Characterization of GUCA1A-associated dominant cone/cone-rod dystrophy: low prevalence among Japanese patients with inherited retinal dystrophies.,Scientific Reports

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Characterization of GUCA1A-associated dominant cone/cone-rod dystrophy: low prevalence among Japanese patients with inherited retinal dystrophies.
Scientific Reports ( IF 3.8 ) Pub Date : 2019-11-14 , DOI: 10.1038/s41598-019-52660-1
Kei Mizobuchi ₁ , Takaaki Hayashi _{1,

2} , Satoshi Katagiri ₁ , Kazutoshi Yoshitake ₃ , Kaoru Fujinami _{4,

5,

6} , Lizhu Yang _{4,

5} , Kazuki Kuniyoshi ₇ , Kei Shinoda ₈ , Shigeki Machida _{9,

10} , Mineo Kondo ₁₁ , Shinji Ueno ₁₂ , Hiroko Terasaki ₁₂ , Tomokazu Matsuura ₁₃ , Kazushige Tsunoda ₄ , Takeshi Iwata ₃ , Tadashi Nakano ₁

Affiliation

Department of Ophthalmology, The Jikei University School of Medicine, Tokyo, Japan.
Department of Ophthalmology, Katsushika Medical Center, The Jikei University School of Medicine, Tokyo, Japan.
Division of Molecular and Cellular Biology, National Institute of Sensory Organs, National Tokyo Medical Center, Tokyo, Japan.
Division of Vision Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
UCL Institute of Ophthalmology associated with Moorfields Eye Hospital, London, UK.
Department of Ophthalmology, Kindai University Faculty of Medicine, Osaka, Japan.
Department of Ophthalmology, Teikyo University School of Medicine, Tokyo, Japan.
Department of Ophthalmology, Dokkyo Medical University Saitama Medical Center, Saitama, Japan.
Department of Ophthalmology, Iwate Medical University School of Medicine, Iwate, Japan.
Department of Ophthalmology, Mie University Graduate School of Medicine, Mie, Japan.
Department of Ophthalmology, Nagoya University Graduate School of Medicine, Aichi, Japan.
Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan.

GUCA1A gene variants are associated with autosomal dominant (AD) cone dystrophy (COD) and cone-rod dystrophy (CORD). GUCA1A-associated AD-COD/CORD has never been reported in the Japanese population. The purpose of this study was to investigate clinical and genetic features of GUCA1A-associated AD-COD/CORD from a large Japanese cohort. We identified 8 variants [c.C50_80del (p.E17VfsX22), c.T124A (p.F42I), c.C204G (p.D68E), c.C238A (p.L80I), c.T295A (p.Y99N), c.A296C (p.Y99S), c.C451T (p.L151F), and c.A551G (p.Q184R)] in 14 families from our whole exome sequencing database composed of 1385 patients with inherited retinal diseases (IRDs) from 1192 families. Three variants (p.Y99N, p.Y99S, and p.L151F), which are located on/around EF-hand domains 3 and 4, were confirmed as "pathogenic", whereas the other five variants, which did not co-segregate with IRDs, were considered "non-pathogenic". Ophthalmic findings of 9 patients from 3 families with the pathogenic variants showed central visual impairment from early to middle-age onset and progressive macular atrophy. Electroretinography revealed severely decreased or non-recordable cone responses, whereas rod responses were highly variable, ranging from nearly normal to non-recordable. Our results indicate that the three pathogenic variants, two of which were novel, underlie AD-COD/CORD with progressive retinal atrophy, and the prevalence (0.25%, 3/1192 families) of GUCA1A-associated IRDs may be low among Japanese patients.

中文翻译：

GUCA1A相关的显性锥体/圆锥体杆营养不良的特征：在患有遗传性视网膜营养不良的日本患者中患病率较低。

GUCA1A基因变异与常染色体显性遗传性（AD）锥体营养不良（COD）和锥体杆性营养不良（CORD）相关。在日本人群中从未报道过与GUCA1A相关的AD-COD / CORD。这项研究的目的是调查来自日本大队列的GUCA1A相关AD-COD / CORD的临床和遗传特征。我们确定了8个变体[c.C50_80del（p.E17VfsX22），c.T124A（p.F42I），c.C204G（p.D68E），c.C238A（p.L80I），c.T295A（p.Y99N），来自我们整个外显子组测序数据库的14个家庭中的c.A296C（p.Y99S），c.C451T（p.L151F）和c.A551G（p.Q184R）]，由1192年的1385例患有遗传性视网膜疾病（IRD）的患者组成家庭。位于EF手域3和4上/周围的三个变体（p.Y99N，p.Y99S和p.L151F）被确认为“致病性”，而其他五个变体，未与IRD共同隔离的被认为是“非致病性的”。来自3个病原体家族的9例患者的眼科检查结果显示，从早期到中年发病以及进行性黄斑萎缩的中心性视力障碍。视网膜电图检查显示锥体反应严重降低或无法记录，而视杆反应高度可变，范围从几乎正常到不可记录。我们的结果表明，三种病原体变异，其中两种是新颖的，是AD-COD / CORD伴进行性视网膜萎缩的根源，与GUCA1A相关的IRD的患病率（0.25％，3/1192家族）在日本患者中可能较低。来自3个病原体家族的9例患者的眼科检查结果显示，从早期到中年发病以及进行性黄斑萎缩的中心性视力障碍。视网膜电图检查显示锥体反应严重降低或无法记录，而视杆反应高度可变，范围从几乎正常到不可记录。我们的结果表明，三种病原体变异，其中两种是新颖的，是AD-COD / CORD伴进行性视网膜萎缩的根源，与GUCA1A相关的IRD的患病率（0.25％，3/1192家族）在日本患者中可能较低。来自3个病原体的9例患者的眼科检查结果显示，从早期到中年发病和进行性黄斑萎缩的中心性视力障碍。视网膜电图检查显示锥体反应严重降低或无法记录，而视杆反应高度可变，范围从几乎正常到不可记录。我们的结果表明，三种病原体变异，其中两种是新颖的，是AD-COD / CORD伴进行性视网膜萎缩的根源，与GUCA1A相关的IRD的患病率（0.25％，3/1192家族）在日本患者中可能较低。

更新日期：2019-11-14

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