Liu Hui, Li Ranran, Chen Chen, Shang Lin, Bai Ying, Chen Duo, Kong Xiangdong, Li Qianqian
Genetics and Prenatal Diagnosis Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
School of Life Science and Technology, Xinxiang Medical University, Xinxiang, China.
BMC Med Genomics. 2025 May 3;18(1):83. doi: 10.1186/s12920-025-02151-2.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare early-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, spasticity, and sensorimotor peripheral neuropathy. This disorder is caused by homozygous or compound heterozygous variants in the sacsin (SACS) gene on chromosome 13q12.12. Three patients with ARSACS from two unrelated Chinese families were recruited for this study. Patient #1 was an 18-year-old male who had been walking unstably for 12 years. Patient #2, the younger sister of Patient #1, was a 5-year-old girl who had been walking unstably for 2 years. Patient #3 was a 19-year-old female who had been walking unstably and a tendency to fall for 17 years. For Patient #1, whole-exome sequencing (WES) identified a hemizygous variant c.8310_8313delAGAT (p.Asp2771fs4*) in SACS (NM_014363.6), with the father being heterozygous, the mother wild-type, and Patient #2 hemizygous, as verified by Sanger sequencing. Additional copy number variant analysis of the WES data indicated that Patient #1 had a heterozygous gross deletion of chr13q12.12 (chr13:23,808,732 - 24,890,322). Low-coverage whole-genome sequencing results revealed that Patient #2 carried a chr13q12.12 deletion (chr13:23,520,000-24,940,000). Together with Sanger sequencing results, this gross deletion was speculated to have been inherited from the mother, further explaining the hemizygous state of c.8310_8313delAGAT (p.Asp2771fs4*) in Patients #1 and #2. Through WES, Patient #3 was identified as having suspected compound heterozygous variants of c.2881 C > T (p.Arg961*) and c.6409 C > T (p.Gln2137*), inherited from the father and mother, respectively, as confirmed by Sanger sequencing. This study identified three variants in SACS. The c.8310_8313delAGAT (p.Asp2771fs4*) is novel, whereas c.2881 C > T (p.Arg961*) and c.6409 C > T (p.Gln2137*) have been reported previously. Moreover, this study highlights the growing trend that ARSACS has become increasingly prevalent worldwide rather than being localized to a specific region or race. As an increasing number of patients with ARSACS are diagnosed, the genetic spectrum of ARSACS will gradually broaden, providing an accurate genetic basis for prenatal diagnosis of mothers in the years ahead, if possible.
夏尔沃 - 萨格奈常染色体隐性痉挛性共济失调（ARSACS）是一种罕见的早发性神经退行性疾病，其特征为进行性小脑共济失调、痉挛和感觉运动性周围神经病变。该疾病由位于13q12.12染色体上的sacsin（SACS）基因的纯合或复合杂合变异引起。本研究招募了来自两个不相关中国家庭的3例ARSACS患者。患者1为一名18岁男性，已行走不稳12年。患者2是患者1的妹妹，为一名5岁女孩，已行走不稳2年。患者3是一名19岁女性，已行走不稳且有跌倒倾向17年。对于患者1，全外显子组测序（WES）在SACS（NM_014363.6）中鉴定出一个半合子变异c.8310_8313delAGAT（p.Asp2771fs4*），经桑格测序验证，父亲为杂合子，母亲为野生型，患者2为半合子。对WES数据进行的额外拷贝数变异分析表明，患者1存在chr13q12.12的杂合大片段缺失（chr13:23,808,732 - 24,890,322）。低覆盖度全基因组测序结果显示，患者2携带chr13q12.12缺失（chr13:23,520,000 - 24,940,000）。结合桑格测序结果，推测该大片段缺失是从母亲遗传而来，进一步解释了患者1和患者2中c.8310_8313delAGAT（p.Asp2771fs4*）的半合子状态。通过WES，患者3被鉴定为分别从父亲和母亲遗传了疑似复合杂合变异c.2881 C>T（p.Arg961*）和c.6409 C>T（p.Gln2137*），经桑格测序确认。本研究在SACS中鉴定出3个变异。c.8310_8313delAGAT（p.Asp2771fs4*）是新发现的，而c.2881 C>T（p.Arg961*）和c.6409 C>T（p.Gln2137*）此前已有报道。此外，本研究突出了ARSACS在全球范围内日益普遍而非局限于特定地区或种族的趋势。随着越来越多的ARSACS患者被诊断出来，ARSACS的遗传谱将逐渐拓宽，若有可能，可为未来几年母亲的产前诊断提供准确的遗传基础。
