Suga Akiko, Mizobuchi Kei, Inooka Taiga, Yoshitake Kazutoshi, Minematsu Naoko, Tsunoda Kazushige, Kuniyoshi Kazuki, Kawai Yosuke, Omae Yosuke, Tokunaga Katsushi, Hayashi Takaaki, Ueno Shinji, Iwata Takeshi
Division of Molecular and Cellular Biology, National Institute of Sensory Organs, NHO Tokyo Medical Center, Tokyo, Japan.
Department of Ophthalmology, The Jikei University School of Medicine, Tokyo, Japan.
Genet Med Open. 2024 Mar 26;2:101843. doi: 10.1016/j.gimo.2024.101843. eCollection 2024.
Achromatopsia (ACHM) is an early-onset cone dysfunction caused by 5 genes with cone-specific functions (, , , and ) and by , a transcription factor with ubiquitous expression. To improve the relatively low variant detection ratio in these genes in a cohort of exome-sequenced Japanese patients with inherited retinal diseases (IRD), we performed genome sequencing to detect structural variants and intronic variants in patients with ACHM.
Genome sequencing of 10 ACHM pedigrees was performed after exome sequencing. Structural, non-coding, and coding variants were filtered based on segregation between the affected and unaffected in each pedigree. Variant frequency and predicted damage scores were considered in identifying pathogenic variants.
A homozygous deletion involving exon 18 of was detected in 5 of 10 ACHM probands, and variant inheritance from each parent was confirmed. This deletion was relatively frequent (minor allele frequency = 0.0023) in the Japanese population but was only homozygous in patients with ACHM among the 199 Japanese IRD probands analyzed by the same genome sequencing pipeline.
The deletion involving exon 18 of is a prevalent cause of ACHM in Japanese patients and contributes to the wide spectrum of -associated IRD phenotypes, from Leber congenital amaurosis to ACHM.
全色盲（ACHM）是一种早发性视锥细胞功能障碍，由5个具有视锥细胞特异性功能的基因（、、、和）以及一个广泛表达的转录因子引起。为了提高在一组经外显子组测序的日本遗传性视网膜疾病（IRD）患者中这些基因相对较低的变异检测率，我们进行了基因组测序，以检测ACHM患者的结构变异和内含子变异。
在进行外显子组测序后，对10个ACHM家系进行基因组测序。根据每个家系中患病者和未患病者之间的分离情况，对结构、非编码和编码变异进行筛选。在鉴定致病变异时考虑变异频率和预测的损伤评分。
在10名ACHM先证者中的5名中检测到涉及的第18外显子的纯合缺失，并证实了来自每个亲本的变异遗传。这种缺失在日本人群中相对常见（次要等位基因频率 = 0.0023），但在通过相同基因组测序流程分析的199名日本IRD先证者中，仅在ACHM患者中为纯合缺失。
涉及的第18外显子的缺失是日本患者ACHM的常见病因，并导致了从莱伯先天性黑蒙到ACHM等与相关的IRD表型的广泛谱系。
