Division of Pediatric Neurology, Children's Medical Center, Taichung Veterans General Hospital, 1650, Taiwan Boulevard Sec. 4, Taichung, 407, Taiwan.
Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, 145, Xingda Rd., Taichung, 402, Taiwan.
Hum Genet. 2023 Aug;142(8):1029-1041. doi: 10.1007/s00439-023-02533-5. Epub 2023 Feb 27.
Biallelic SHQ1 variant-related neurodevelopmental disorder is extremely rare. To date, only six affected individuals, from four families, have been reported. Here, we report eight individuals, from seven unrelated families, who exhibited neurodevelopmental disorder and/or dystonia, received whole-genome sequencing, and had inherited biallelic SHQ1 variants. The median age at disease onset was 3.5 months old. All eight individuals exhibited normal eye contact, profound hypotonia, paroxysmal dystonia, and brisk deep tendon reflexes at the first visit. Varying degrees of autonomic dysfunction were observed. One individual had cerebellar atrophy at the initial neuroimaging study, however, three individuals showed cerebellar atrophy at follow-up. Seven individuals who underwent cerebral spinal fluid analysis all had a low level of homovanillic acid in neurotransmitter metabolites. Four individuals who received Tc-TRODAT-1 scan had moderate to severe decreased uptake of dopamine in the striatum. Four novel SHQ1 variants in 16 alleles were identified: 9 alleles (56%) were c.997C > G (p.L333V); 4 (25%) were c.195T > A (p.Y65X); 2 (13%) were c.812T > A (p.V271E); and 1 (6%) was c.146T > C (p.L49S). The four novel SHQ1 variants transfected into human SH-SY5Y neuronal cells resulted in a retardation in neuronal migration, suggestive of SHQ1 variant correlated with neurodevelopmental disorders. During the follow-up period, five individuals still exhibited hypotonia and paroxysmal dystonia; two showed dystonia; and one had hypotonia only. The complex interactions among movement disorders, dopaminergic pathways, and the neuroanatomic circuit needs further study to clarify the roles of the SHQ1 gene and protein in neurodevelopment.
双等位基因 SHQ1 变异相关的神经发育障碍极为罕见。迄今为止，仅有来自四个家庭的六名受影响个体被报道。在这里，我们报告了来自七个无关家庭的八名个体，他们表现出神经发育障碍和/或肌张力障碍，接受了全基因组测序，并遗传了双等位基因 SHQ1 变异。疾病发作的中位年龄为 3.5 个月。所有八名个体在首次就诊时均表现出正常的眼神接触、严重的张力减退、阵发性肌张力障碍和腱反射亢进。观察到不同程度的自主神经功能障碍。一名个体在初始神经影像学研究时出现小脑萎缩，但三名个体在随访时出现小脑萎缩。接受脑脊液分析的七名个体均显示神经递质代谢产物中高香草酸水平降低。接受 Tc-TRODAT-1 扫描的四名个体纹状体中多巴胺摄取均有中度至重度减少。在 16 个等位基因中发现了 4 个新的 SHQ1 变异：9 个等位基因（56%）为 c.997C>G（p.L333V）；4 个（25%）为 c.195T>A（p.Y65X）；2 个（13%）为 c.812T>A（p.V271E）；1 个（6%）为 c.146T>C（p.L49S）。将这 4 个新的 SHQ1 变异转染到人类 SH-SY5Y 神经元细胞中，导致神经元迁移延迟，提示 SHQ1 变异与神经发育障碍有关。在随访期间，五名个体仍存在张力减退和阵发性肌张力障碍；两名个体表现为肌张力障碍；一名个体仅表现为张力减退。运动障碍、多巴胺能途径和神经解剖回路之间的复杂相互作用需要进一步研究，以阐明 SHQ1 基因和蛋白在神经发育中的作用。
