Pathogenic variants in L1CAM, the gene encoding the L1 cell adhesion molecule, are responsible for a wide clinical spectrum including X-linked hydrocephalus with stenosis of the Sylvius aqueduct, MASA syndrome (mental retardation, aphasia, shuffling gait, adducted thumbs), and a form of spastic paraplegia (SPG1). A moderate phenotype with mild intellectual disability (ID) and X-linked partial corpus callosum agenesis (CCA) has only been related to L1CAM in one family. We report here a second family, including 5 patients with mild to moderate ID and partial CCA without signs usually associated with L1CAM pathogenic variations (such as hydrocephalus, pyramidal syndrome, thumb adductus, aphasia). We identified a previously unreported c.3226A > C transversion leading to a p.Thr1076Pro amino acid substitution in the fifth fibronectin type III domain (FnIII) of the protein which co-segregates with the phenotype within the family. We performed in vitro assays to assess the pathogenic status of this variation. First, the expression of the novel p.Thr1076Pro mutant in COS7 cells resulted in endoplasmic reticulum (ER) retention and reduced L1CAM cell surface expression, which is expected to affect both L1CAM-mediated cell-cell adhesion and neurite growth. Second, immunoblotting techniques showed that the immature form of the L1CAM protein was increased, indicating that this variation led to a lack of maturation of the protein. ID associated with CCA is not a common clinical presentation of L1CAM pathogenic variants. Genome-wide analyses will identify such variations and it is important to acknowledge this atypical phenotype.

L1CAM 中的致病变异是编码 L1 细胞粘附分子的基因，导致广泛的临床谱，包括 X 连锁脑积水伴 Sylvius 导水管狭窄、MASA 综合征（智力低下、失语、步态蹒跚、拇指内收）和痉挛性截瘫 (SPG1) 的形式。具有轻度智力障碍 (ID) 和 X 连锁部分胼胝体发育不全 (CCA) 的中度表型仅与一个家族中的L1CAM相关。我们在此报告第二个家族，包括 5 名患有轻度至中度 ID 和部分 CCA 的患者，没有通常与L1CAM相关的体征致病变异（如脑积水、锥体综合征、拇指内收、失语）。我们发现了先前未报告的 c.3226A > C 颠换，导致该蛋白质的第五个纤连蛋白 III 型结构域 (FnIII) 中 p.Thr1076Pro 氨基酸取代，该结构域与家族内的表型共分离。我们进行了体外测定以评估这种变异的致病状态。首先，新的 p.Thr1076Pro 突变体在 COS7 细胞中的表达导致内质网 (ER) 保留和 L1CAM 细胞表面表达降低，这预计会影响 L1CAM 介导的细胞 - 细胞粘附和神经突生长。其次，免疫印迹技术显示 L1CAM 蛋白的未成熟形式增加，表明这种变异导致蛋白质缺乏成熟。L1CAM致病性变异。全基因组分析将识别此类变异，承认这种非典型表型很重要。