Genetic and Metabolic Central Laboratory, Birth Defect Prevention Research Institute, Maternal and Child Health Hospital, Children's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530002, China.
Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
BMC Med Genet. 2020 May 11;21(1):100. doi: 10.1186/s12881-020-01039-5.
Neuronal ceroid lipofuscinosis type 5 (CLN5) is a rare form of neuronal ceroid lipofuscinoses (NCLs) which are a group of inherited neurodegenerative diseases characterized by progressive intellectual and motor deterioration, visual failure, seizures, behavioral changes and premature death. CLN5 was initially named Finnish variant late infantile NCL, it is now known to be present in other ethnic populations and with variable age of onset. Few CLN5 patients had been reported in Chinese population.
In this paper, we report the symptoms of a Chinese patient who suffer from developmental regression and grand mal epilepsy for several years. The DNA was extracted from peripheral blood of proband and both parents, and then whole exome sequencing was performed using genomic DNA. Both sequence variants and copy number variants (CNVs) were analyzed and classified according to guidelines. As the result, a novel frameshift mutation c.718_719delAT/p.Met240fs in CLN5 and a de novo large deletion at 13q21.33-q31.1 which unmasked the frameshift mutation were identified in the proband. Despite the large de novo deletion, which can be classified as a pathogenic copy number variant (CNV), the patient's clinical presentation is mostly consistent with that of CLN5, except for early developmental delay which is believed due to the large deletion. Both variants were detected simultaneously by exome sequencing.
This is the first report of whole gene deletion in combination with a novel pathogenic sequence variant in a CLN5 patient. The two mutations detected with whole exome sequencing simultaneously proved the advantage of the sequencing technology for genetic diagnostics.
神经元蜡样脂褐质沉积症 5 型（CLN5）是神经元蜡样脂褐质沉积症（NCL）的一种罕见形式，NCL 是一组遗传性神经退行性疾病，其特征为进行性智力和运动恶化、视力丧失、癫痫发作、行为改变和过早死亡。CLN5 最初被命名为芬兰变异型晚婴型 NCL，现在已知它存在于其他种族人群中，且发病年龄存在差异。在中国人群中报道的 CLN5 患者较少。
本文报道了一位中国患者的症状，该患者患有进行性发育倒退和大发作性癫痫数年。从先证者及其父母的外周血中提取 DNA，然后使用基因组 DNA 进行全外显子组测序。根据指南分析和分类序列变异和拷贝数变异（CNV）。结果，在先证者中发现了 CLN5 中的一个新的移码突变 c.718_719delAT/p.Met240fs 和 13q21.33-q31.1 处的从头大片段缺失，该缺失使移码突变暴露。尽管存在大片段缺失（可归类为致病性拷贝数变异（CNV）），但患者的临床表现与 CLN5 大多一致，除了早期发育迟缓，这被认为是由于大片段缺失所致。全外显子组测序同时检测到这两种变异。
这是首例报道的 CLN5 患者全基因缺失与新的致病性序列变异同时存在的病例。全外显子组测序同时检测到的两种突变证明了测序技术在遗传诊断中的优势。
