavated optic nerve appearance may develop after birth and into adulthood. In silico analysis of the CNA, may explain why vairable expressivity is observed in CODA.
我们对一个患有空洞性视盘异常（CODA）的家族进行了临床和基因特征分析，CODA是一种常染色体显性疾病，在大多数情况下会因成人期黄斑病变导致视力丧失。CODA的特征是视神经外观呈不同程度的凹陷，如牵牛花综合征、视盘小凹、非典型缺损和严重的视神经杯状凹陷。
对一个多代家系中的4名患病和14名未患病家庭成员进行了视力、眼压、散瞳眼底检查、眼底摄影和光学相干断层扫描等表型分析。通过断点聚合酶链反应（PCR）、长程PCR和直接桑格测序进行基因分析。通过计算机分析评估拷贝数改变区域的功能相关性。
我们在一个患有CODA的家族的3名患病成员中发现了进行性视神经杯状凹陷。在一个个体中，视盘小凹随着时间的推移从正常视神经发展而来。通过两种独立的方法，我们检测到一个先前描述的基因间重复，该重复在家族中的所有成年人中与疾病分离。在5名视神经正常的儿童中也检测到了拷贝数改变。eQTL分析表明，这个拷贝数改变区域在顺式中调节多达4个基因的表达。
牵牛花综合征、视盘小凹和非典型缺损目前被认为是先天性视神经异常，但我们的数据表明，在CODA中，凹陷的视神经外观可能在出生后并持续到成年期才出现。对拷贝数改变的计算机分析可能解释了为什么在CODA中观察到可变表达。
