Background

S-adenosylhomocysteine hydrolase deficiency due to pathologic variants in AHCY gene is a rare neurometabolic disease for which no eye phenotype has been documented. Pathologic variants in CRB1 gene are known to cause a wide spectrum of autosomal recessive retinal diseases with Leber’s congenital amaurosis as a most common. The aim of this study is to report co-inheritance of neurometabolic disease and eye disease in a pedigree.

Materials and Methods

Comprehensive eye examination was performed in available family members together with color vision test, visual fields, fundus images, OCT, electroretinogram and visual evoked potentials. Genetic testing included whole-exome sequencing (WES), retinal dystrophy gene panel and segregation analysis.

Results

Two children from a family not known to be consanguineous were affected with neurometabolic disease and one of them presented with reduced vision due to maculopathy. The mother had symptoms of retinal degeneration of unspecified cause. Clinical WES revealed homozygous missense pathologic variants in AHCY gene c.148G>A, p.(Ala50Thr) as a cause of S-adenosylhomocysteine hydrolase deficiency. Retinal dystrophy gene panel sequencing revealed two heterozygous missense pathologic variants in CRB1 gene c.1831T>C, p.(Ser611Pro) and c.3955T>C, p.(Phe1319Leu) in the proband and her mother. These variants segregated with disease phenotype in family members.

Conclusions

Establishing an ocular genetic diagnosis may be challenging with the co-existence of a rare systemic genetic disease with previously unknown eye involvement. Extensive phenotyping and genotyping of available family members showed that the proband and her mother shared a CRB1-related retinopathy at different stages while the brother did not.

中文翻译：

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CRB1相关性视网膜病变与S-腺苷同型半胱氨酸水解酶缺乏症的眼表型重叠。

背景

由于AHCY基因的病理变异而导致的S-腺苷半胱氨酸水解酶缺乏症是一种罕见的神经代谢疾病，目前尚无眼表型的文献报道。已知CRB1基因的病理变异会导致多种常染色体隐性视网膜疾病，其中以Leber先天性黑病最为常见。这项研究的目的是报告谱系中神经代谢疾病和眼部疾病的共同遗传性。

材料和方法

在可用的家庭成员中进行了全面的眼部检查，并进行了色觉测试，视野，眼底图像，OCT，视网膜电图和视觉诱发电位。遗传测试包括全外显子测序（WES），视网膜营养不良基因组和分离分析。

结果

来自一个不知名的近亲家庭的两名儿童患有神经代谢疾病，其中一名儿童因黄斑病变而视力下降。母亲有未明原因的视网膜变性症状。临床WES发现AHCY基因c.148G> A，p。（Ala50Thr）中的纯合性错义病理变异是S-腺苷同型半胱氨酸水解酶缺乏症的原因。视网膜营养不良基因组测序显示，先证者及其母亲在CRB1基因c.1831T> C，p。（Ser611Pro）和c.3955T> C，p。（Phe1319Leu）中有两个杂合的错义病理变异。这些变异与家庭成员的疾病表型分开。

结论

与以前未知的眼部受累的罕见系统性遗传病并存，建立眼部遗传诊断可能具有挑战性。现有家庭成员的广泛表型和基因型分析表明，先证者和她的母亲在不同阶段患有CRB1相关的视网膜病变，而兄弟姐妹则没有。