Clinical, neuroimaging, and genetic characterization of 3 patients with LINS1-associated developmental regression, intellectual disability, dysmorphism, and further neurologic deficits.

Three affected brothers from a consanguineous family from Afghanistan, their 2 healthy siblings, and both parents were all assessed in the clinic. General and neurologic examination, expert dysmorphology examination, and 3T brain MRI were performed. Whole-exome sequencing was performed for the 3 affected brothers, followed by Sanger sequencing in all available family members.

The index patient and his 2 affected brothers presented a complex neurologic syndrome with similar features but marked intrafamilial phenotypical variability, including varying degrees of cognitive impairment, speech impairment, dystonia, abnormal eye movements, and dysmorphic features. All 3 affected brothers are homozygous for a novel, pathogenic frameshift mutation in LINS1, c.1672_1679del, and p.Gly558Profs*22, whereas both parents and healthy siblings are heterozygous for the mutation. No major brain malformations were evident in 3T brain MRI of the affected brothers.

This consanguineous family with a novel mutation expands the spectrum of LINS1-associated disorder to include developmental regression, oculomotor signs, and dystonia, previously not described in the published 9 cases of this rare disorder. The 3T-MRI data from our 3 patients and review of the neuroimaging data in the literature showed unspecific brain MRI changes. LINS1 protein is a known modulating factor of the Wnt signaling pathway, with important roles in organogenesis including of the cerebral cortex. More research is warranted to disentangle the underlying pathophysiologic mechanisms, leading to cognitive impairment and the complex phenotype of LINS1-associated disorder.

3 名患有LINS1相关发育退化、智力障碍、畸形和进一步神经功能缺陷的患者的临床、神经影像学和遗传特征。

来自阿富汗近亲家庭的三个受影响的兄弟、他们的两个健康兄弟姐妹和父母双方都在诊所接受了评估。进行了一般和神经系统检查、专家畸形检查和 3T 脑 MRI。对 3 名受影响的兄弟进行了全外显子组测序，然后对所有可用的家庭成员进行了 Sanger 测序。

指示患者和他的 2 个受影响的兄弟出现了具有相似特征但明显的家族内表型变异性的复杂神经系统综合征，包括不同程度的认知障碍、言语障碍、肌张力障碍、异常眼球运动和畸形特征。所有 3 名受影响的兄弟都是LINS1、c.1672_1679del 和 p.Gly558Pro fs *22 中新的致病性移码突变的纯合子，而父母和健康的兄弟姐妹都是该突变的杂合子。受影响兄弟的 3T 脑 MRI 中没有明显的脑部畸形。

这个具有新突变的近亲家族扩大了LINS1相关疾病的范围，包括发育退化、动眼神经症状和肌张力障碍，以前在已发表的 9 例这种罕见疾病中没有描述。来自我们 3 名患者的 3T-MRI 数据和对文献中神经影像学数据的回顾显示了非特异性的脑部 MRI 变化。LINS1 蛋白是已知的 Wnt 信号通路调节因子，在包括大脑皮层在内的器官发生中具有重要作用。需要更多的研究来解开导致认知障碍和LINS1相关疾病的复杂表型的潜在病理生理机制。